To see the other types of publications on this topic, follow the link: Targetted liposome.
Dissertations / Theses on the topic 'Targetted liposome'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Targetted liposome.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Baki, Mert. "Bone Marrow Targeted Liposomal Drug Delivery Systems." Master's thesis, METU, 2011. http://etd.lib.metu.edu.tr/upload/12613251/index.pdf.
Full textAbstract:
Homing is the process that stem cells move to their own stem cell niches under the influence of chemokines like stromal-derived factor-1&alpha(SDF-1&alpha
) upon bone marrow transplantation (BMT). There is a need for increasing homing efficiency after BMT since only 10-15% of the transplanted cells can home to their own niches and a limited amount of donor marrow can be transplanted. In this study, we aimed to develop and characterize bone marrow targeted liposomal SDF-1&alpha
delivery system prepared by extrusion method. Alendronate conjugation was chosen to target the liposomes to bone marrow microenvironment, particularly the endosteal niche. Optimization studies were conducted with the model protein (
2
Loughrey, Helen. "Targeted liposomes." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/29180.
Full textAbstract:
This thesis presents an optimized and general procedure for coupling proteins to liposomes and investigates certain aspects of the interaction of liposomes with components of the circulation. The object of these studies was to develop straightforward methods for the preparation of well characterized protein-liposome conjugates which exhibit extended circulation half-lives in the blood. These favorable properties should potentiate the use of protein coupled vesicles in in vivo applications such as targeting or diagnostic protocols.
A general approach for the preparation of protein-liposome conjugates was developed which employs the high affinity binding of streptavidin for biotinated proteins. Streptavidin was initially attached in a non-covalent manner (via biotin phosphatidylethanolamine) or covalently (via maleimidophenyl-butyryl phosphatidyl-ethanolamine, MPB-PE or pyridyldithio-propionyl phosphatidylethanolamine, PDP-PE) to pre-formed liposomes containing the various lipid derivatives. It was shown that the procedure based on the maleimide derivative MPB-PE, was the most efficient coupling method. Standard procedures for the preparation of MPB-PE however, were found to result in an impure product. Recently a new method for the synthesis of a pure SMPB derivative of phosphatidylethanolamine was developed (Lewis Choi, unpublished). Efficient coupling of proteins to liposomes containing low amounts of pure MPB-DPPE was achieved. Subsequently it was shown that gentle incubation with biotinated proteins results in the rapid and efficient generation of protein coupled vesicles. These retain their ability to interact with defined target celte.
Aggregation of liposomes during the coupling reaction is a common consequence of the efficient coupling of protein to liposomes. A method was therefore developed for the preparation of small homogeneously sized protein-liposome conjugates by an extrusion process which does not denature the attached protein. These extruded samples exhibited extended blood circulation times and were stable for significant periods in vivo. The second part of this thesis investigated the in vitro interaction of liposomes of various lipid compositions with platelets. It was demonstrated that large liposomes (> 200 nm in diameter) containing negatively charged lipids (such as EPG) or thiol reactive lipid derivatives (such as MPB-PE) can induce aggregation of platelets in vitro. This interaction was mediated by complement. It is suggested that the formation of platelet-liposome microaggregates in vivo on intravenous administration of negatively charged liposomes, resulted in the transient thrombocytopenia observed in rats. This adhesion event may have also contributed to the rapid removal of aggregated protein-liposome conjugates (containing MPB-PE) from the circulation.Medicine, Faculty of
Biochemistry and Molecular Biology, Department of
Graduate
3
Harasym, Troy O. "Antibody-targeted liposomal systems." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25066.pdf.
Full text
4
Bowen, Tian. "Liposome-QD hybrids and the development of targeted theranostic modalities." Thesis, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535499.
Full text
5
Javadi, Marjan. "Novel Liposomes for Targeted Delivery of Drugs and Plasmids." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/3879.
Full textAbstract:
People receiving chemotherapy not only suffer from side effects of therapeutics but also must buy expensive drugs. Targeted drug and gene delivery directed to specific tumor-cells is one way to reduce the side effect of drugs and use less amount of therapeutics. In this research, two novel liposomal nanocarriers were developed. This nanocarrier, called an eLiposome, is basically one or more emulsion droplets inside a liposome. Emulsion droplets are made of perfluorocarbons which usually have a high vapor pressure. Calcein (as a model drug) and Paclitaxel were used to demonstrate drug delivery, and plasmids and siRNA were used to exemplify gene delivery. Drugs or genes were encapsulated inside the interior of the liposomes along with emulsion droplets; targeting moieties were attached to the outside of the phospholipid bilayer. Ultrasound was used to break open the bilayer by changing the liquid emulsion droplets to gas, which released the content of the eLiposomes. Transmission electron microscopy (TEM) was used to prove the formation of eLiposomes and confocal microscopy showed the uptake of drugs and genes in vitro. Cell viability was measured to show the effect of uptake in cancer cells. Results indicate that eLiposomes were successfully made and that they were endocytosed into the cell. It was observed that the emulsion and the targeting moiety in combination with ultrasound are the essential elements required to produce release from eLiposomes.
6
Harrington, Kevin Joseph. "Pegylated Liposome-targeted Radiosensitisers for the Treatment of Head and neck Cancer." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506160.
Full text
7
Divi, Murali Krishna. "Development and evaluation of brain tumor targeted liposome delivery system for paclitaxel." View the abstract Download the full-text PDF version, 2008. http://etd.utmem.edu/ABSTRACTS/2007-012-Divi-index.html.
Full textAbstract:
Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008.Title from title page screen (viewed on January 6, 2009). Research advisor: George C Wood, Ph.D. Document formatted into pages (xii, 126 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 112-126).
8
Stevens, Phillip James. "An approach to drug formulation and targeting liposomes and lipid nanoparticles for folate receptor targeting." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1111092653.
Full textAbstract:
Thesis (Ph. D.)--Ohio State University, 2005.Title from first page of PDF file. Document formatted into pages; contains xvi, 110 p.; also includes graphics (some col.) Includes bibliographical references (p. 98-110). Available online via OhioLINK's ETD Center
9
Hartley, Jonathan Michael. "Surface Modification of Liposomes Containing Nanoemulsions." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2846.
Full textAbstract:
Many attempts have been made to make cancer therapy more selective and less detrimental to the health of the patients. Nanoparticles have emerged as a way to solve some of the problems of traditional chemotherapy. Nanoparticles can provide protection for the therapeutic from degradation or clearance, as well as protection to healthy tissue from the damaging effects of chemotherapy drugs. Researchers are pursuing different strategies but all have the same goals of improving the outcomes of cancer patients. The field of controlled release of drugs has increased significantly in hopes of better treating diseases like cancer. Improved control of drug release has great potential for improving patient outcomes. Still there exist certain barriers such as circulation time, cell specificity, and endosomal escape.In this study a novel drug delivery vehicle was studied in vitro. The novel construct consisted of a liposome containing perfluorocarbon emulsions—an eLiposome—that was activated by ultrasound to break open on demand. Two targeting moieties were attached to the eLiposome to increase cell specificity and induce endocytosis. These studies determined the localization of eLiposomes in vitro using flow cytometry and confocal microscopy. Results indicated that eLiposomes modified with a targeting moiety attached to HeLa cells to a greater extent than non-targeting eLiposomes. Confocal images indicated localization of eLiposomes around the membrane of cells. Flow cytometer results indicated that ultrasound does in fact disrupt the eLiposomes but evidence of significant delivery to the cytoplasm was not obtained. However cells that were incubated with eLiposomes for 24 hours showed over 60% of the cells had green color association indicating eLiposome uptake.
10
Jayanna, Prashanth K. Petrenko Valery. "Therapeutic liposomes for prostate cancer targeted by phage fusion coat proteins." Auburn, Ala., 2009. http://hdl.handle.net/10415/1994.
Full text
11
Kaimal, Vinod. "In vivo MR microscopy of tumor-targeted liposome combining USPIO and saposin-C." Cincinnati, Ohio : University of Cincinnati, 2007. http://www.ohiolink.edu/etd/view.cgi?ucin1195496800.
Full textAbstract:
Thesis (Ph.D.)--University of Cincinnati, 2007.Advisor: Scott K. Holland. Title from electronic thesis title page (viewed Feb. 18, 2008). Keywords: USPIO; Saposin-C; liposome; magnetic resonance imaging; MRI. Includes abstract. Includes bibliographical references.
12
Huang, Guofeng. "ENGINEERING RGD-MODIFIED LIPOSOMES FOR TARGETED DRUG DELIVERY TO ACTIVATED PLATELETS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1153187042.
Full text
13
Triantafilllou, Georgia. "CD74 Targeted Nanoparticles as Dexamethasone Delivery System for B lymphoid Malignancies." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1307069335.
Full text
14
Anderson, Keith E. "Formulation of targeted liposomes for the oral delivery of poorly-absorbed drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0004/NQ34726.pdf.
Full text
15
KAIMAL, VINOD. "In VivoMR Microscopy of Tumor Targeted Liposome Combining USPIO and Saposin-C." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1195496800.
Full text
16
Motala, Ismail Mohammed, and Saartjie Roux. "Formulation of an optimal non-targeted liposome preparation for fusion with tumour cell line membranes." Thesis, Nelson Mandela Metropolitan University, 2016. http://hdl.handle.net/10948/12220.
Full textAbstract:
The most common treatment used for cancer is chemotherapy. Chemotherapeutic agents have a greater affinity for rapidly dividing cells which is a characteristic of tumour cells. Although anti-cancer agents have their advantages in providing anti-cancer effects, they can be seen as highly toxic molecules posing a threat to normal healthy tissue within the human body. However, these toxic therapies need to be delivered to tumour sites without damaging healthy tissue. Liposomes can serve as a delivery system for these toxic molecules and be delivered to the tumour site via the EPR effect. Hence, liposomes that fuse with tumour cell line membranes are advantageous in delivering payloads of drugs directly into the tumour cell without damaging normal healthy tissue. The aim of the study was to formulate an optimised liposome preparation in order to enhance cellular uptake by MCF-7, Caco-2 and C3A cancer cell lines via membrane fusion. The optimal liposome formulation was aimed to be prepared utilising a statistical design approach in order to determine the ranges of the parameters that were furthermost optimal in formulating an ideal liposome preparation. The primary screening design was conducted using a 24-1 fractional factorial design that took into account the four parameters that were used to determine the optimisation of the liposomal preparation. The four variables used in the liposome preparation were the phospholipid type (PS or DOPE), the concentration of cholesteryl hemisuccinate (CHEMS) (10 – 40 %), the concentration of PEG2000-PE (0.5 – 4 %) and liposome size (100 or 200 nm). Liposomes were prepared using thin film hydration method and characterisation for size and zeta potential was carried out using photon correlation spectroscopy (PCS). Visual characterisation of liposome size was carried out using atomic force microscopy (AFM). Liposomes were exposed the cancer cell lines with visualisation and uptake being measured using fluorescent microscopy and flow cytometry, respectively. An optimal liposome preparation was prepared following the statistical design method. The optimal liposome preparation consisted of phospholipid type PS, 22.91 % of CHEMS, 4 % of PEG2000-PE and a liposome size of 200 nm. AFM analysis has shown that optimal liposome sizes ranged between 130 and 170 nm. Flow cytometry analysis indicated high level of liposome uptake with actual values falling below the predicted values set out by the statistical design. Fluorescence microscopy captured images of the fluorescent liposomes concentrated on the membrane of cells. The objective of the study was to determine from literature which variables would be desirable in preparing an optimal non-targeted liposome preparation. This was achieved by identifying four such variables and utilising them in a statistical design approach which was screened in order to determine the ideal parameters in preparing the optimised liposome batch. Therefore, from the results obtained it can be concluded that the aim of the study were met by preparing an optimal liposome preparation that has the ability to fuse with the tumour cell line membranes.
17
Cureton, Natalie. "Development of nanocarriers for targeted drug delivery to the placenta." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/development-of-nanocarriers-for-targeted-drug-delivery-to-the-placenta(696cfc4f-0bd7-4fbe-9b23-d2b83a7fec7d).html.
Full textAbstract:
Pregnancy complications such as fetal growth restriction (FGR) are often attributed to poor uteroplacental blood flow, but the risk of systemic side-effects hinders therapeutic intervention. We have utilised novel placental-specific homing peptides to overcome this and have conjugated these to biocompatible liposomes. Peptide-conjugated liposomes were found to selectively bind to the outer syncytiotrophoblast layer of the human placenta and to the uteroplacental vasculature and labyrinth region of the mouse placenta. The novel vasodilator SE175 was selected as a nitric oxide donor with a favourable stability and release profile, to encapsulate in peptide-conjugated liposomes in an attempt to restore impaired uteroplacental blood flow in a mouse model of FGR, the endothelial nitric oxide synthase knockout mouse. Liposomes containing SE175 or PBS were prepared by lipid film hydration and targeting peptides coupled to the liposomal surface. Vehicle control, free SE175, PBS- or SE175-containing liposomes were intravenously injected on embryonic (E) days 11.5, 13.5, 15.5 and 17.5. Animals were sacrificed at E18.5 and fetal and placental weights recorded. Targeted delivery of SE175 significantly increased fetal weight compared to vehicle control but no other treatment groups, whilst significantly decreasing placental weight, indicating improved placental efficiency. Treatment was well tolerated, having no impact on litter size or resorptions. Targeted delivery of SE175, but no other treatment group, reduced a marker of lipid peroxidation in the placenta, indicating a reduction in oxidative stress. These data suggest that selective delivery of SE175 to the uteroplacental vasculature in peptide decorated liposomes may represent a novel treatment for FGR.
18
Riviere, Kareen. "Investigation of the enhancement of drug synergy by co-delivery in targeted liposomes." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390075.
Full text
19
Zhang, Xin. "Development of thermal sensitive liposomes for targeted delivery and controlled release of drug." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/25125.
Full textAbstract:
One of the clinical challenges in the treatment of diseases with a discrete distribution is the local delivery of active drugs without causing systemic side effects. Doxorubicin, an anti-cancer drug, is an example that may cause damage to patients due to its interaction with normal cells. Tissue plasminogen activator (tPA) is another active agent whose effectiveness is compromised due to its unselective effect on both healthy and pathological blood clots. Thermal sensitive liposome is a drug carrier that is not only able to entrap drug into it hydrophilic interior but can also release encapsulated agents upon mild hyperthermia. Currently, lysolipid-containing thermal sensitive liposome (LTSL) is a standard formulation due to its rapid release behaviour. However, concerns have been raised regarding the negative effect of lysolipid on LTSL stability that results in undesirable leakage of encapsulated drug in vivo at physiological temperature. Therefore, the first aim of the project was to develop a lysolipid-free thermal sensitive liposome (TSL) formulation. For this purpose, doxorubicin was adopted as a model drug. The amount of doxorubicin molecules encapsulated in TSL (0.0123 mg of doxorubicin per 1 mg of lipid) was 2 times the amount in the existing publications (0.05 mg of doxorubicin per 1 mg of lipid ). This was done by optimizing the incubation temperature (36oC for 1 hour) during preparation of TSL. When heated from room temperature to 42 oC, doxorubicin-encapsulated-TSLs release encapsulated doxorubicin molecules faster than their LTSL counterpart. This may result from a higher membrane-bound doxorubicin concentration in dox-TSLs. The second objective of the project was to develop a tPA-encapsulated TSL (tPA-TSL) formulation that can release encapsulated tPA molecules under hyperthermia condition. It has been demonstrated that the developed tPA-TSL was able to release encapsulated tPA upon 7 minute heating at 45oC. The release of tPA molecules was expected to result from irreversible destruction of liposome upon heating, as was demonstrated by reduction of particle size.
20
Helfrich, Marcus Robert. "Preliminary investigations into the development of novel layered phosphonic acid vesicles for targeted drug delivery applications /." view abstract or download file of text, 2002. http://wwwlib.umi.com/cr/uoregon/fullcit?p3045088.
Full textAbstract:
Thesis (Ph. D.)--University of Oregon, 2002.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 184-193). Also available for download via the World Wide Web; free to University of Oregon users. Address: http://wwwlib.umi.com/cr/uoregon/fullcit?p3045088.
21
Catania, Rosa. "Glycoligands for targeted liposomes : design, development and ab-initio understanding of cell-vesicle recognition." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/49885/.
Full textAbstract:
In nature, several known proteins are glycosylated, and carbohydrate-cell receptor interactions mediate a plethora of key biological events, e.g. parasitisation and immune responses. Cell membranes display carbohydrate-binding proteins (lectins), which are able to selectively recognise specific sugar-ligands, decipher sugar-encoded instructions, and convert them into downstream biological processes. To overcome low binding affinities, which are typically observed for simple monosaccharides, protein-binding sugars are typically displayed within large multivalent ligands, where biological systems rely on multivalent interactions as a way to enhance selectivity and binding avidity. Glycoliposomes, phospholipid vesicles coated with sugars, can be designed to exploit this phenomenon through the presentation of multiple glycosylated ligands for actively targeting specific receptors, enhancing uptake of nanomedicines into target cells, or both. Among all the nanocarriers, liposomes are an advantageous strategy for drug delivery for their biocompatibility and high drug encapsulation efficiency. Functionalised liposomes have been developed over the last 30 years to optimise these nanocarriers by improving stability, circulation time and targeting. This thesis work focussed on the use of glycosylated liposomal systems for the treatment of intracellular bacterial infection in cells presenting lectin endocytic receptors. Antimicrobial resistance is one of the current main global healthcare challenges. In particular, antimicrobial resistance in Salmonella Enterica serotypes is responsible for 16 million cases of typhoid fever, 94 million cases of gastroenteritis and 600.000 deaths worldwide. Salmonella is able to survive in intracellular compartments of macrophages. Mannose Receptor (MR, CD206) is a potential access gate to Salmonella infected macrophages which could be selectively targeted with mannosylate-decorated liposomes. In this work, we present the design, the development and investigation of liposomal systems to deliver antimicrobials into Salmonella-infected macrophages. In order to investigate and identify the key structural parameters for efficient delivery of glycotargeted liposomes to selected cell targets (MR+ macrophages), two sets of monovalent glycoligands and two sets of multivalent polyglycosides - synthetic lipid-terminated glycopolymers - bearing a range of membrane-inserting anchors were synthesised. These synthesised membrane-inserting glycoligands have been used to formulate glycosylated liposomes with different glycosylation patterns and lipid composition through the Bangham method. Concanavalin A – a carbohydrate-binding protein – has been initially utilised as model protein target to study the surface presentation of the carbohydrate ligands. Firstly, the effect of lipid composition on the rate of liposomal clustering mediated by Concanavalin A (Con A) model lectin has been established. Our results showed that the binding properties of glycoliposomes are affected by the nature of both lipid constituents and carbohydrate ligands. Next, the uptake of glycosylated liposomes was investigated in salmonella infected macrophage-like cells. This in vitro infection model was used to evaluate the effect of different glycosylation patterns on the liposomal surface on mannose receptor (MR, CD206) targeting efficacy. Liposomes coated with mannose-containing glycopolymer significantly enhanced uptake compared to uncoated liposome control, and showed higher gentamicin delivery, resulting in reduction in internal infection.
22
Lattin, James R. "Ultrasound-Induced Phase Change of Emulsion Droplets for Targeted Gene and Drug Delivery." BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3377.
Full textAbstract:
This dissertation explores the potential of using perfluorocarbon emulsion droplets to add an ultrasound-sensitive element to drug delivery systems. These emulsion droplets may be induced to vaporize with ultrasound; during the rarefactional phase of an ultrasound wave, the pressure around the droplets may fall below the vapor pressure of the liquid forming the emulsion, providing a thermodynamic potential for vaporization. This ultrasound-induced phase change of the emulsion droplet could release therapeutics attached to the droplet surface or aid in drug delivery due to mechanical effects associated with vaporization and expansion, similar to the ability of cavitating bubbles to aid in drug delivery. In contrast to bubbles, stable emulsions can be formed at nano-scale sizes, allowing them to extravasate into tissues and potentially be endocytosed into cells. Perfluorohexane and perfluoropentane were selected to form the emulsions due to their relatively high vapor pressure, low water solubility, and biocompatibility. Acoustic droplet vaporization was explored for its potential to increase ultrasound-induced drug release from liposomes. Liposomes have proven to be versatile and effective drug carriers, but are not inherently responsive to ultrasound. eLiposomes, defined as a liposome with encapsulated emulsion droplets, were developed due to the potential of the expanding vapor phase to disrupt bilayer membranes. The resulting vesicle retains the advantages of liposomes for drug delivery, while adding an ultrasound-sensitive element. eLiposomes were loaded with calcein, a fluorescent molecule, as a model drug in order to quantify ultrasound-mediated drug release compared to release from conventional liposomes. Upon exposure to ultrasound, eLiposomes typically released 3 to 5 times as much of the encapsulated load compared to conventional liposomes, with some eLiposome samples approaching 100% release. Emulsion droplets were also added to the outside of conventional liposomes, but resulted in little to no increase compared to control samples without emulsions. Lastly, in vitro experiments were performed with HeLa cells to explore the ability of emulsion droplets and eLiposomes to deliver calcein inside of cells. Calcein delivery to the cytosol was accomplished, and the emulsion-containing samples demonstrated the ability to aid in endosomal escape.
23
Iden, Debbie Lynne. "A novel method to prepare ligand-targeted liposomal drugs for clinical applications." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ60440.pdf.
Full text
24
Barea, Matthew Ernest John. "An investigation into liposomal formulations for targeted drug delivery to the colon." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3430/.
Full textAbstract:
Recent studies have shown the numerous advantages associated with specific drug delivery to the colon, highlighting its favourable conditions and long transit time as the main advantages. A number of in vitro studies also show that the delivery of liposomes to the colon could provide further advantages due to bonding to the colonic mucosa in both healthy and inflamed regions. Despite these apparent advantages no oral liposomal formulation has been developed for targeted delivery to the colon as yet. Initially, experiments were conducted in which liposomes were directly coated with the pH responsive polymer Eudragit S100. Although the coating was shown to slow drug release in simple pH buffers, it was realised it could not protect the lipid membrane from the model bile salt sodium taurocholate. Development of the formulation moved onto the production of Eudragit S100 microspheres to provide a solid barrier to protect the liposomes. Due to the solvents required in the microsphere production it was essential to protect the liposomes, which was done by coating them with the enzyme controlled polymer chitosan. The final stage involved encapsulating chitosan-coated liposomes within the Eudragit microspheres to produce a novel, colon targeting liposome-in-microsphere (LIM) formulation.
25
Sodha, Anirudhasingh. "DEVELOPMENT AND COMMERCIALIZATION OF HEPATOCYTE TARGETED DRUG DELIVERY VEHICLE FOR PHARMACEUTICAL APPLICATION." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1247192896.
Full text
26
Mao, Yicheng. "Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911.
Full text
27
Chu, Hanwen [Verfasser]. "Prospect application of magneto-enzymatic sensitive liposome for imaging and targeted release in oral squamous cell carcinoma / Hanwen Chu." Kiel : Universitätsbibliothek Kiel, 2019. http://d-nb.info/119117980X/34.
Full text
28
Zhang, Xue. "Development of a targeted liposomal delivery system for encapsulated cantharidin to treat hepatocellular carcinoma." HKBU Institutional Repository, 2017. https://repository.hkbu.edu.hk/etd_oa/429.
Full textAbstract:
Background: Despite increasing incidence and morbidity globally, hepatocellular carcinoma (HCC) remains a big challenge clinically. The difficulty to treat HCC is largely due to non-specific chemotherapy causing life-threatening toxicity and severe drug-related adverse effects. Extensive studies on targeted drug delivery systems (DDS) have revealed a great potential in specific delivery of chemotherapeutics for cancer treatment, which should be a way to overcome the limitations of conventional chemotherapy. Cantharidin (CTD) is a natural product from Chinese medicine showing a great potency but narrow therapeutic window with high toxicity. Its therapeutic potential is proposed to be improved with nanoliposomal encapsulation. To explore the potential of this liposomal delivery system for HCC treatment, in this study we developed and characterized liposomal carriers with CTD encapsulated and liposomal surface modified for targeted delivery to the HCC models in vitro and in vivo. Methods: In the present study, liposomal delivery system was developed with cantharidin (CTD) encapsulated as anticancer assembly for HCC treatment. Firstly, in order to demonstrate the feasibility of liposomal encapsulation for CTD, the plain liposomal CTD was prepared and the anticancer effects were evaluated in vitro and in vivo with comparison to the free CTD formulation (Chapter 2). Then, to achieve specific penetrability of the liposomal CTD for HCC, it was further modified with a cancer cell specific penetrating peptide BR2, and its superior penetrability was evaluated on both in vitro monolayer and 3D HepG2 cells including MTT assay, cellular uptake, internalization, tumor spheroid penetration and inhibition, and in vivo subcutaneous HCC mice model (Chapter 3). Finally, the dual-functionalized liposomes with BR2 and anti-carbonic anhydrase IX (CA IX) antibody were achieved for more efficient delivery with specific penetrating and targeting properties on orthotopic HCC model (Chapter 4). Results: The key results of the study are: (1) liposomal CTD can augment the anti-proliferative effects of CTD, and enhance the anticancer efficacy on subcutaneous HepG2-bearing nude mice, which might be due to the enhanced solubility of the drug as well as intracellular delivery (Chapter 2); (2) with BR2 penetrating peptide modification, the liposomal CTD can get into cancerous cells specifically and penetrate deeper in 3D tumor models. A better tumor growth inhibition was also seen in the subcutaneous HCC mice of BR2-modified liposomes treatment than that of the other group, which could be contributed to the passive targeting of liposomes as well as the specific penetrating properties induced by BR2 peptide (Chapter 3); (3) the dual-functionalized liposomes with BR2 peptide and anti-CA IX antibody modification can enhance the drug internalization into HepG2 cells and further improve the anticancer efficacy of drugs compared to other formulations on orthotopic HCC nude mice (Chapter 4). Conclusion: These results demonstrate 1) the liposomal delivery system as a powerful tool to improve anticancer effects of chemotherapeutic agent; 2) the usefulness of BR2 and CA IX modified-liposomal nano-delivery of CTD and their combination might be a potential modality for HCC treatment. The study paved a way for clinical translational medicine of this ligands-modified liposomal delivery system for targeted treatment of HCC.
29
Zhao, Xiaobin. "Targeting CD37 and folate receptor for cancer therapy strategies based on engineered protein and liposomes /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1174678307.
Full text
30
Lyon, P. C. "Targeted release from lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:4817361a-e7f8-4773-ac81-8445ace05301.
Full text
31
Kheradmandi, Mahsa. "Surface and Structural Engineering of Liposomes and Cell-Derived Vesicles for Targeted Drug Delivery and Membrane Mimetics Design." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1624556116164427.
Full text
32
Rohrbach, Florian. "Induction of anti-tumor immunity by targeted delivery of ErbB2 cancer vaccines to antigen-presenting cells." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. http://www.theses.fr/2004STR13026.
Full text
33
Rosano, Jenna Marie. "Engineering Nanoparticles for Targeted Delivery of Growth Factors to Prevent Cardiac Remodeling After an MI." Master's thesis, Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/82332.
Full textAbstract:
Mechanical EngineeringM.S.E.
Myocardial infarction (MI) is a leading cause of death in the United States, claiming the lives of approximately 500,000 people each year. The infarcted heart undergoes a compensatory process called cardiac remodeling, which adversely changes left ventricular (LV) size and function and eventually may lead to heart failure. To date, the only clinical treatments for this condition include surgical restoration of blood flow to the ischemic region (e.g., angioplasty), or pharmacological treatments (e.g., angiotensin converting enzyme inhibitors) which indirectly manage the symptoms of cardiac remodeling. Reperfusion of ischemic heart tissue significantly limits myocardial damage after an MI; however, many MI patients are not candidates for traditional reperfusion surgery. Recently, there has been much interest in non-surgical myocardial reperfusion via pro-angiogenic compounds, specifically vascular endothelial growth factor (VEGF). Although animal studies using therapeutic VEGF have shown promising results, these results have failed to translate into successful clinical trials. This may be due to the short half-life of VEGF in circulation. Increasing the dose of VEGF may increase its availability to the target tissue, but harmful side-effects remain a concert. Encapsulating VEGF and selectively targeting it to the MI border zone may improve vascularization, cardiac function, reduce adverse remodeling associated with MI, and may avoid harmful side effects associated with systemic delivery. Anti-P-selectin conjugated immunoliposomes containing VEGF were developed to target the P-selectin ligand overexpressed in the infarct border zone in a rat MI model. Serial echocardiography and Doppler imaging were used to characterize evolutionary changes in LV geometry and function over a period of four weeks after MI. At four weeks, hearts were excised and stained to measure vascularization and collagen deposition. Targeted VEGF treatment resulted in significant improvements in fractional shortening at four weeks post-infarction (32.9 ± 2.2% for targeted VEGF treated vs. 16.9 ± 1.4% for untreated MI). Functional improvements in treated MI hearts were accompanied by a 74% increase in perfused vessels in the MI border zone, compared to untreated MI hearts. Left ventricular filling dynamics were significantly improved in the targeted VEGF treated group, which resulted in a decrease in LV end diastolic pressure in VEGF treated hearts (23.4 ± 2.9 mm Hg), compared to untreated MIs (81.8 ± 31.8 mm Hg). At four weeks after infarction, hearts treated with targeted VEGF therapy exhibited a 37% reduction in collagen deposition, compared to untreated MI hearts. Targeted VEGF therapy significantly improves vascularization, cardiac function, and moderates adverse cardiac remodeling after an infarction.
Temple University--Theses
34
CHANTARASRIVONG, CHANIKARN. "Development and evaluation of novel structurally simplified sialyl LewisX mimic-decorated liposomes for targeted drug delivery to E-selectin-expressing endothelial cells." Kyoto University, 2019. http://hdl.handle.net/2433/242670.
Full text
35
Dattani, Poonam. "Development and Characterization of LDV Peptide Targeted Nanocarriers for Paclitaxel Delivery: A Comparative Study of Micelles, Liposomes and Solid Lipid Nanoparticles." Scholarly Commons, 2019. https://scholarlycommons.pacific.edu/uop_etds/3623.
Full textAbstract:
Nanocarriers have been established as delivery vehicles to target cancer tumors. However, premature drug leakage is one of the major reasons for inefficient drug delivery of nanocarriers to the tumor. Drug diffusion out of the nanocarriers or destabilization of drug loaded nanocarriers by physiological interactions with blood cells, serum proteins, and cell membranes upon systemic administration contribute to premature drug release. In this study, targeted micelles, liposomes and solid lipid nanoparticles (SLNs) of similar composition were prepared and characterized to compare physicochemical characteristics, in vitro stability, in vitro release rates in release media and in vivo performance. Peptide Amphiphiles (PAs) formed micelles with critical micelle concentration (CMC) values ranging between 23.68 ± 0.72 µM to 38.76 ± 2.27 µM. Transmission Electron Microscopy (TEM) images confirmed the self-assembly of PAs into spherical structures where the largest sizes were seen for C16-(PEG2)6-LDV micelles. Dynamic Light Scattering (DLS) results confirmed the presence of targeted liposomes and SLNs with sizes smaller than 100 nm. Forster Resonance Energy Transfer (FRET) studies revealed that targeted micelles, liposomes and SLNs were all stable upon dilution in aqueous medium, however the stability was significantly reduced in human serum, with micelles being the least stable and SLNs being the most stable. The same trend was observed for the in vitro release profiles, where targeted paclitaxel-loaded micelles (PTX-micelles) had the fastest release rate and paclitaxel-loaded SLNs (PTX-SLN) exhibited the slowest release rate. DLS results showed that sizes of PTX-SLNs were smaller than PTX-liposomes (80.53 ± 5.37 nm vs 123.31 ± 5.87 nm). Cryogenic TEM observation showed increasing size in the order of PTX-micelles (6 to 12 nm) < PTX-SLNs (10-120 nm) < PTX-liposomes (48-145 nm). Drug Loading Content (DLC) of PTX-SLNs was greater than PTX-micelles and PTX-liposomes (7.45 ± 0.41 % vs 1.70 ± 0.42 % and 0.92 ± 0.09 %). Compared to initial aqueous dispersions, reconstituted spray dried formulations maintained their nanosize and paclitaxel content over 7 days at 4⁰C. In A375 melanoma xenograft mouse model, the tumor volumes were significantly smaller for mice treated with PTX-SLNs compared to the control group. Furthermore, tumor volumes were significantly smaller for mice treated with PTX-SLNs compared to those treated with PTX-micelles and PTX-liposomes. These studies demonstrate the potential of stable PTX-SLNs for targeted delivery in cancer.
36
Hendricks, Gabriel L. "Modulating Influenza and Heparin Binding Viruses’ Pathogenesis with Extrinsic Receptor Decoy Liposomes: A Dissertation." eScholarship@UMMS, 2013. http://escholarship.umassmed.edu/gsbs_diss/674.
Full textAbstract:
Influenza is a severe disease in humans and animals, causing upwards of 40,000 deaths every year in America alone. Influenza A virus (IAV) also causes periodic pandemics every 10 to 50 years, killing millions of people. Despite this, very few effective therapies are available. All strains of IAV are prone to developing resistance to antibodies due to the high mutation rate in the viral genome. Because of this mutation rate, a yearly vaccine must be generated before every flu season, and efficacy varies year to year. IAV has also mutated to escape several of the clinically-approved small molecule inhibitors. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of IAV. IAV attachment is mediated by many individually weak hemagglutinin–sialic acid interactions that all together make a strong attachment to a host cell. Polymerized sialic acid analogs can recreate these interactions and block infection. However, they are not ideal therapeutics due to solubility issues and in vivo toxicity. We used liposomes as a novel means for delivery of the sialic acid-containing glycan, sialylneolacto-N-tetraose c (LSTc). LSTcbearing decoy liposomes form multivalent, polymer-like interactions with IAV. Decoy liposomes competitively bind IAV in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. LSTc decoy liposomes co-localize with IAV, while control liposomes do not. Inhibition is specific, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind IAV or inhibit infectivity. LSTc decoy liposomes prevent the spread of IAV during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high-avidity interactions with IAV hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging strains.
37
Moles, Meler Ernest. "Development of polyvalent erythrocyte- and parasitized erythrocyte-targeted nanovectors as novel site-specific drug delivery approaches for Plasmodium falciparum malaria chemotherapy." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/360333.
Full textAbstract:
Bearing in mind the absence of an effective preventive vaccine against malaria (WHO, 2015) and its severe clinical manifestations that are principally associated with red blood cell (RBC) destruction and parasitized-RBC (pRBC) cytoadherence to host cells causing in turn nearly half a million deaths every year, this disease represents nowadays a major threat to life and consequently its control and ultimate global eradication must be undertaken without preconceptions.
Additionally, the basic rationale followed by most of the currently marketed antimalarial approaches is based on the administration of single/multiple drugs on their own, strategy that promotes the emergence of drug-resistant parasites owing to the limitation in delivering drug payloads into the pRBC high enough to kill the intracellular parasite while at the same time minimizing the risk of causing toxic side effects to the patient. Such dichotomy has been successfully addressed through the preparation of RBC- and pRBC-targeted drug delivery systems in the form of antibody-vectorized liposomes (iLPs), among other types of nanovectors, improving in this way the activity of antimalarials (Chandra, 1991; Owais, 1995; Urbán, 2011).
Nevertheless, the aforesaid iLP models have been poorly characterized with a minimal knowledge regarding: their mechanism of interaction with the target cell, release kinetics of encapsulated material or antibody coupling yield; and their recognized antigens have not been reported or are still unknown. Besides, the improvement in drug activity they have provided has been rather modest when evaluated against the human-infecting Plasmodium falciparum species. The main scope of this PhD thesis has been in this regard the characterization and development of more effective immunoliposomal nanovectors against P. falciparum with special attention given to the obtainment of chemotherapeutic approaches displaying multiple mechanisms of action.
Antibody coupling yields of >40% were obtained by means of their derivatization with the SATA crosslinker and the incorporation of maleimide-containing, PEGylated phospholipids into LPs, which results in the highly stable thioether linkage. SATA/antibody molar ratios of up to 10× provided adequate antigen recognition and minimal iLP aggregation. Furthermore, the pH- driven active encapsulation of chloroquine (CQ) and primaquine antimalarials into DSPC-based LPs together with their conjugation with a monoclonal antibody specific for the glycophorin A antigen of RBCs (GPA-iLPs) enabled these iLPs (i) to completely recognize and become retained into both RBCs/pRBCs, as well as (ii) a total and stable drug encapsulation along with its effective intracellular release under parasite culture conditions. The improved antimalarial efficacy of CQ-loaded, GPA-iLPs was demonstrated in vivo in P. falciparum-infected, humanized mice through the reduction of their parasite densities to undetectable levels (<0.01% parasitemia) and following a 4 × 0.5 mg CQ/kg dosage schedule. Free CQ at a dosage 3.5 times higher was at least 40-fold less effective.
Moreover, lumefantrine-laden iLPs targeted against rosette-forming variants of PfEMP1 exhibited a great potential for severe malaria therapeutics by means of mechanically disrupting already generated rosettes while at the same time eliminating those parasites forming them. An increased activity of lumefantrine in reducing the number of rosette-forming pRBCs was obtained when delivered by homologous PfEMP1-targeted-iLPs with a ~5.5-fold decreased IC50 compared to either free drug or non-targeted LPs. The rosette-disrupting activity of anti- PfEMP1 antibodies was importantly preserved after their conjugation to LPs. Finally, based on a recent study in Toxoplasma gondii (Nagamune, 2008), the biosynthesis of ABA by P. falciparum was explored as a new target route for the design of antimalarials. However, ABA could not be found in late form-pRBC extracts even though the sensitivity for its detection had been extraordinarily improved (LOD of 0.03 ng/ml).
38
Brandao, palacio Sarah. "Development and characterization of targeted MART-1-nanoparticles for melanoma treatment and β-lapachone-loaded liposomal in hydrogel for wound healing." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS487/document.
Full textAbstract:
L’objectif principal de cette thèse a été le développement, la caractérisation et l’évaluation in vitro et in vivo de différents nanovecteurs plus spécifiquement les nanoparticules spécifiques pour le traitement de la mélanome et β-lapachone-lipossomale incorporée dans des hydrogels de biopolymère pour la cicatrisation de blessures topiques. La première étape de cette thèse a consisté en la révision de la littérature liées aux résentes avancées sur les nanoparticules pour le ciblage d’agents thérapeutiques pour des cellules circulantes et des mésenchymateuses de mélanomes. De plus, cette révision a approfondi la connaissance sur les principaux biomarcateurs qui étaient déjà identifiés dans ces cellules et quelles caractéristiques des nanovecteurs peuvent influencer leur performance in vivo. Dans la phase expérimentale, les nanoparticules ont été développées en utilisant la méthode de nanoprécipitation de polymères dérivés du poli(γ-benzyl-L-glutamate). Ensuite, des immuno-nanoparticules combinées avec l’anticorps MART-1 spécifique pour les cellules de mélanome, ont été obtenues par le lien streptavidine-biotine. La combinaison de l’anticorps sur la superficie des nanoparticules a été évaluée par western blot. Les nanoparticules ont été caractérisées et évaluées in vitro dans des cellules de mélanome B 16-GFP et des cellules endothéliales de la veine ombilicale humaine (HUVECs), l’activation de complément a été recherchée par la technique d’immunoélectrophorèse bidimensionnelle. Les nanoparticules ont présenté des tailles comprises entre 20 et 100 nm et une charge négative (-3 à -30 mV). La combinaison de l’anticorps sur la superficie des nanoparticules a été observée par la technique western blot et confirmée par les altérations de la taille et de la charge de superficie des particules. Les nanoparticules développées n’ont pas été capables d’activer le systhème complémentaire étant considérées de longue circulation sanguine. Pour l’analyse in vitro, les nanoparticules n’ont pas présenté de cytotoxixité lorsqu’elles ont été testées dans des cellules de mélanome ou dans des cellules normales endothéliales. Lors des tests de capture cellulaire, les immuno-nanoparicules, qui contenaient l’anticorps spécifique pour la reconnaissance de l’antigène surexprimé dans des cellules de mélanome, ont présenté une augmentation de 40 à 50% lors de la capture pour ces cellules, cela indiquant une plus grande spécificité de ce nanovecteurs. La deuxième partie de cette thèse a été le développement, la caractérisation et l’évaluation de l’activité cicatrisante in vivo de β-lapacho encapsulé dans des liposomes multilamellaires incorporés dans de l’hydrogel de biopolymère produit par la bactérie Zoogloea sp. (β-lap-Lipo/ZBP/HEC). β-lap-Lipo/ZBP/HEC a présenté un pH et un comportement rhéologique approprié pour l’application topique, ainsi qu’un profil de libération plus lent de la β-lapachone à partir de l’hydrogel. Les analyses hystopotologiques de l’activité cicatrisante in vivo ont montré que le véhicule hydrogel de biopolymère a été capable de stimuler les réparations du tissu, augmenter la cellularité locale, les fibroblastes, les cellules inflamatoires, les vaisseaux sanguins et les fibrilles de collagène pendant la phase proliférative de la cicatrisation. De plus, β-lap-Lipo/ZBP/HEC a favorisé une augmentation de l’angiogenèse locale et une dimminution de l’inflamation de la blessure. Ces résultats ont montré le potentiel de l’application topique de β-lap-Lipo/ZBP/HEC pour la thérapie des lésions. Pour conclure, cette thèse a contribué au développement de nanovecteurs promisseurs ayant différentes applications biologiques et formes d’administration, comme le traitement systémétique de la mélanome et l’action topique lors de la cicatrisation des blessuresThis thesis had as general objective the development, characterization and evaluation in vitro or in vivo of different nanocarriers, specifically site-specific nanoparticles for the treatment of melanoma and liposomal-hydrogel containing β-lapachone for topical wound healing. The first part of this thesis consisted in a literature review about the recent advances in nanoparticles for the targeting of therapeutic agents to circulating and mesenchymal melanoma cells. In addition, this review deepened the knowledge about the main biomarkers identified in these cells and which characteristics of nanocarriers may influence on their in vivo performance. In the experimental phase, nanoparticles were developed through the nanoprecipitation method of polymers derived from poly (γ-benzyl-L-glutamate). Next, immunonanoparticles conjugated with MART-1 antibody specific for melanoma cells were obtained through the streptavidin-biotin binding. The conjugation of this antibody on the nanoparticles surface was evaluated by western blot. The nanoparticles were characterized and evaluated in vitro in B16-GFP melanoma cells and human umbilical vein endothelial cells (HUVECs) and the complement activation was investigated by bidimensional immunoelectrophoresis. The nanoparticles presented sizes between 20 and 100 nm and negative surface charge (-3 to -30 mV). The conjugation of antibody on the nanoparticle surfaces was detected by the western blot technique and confirmed by the changes in particle size and surface charge. The developed nanoparticles were not able to activate the complement system being considered long blood circulation. Regarding the in vitro analysis, the particles did not show cytotoxicity when tested in melanoma cells or normal endothelial cells. In the cell capture assays, the immunonanoparticles, containing a specific antibody for the recognition of the overexpressed antigen in melanoma cells, showed an increase of 40 to 50% in the uptake for these cells, indicating a specificity of this nanocarrier. The second part of this thesis consisted of the development, characterization and evaluation of the in vivo wound healing activity of β-lapachone encapsulated in multilamellar liposomes and incorporated in a biopolymer hydrogel produced by Zoogloea sp (β-lap-Lipo/ZBP/HEC). β-lap-Lipo/ZBP/HEC presented pH and rheological behavior suitable for topical application, as well as a slower release profile of β-lapachone through the hydrogel. Histopathological analyzes of the healing activity in vivo, showed that the biopolymer hydrogel vehicle was able to stimulate tissue repair, with the increase of local cellularity, fibroblasts, inflammatory cells, blood vessels and collagen fibers, during the proliferative phase of wound healing. In addition, β-lap-Lipo/ZBP/HEC promoted an increase in local angiogenesis and a decrease of inflammation at the wound site. These results demonstrate a promising topical application of β-lap-Lipo/ZBP/HEC for wound therapy. In conclusion, this thesis contributed for the development of promising nanocarriers with different biological applications and administration routes, such as systemic treatment of melanoma and topical action in wound healing
39
Ayesa, Umme. "CHARACTERIZATION OF THERMOSENSITIVE HYBRID ARCHAEOSOMES AND DPA-CY3[22,22]/POPC LIPOSOMES AND IN VITRO EVALUATION OF THEIR POTENTIAL USEFULNESS IN TARGETED DELIVERY AND CONTROLLED RELEASE." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/368614.
Full textAbstract:
BiochemistryPh.D.
One of earlier challenges in treating cancer was utilizing drugs that are powerful yet do not cause severe toxicity to patients. Although the use of liposomal drugs has somewhat met that challenge, our objective now is to create liposomal drugs with an even better drug efficacy and further reduced toxicity. Doxorubicin hydrochloride (DXO), for example, is an anticancer drug used to treat many types of cancers, but it is toxic to the gastrointestinal tract and the heart. Encapsulating DXO into liposomes as done in the first FDA-approved liposomal DXO, Doxil, minimizes toxicity and improves the half-life, allowing more opportunities for the drug to reach the tumor. While liposomal DXO is in the market with an annual sale of approximately 450 million dollars, the addition of cholesterol and lipids with polyethylene glycol (PEG) in the formulation increase liposome stability and circulation time, but can give rise to other concerns such as potential harm to the patient and reduction in drug loading/release. In addition, in hopes of increasing drug accumulation at the diseased tissue, the use of active or targeted nanoparticles has been explored for selective drug delivery. However, despite ongoing efforts to design and test targeted nanocarriers for drug delivery, there is no known targeted liposome commercially available at this time. This illustrates that there is still room to improve the formulation of the liposomal carriers in the areas of stability, specificity to the cancer sites, and maximum drug at diseased sites. The main focus of our research is to develop novel liposomal carriers that have a higher therapeutic index and lower cytotoxicity than currently used liposomal drugs. In this research, we were able to construct two stable liposomal systems. First, we constructed a liposomal system having the ability to specifically target phosphatidylserine (PS) exposed tissues. This liposomal system contains 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and hydrophobic PS-targeting molecule bis-dipicolylamine-Zn-Cy3[C22,22] (abbreviated DPA-Cy3[22,22]). We have tested stability and PS binding ability of DPA-Cy3[22,22]/POPC liposomal carriers using light scattering and ion-exchange chromatography, respectively. In addition, with confocal microscopy and flow cytometry, we have tested DPA-Cy3[22,22]/POPC liposomes’ affinity to cancer cells. Furthermore, cell viability assay was used to determine the cytotoxic effect of DPA-Cy3[22,22]/POPC liposomes on cancer cells and non-cancer cells. In short, we found that DPA-Cy3[22,22]/POPC liposomes were stable, displayed binding to PS-exposed cells, and were taken up by PS-exposed cells inducing considerable cytoxicity. Second, we have developed and characterized the physical properties of thermosensitive liposomes made of archaeal bipolar tetraether lipids (BTL) and “conventional” monopolar diester lipids. These liposomes are also termed hybrid archaeosomes. Specifically, we used the polar lipid fraction E (PLFE) isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius as the BTL component of the hybrid archaeosomes. Dynamic light scattering and zeta potential measurements showed that the presence of PLFE greatly stabilizes liposomes. The most striking result is that at 25-30 mol% PLFE in DPPC liposomes, there is a dramatic change in zeta potential with temperature. The most abrupt change was detected in 30 mol% PLFE in DPPC, where the zeta potential changes from ~45mV at 37˚C to ~5mV at 42˚C. This drastic change in liposome zeta potential by temperature is unprecedented and could be used to develop new thermosensitive liposomes. This dramatic change in zeta potential is likely to result from gross changes in membrane structure by temperature at particular PLFE mole fractions. To further characterize PLFE/DPPC hybrid archaeosomes, we have used steady state nano-second fluorometry. The fluorescent data show that from 37˚C to 43˚C, the probe diphenylhexatrine (DPH) in the PLFE/DPPC mixtures experience a decrease in order parameter and an increase in rotational motion. With entrapped DXO we found that below 37˚C, the drug release from hybrid archaeosomes is slow. However, when the temperature was raised to above 39˚C, the initial drug release rate constant was increased by a factor of 2. Taken together, the findings suggest that a mild temperature jump changes the membrane packing and dynamics of the PLFE/DPPC mixture, making the membrane more permeable for small molecules. Additionally, confocal fluorescence microscopy showed that these hybrid archaeosomes can be taken up by live cells (e.g., MCF-7 breast cancer cells) and deliver entrapped drug molecules to the cell’s nucleus, with a rate significantly lower than that obtained from conventional diester liposomes. Our results indicate that both of these two novel liposomal systems have great potential to be used for delivery of therapeutic agents such as small drug molecules (e.g., DXO), siRNA, DNA, or peptides/proteins for cancer treatment and various other purposes. Unlike currently available liposomal drugs, DPA-Cy3[22,22] containing liposomes could be useful for targeting PS-exposed diseased tissues. 30 mol% PLFE/DPPC archeosomes are a unique thermosensitive liposome system with extraordinary stability at the body temperature and able to release entrapped drugs molecules when the local temperature of the diseased tissue is subject to hyperthermic treatment.
Temple University--Theses
40
Elliott, John A. "PEGylation of Niosomes." Scholar Commons, 2009. http://scholarcommons.usf.edu/etd/3448.
Full textAbstract:
The research presented in this dissertation describes the creation and characterization of a novel antibody-vesicle conjugate modified with polyethylene glycol (PEG) that possesses enhanced binding to and uptake by inflammation-activated endothelial cells with improved storage stability and longer shelf-life and potential reduction in immunogenic potential compared to previous designs.
Targeted drug delivery provides an effective means of delivering therapeutic concentrations of a drug to the site or organ of action. The drug is delivered using a niosome, a vesicle with an aqueous core and a bilayer membrane composed of non-ionic surfactants and cholesterol. Antibodies that recognize specific cell antigens are attached to the niosome to complete the targeting molecule, an immuno-niosome (IN). When functionalized PEG, a water soluble, biologically inert polymer, is attached to proteins, it can protect the protein, increasing its half-life in vivo. The immuno-niosome synthesis process is modified to include PEG incorporation into the niosome membrane, a process known as PEGylation.
Since the vasculature connects the entire body, immuno-niosomes targeted to endothelial cells were used. When endothelial cells are activated during disease, stress and injury, certain receptors are expressed and upregulated. One such receptor, CD44, is upregulated in response to vascular inflammation associated with atherosclerosis.
The research hypothesis is that the addition of polyethylene glycol to the drug delivery vesicle (immuno-niosome) using cyanuric chloride linking chemistry will improve colloidal stability and binding performance of the PEGylated immuno-niosomes to endothelial cell surface receptors expressed during an inflammatory response. The research presented in this dissertation provides the following evidence to support this hypothesis:
Construction and characterization of a modified drug delivery vesicle using non-ionic surfactants conjugated with PEG and functionalized with antibodies against endothelial cell surface receptors (PEGylated immuno-niosomes) improves the colloidal stability over previously designed vesicles.
Binding of PEGylated CD44-IN to activated endothelial cells is improved over previously designed vesicles.
Binding of PEGylated CD44-IN to activated endothelial cells under physiological conditions (flow) is demonstrated.
Uptake of PEGylated immuno-niosomes by activated or injured endothelial cells is demonstrated using confocal microscopy.
41
Sánchez, Purrà Maria. "Development of novel vesicle-like nanocarriers for targeted drug delivery." Doctoral thesis, Universitat Ramon Llull, 2015. http://hdl.handle.net/10803/288318.
Full textAbstract:
Les dificultats existents en l’administració de certs fàrmacs, que es tradueix en una considerable reducció de la seva eficàcia terapèutica, ha portat a l’exploració d’un nou camp en la recerca de fàrmacs, l’ús de polímers per a transportar fàrmacs. Aquests polímers es presenten com a vehicles transportadors que aporten protecció al fàrmac, evitant la seva degradació, i permeten la seva distribució dirigida fins la diana terapèutica, disminuint així els efectes secundaris. Una combinació adequada del polímer transportador amb el fàrmac, permet l’alliberament d’aquest en el teixit on ha de desenvolupar el seu efecte terapèutic. Tot i així, per tal de garantir l’èxit d’aquests sistemes de distribució de fàrmacs, aquests han de complir una sèrie de requisits pel que fa a la mida, càrrega superficial, composició, capacitat d’encapsular i d’alliberar un fàrmac, funcionalització i biocompatibilitat.
En aquest treball, s’ha explorat la fabricació de diversos sistemes de distribució de fàrmacs per tal d’aportar coneixement sobre la modificació d’aquests polímers, que permetin obtenir plataformes de distribució de fàrmacs que reuneixi els requisits prèviament esmentats.
Per una banda, s’ha obtingut un sistema termosensible i versàtil a través d’una estratègia de core-shell, que permet ajustar la seva mida i el seu comportament termosensible, com també la seva modificació superficial mitjançant un mètode fàcil i ràpid basat en una química clàssica.
Per altra banda, la preparació de sistemes polimersòmics s’ha explorat per polimerització de tipus RAFT, és a dir, s’empra una química més sofisticada, que permet la síntesi de copolímers de multibloc amfifílics i auto-ensamblables, des de dos fins a cinc blocs, de manera controlada, obtenint polímers de pes molecular determinada amb distribucions de pes molecular molt estretes. De manera similar a l’anterior sistema, la modulació de la proporció entre blocs i del nombre de blocs permet el control de la mida de les nanoestructures formades i de la seva capacitat d’encapsular fàrmacs.
Finalment, els sistemes polimersòmics desenvolupats s’han comparat amb un sistema de distribució de fàrmacs molt ben establert, com ara els liposomes, pel que fa a funcionalització, encapsulació i alliberament de fàrmacs, com a potencials sistemes de distribució de fàrmacs per al tractament de metàstasis de càncer de mama al cervell a través d’una estratègia de doble funcionalització, per tal d’avaluar la idoneïtat del sistema desenvolupat en aquest treball.Las dificultades existentes en la administración de ciertos fármacos, que se traduce en una considerable reducción de su eficacia terapéutica, ha llevado a la exploración de un nuevo campo en el desarrollo de fármacos, el uso de polímeros como transportadores de estos. Estos polímeros se presentan como vehículos transportadores que aportan protección al fármaco, evitando así su degradación i permitiendo su distribución dirigida hasta la diana terapéutica, disminuyendo a su vez los efectos secundarios. Una combinación adecuada del polímero transportador con el fármaco, permite la liberación de este en el tejido dónde debe desarrollar su efecto terapéutico. Aun así, con tal de garantizar el éxito de estos sistemas de distribución de fármacos, estos deben cumplir una serie de requisitos por lo que respecta a tamaño, carga superficial, composición, capacidad de encapsular i liberar un fármaco, funcionalización i biocompatibilidad. En este trabajo, se ha explorado la fabricación de varios sistemas de distribución de fármacos con la finalidad de aportar conocimiento sobre la modificación de estos polímeros, que permitan obtener plataformas de distribución de fármacos que reúnan los requisitos previamente mencionados. Por un lado, se ha obtenido un sistema termosensible i versátil a través de una estrategia de core-shell, que permite ajustar su tamaño i su comportamiento termosensible, como también su modificación superficial mediante un método fácil i rápido basado en química clásica. Por otro lado, la preparación de sistemas polimersómicos se ha explorado mediante polimerización RAFT, es decir, utilizando una química más sofisticada, que permite la síntesis de copolímeros de multibloque amfifílicos i auto-ensamblables, desde dos a cinco bloques, de manera controlada, obteniendo polímeros de peso molecular determinado con distribución de peso molecular muy estrecha. De manera similar al anterior sistema, la modulación de la proporción entre bloques i del número de bloques permite el control del tamaño de las nanoestructuras formadas i de su capacidad de encapsular fármacos. Finalmente, los sistemas polimersómicos desarrollados se han comparado con un sistema de distribución de fármacos muy bien establecido, como son los liposomas, por lo que respecta a su funcionalización, encapsulación i liberación de fármacos, como potenciales sistemas de distribución de fármacos para el tratamiento de metástasis de cáncer de mama al cerebro a través de una estrategia de doble funcionalización, con tal de evaluar la idoneidad del sistema desarrollado en este trabajo.
The existing difficulties in the delivery of certain drugs, having a direct influence on their therapeutic efficiency, has lead to the exploration of a new field in pharmaceuticals, the use of polymers as drug carriers. Polymers are presented as carrier vehicles, which provide drug protection preventing its degradation and targeted delivery to the site of action diminishing side effects. An appropriate combination of the drug and the polymer allows the release of the drug in the tissue where it has to develop its therapeutic effect. However, in order to ensure the success of these drug delivery systems, they must fulfil a list of requirements according to size, surface charge, composition, drug loading capacity and release, targetability and biocompatibility. In this work, the fabrication of diverse drug delivery systems has been explored in order to provide know-how regarding polymers’ tunability to achieve delivery platforms that fulfil the aforementioned requirements. On one hand, a versatile thermo-responsive delivery system has been obtained trough a core-shell approach, allowing the tailoring of its size and thermosensitivity, while providing a simple and fast method to decorate its surface by means of classic chemistry. On the other hand, the preparation of polymersomic systems was explored by RAFT polymerization, a more sophisticated chemistry, which allowed the synthesis of self-assembling amphiphilic multiblock copolymers, ranging from diblock to pentablock, in a controlled manner, obtaining predetermined molecular weight polymers with narrow molecular weight distributions. Similarly to the previous system, the tunability of blocks ratio and number allowed the control over nanostructures size and loading capacity. Finally, polymersomes have been compared with a very well established delivery system, such as liposomes, in terms of targeting and drug loading and release, as potential drug delivery systems to breast cancer metastasis in the brain through a dual-targeting approach, in order to evaluate the suitability of the system developed in this work.
42
Peres, Filho Marco Júnio. "Desenvolvimento de lipossomas vetorizados ao receptor folato contendo paclitaxel e imatinibe coencapsulados: avaliação da atividade antiproliferativa e da expressão gênica do VEGF em células tumorais." Universidade Federal de Goiás, 2014. http://repositorio.bc.ufg.br/tede/handle/tede/7452.
Full textAbstract:
Submitted by JÚLIO HEBER SILVA (julioheber@yahoo.com.br) on 2017-06-09T20:26:25Z
No. of bitstreams: 2
Tese - Marco Júnio Peres Filho - 2014.pdf: 2890867 bytes, checksum: 94c9616394d6a389aadabf3d9a0b128c (MD5)
license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-06-12T12:31:24Z (GMT) No. of bitstreams: 2 Tese - Marco Júnio Peres Filho - 2014.pdf: 2890867 bytes, checksum: 94c9616394d6a389aadabf3d9a0b128c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5)
Made available in DSpace on 2017-06-12T12:31:24Z (GMT). No. of bitstreams: 2 Tese - Marco Júnio Peres Filho - 2014.pdf: 2890867 bytes, checksum: 94c9616394d6a389aadabf3d9a0b128c (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014-04-30
The impact of Nanotechnology is constantly raising in different areas of science, with the development of new products that bring benefits in comparison with the alternatives available in the market. When encapsulated in nanoparticles, anticancer drugs can achieve several advantages, most importantly the possibility of reducing the amount of drug administered through targeting strategies, which are not accomplished by conventional medication. Passive targeting is related to leaky vasculature in pathological sites, and active targeting comprehends the attachment of specific ligands, anchored in nanoparticles surface, to recognize and bind receptors overexpressed in cancer cells. Coencapsulation of anticancer drugs in the same pharmaceutical carrier can coordinate pharmacokinetics of encapsulated drugs. In the present work, liposomal formulations targeted to folate receptor with paclitaxel (PTX) and imatinib (IB) coencapsulated were obtained, aiming to combine cytotoxic and antiangiogenic effects of the drugs, respectively. New analytical method was developed and validated for simultaneous quantification of IB and PTX. Soy phosphatidylcholine liposomes were prepared, with cholesterol and DSPEmPEG( 2000), to obtain long circulation particles. DSPE-PEG(2000)-FA was obtained by an unpublished method of synthesis, and this product was further used in the formulation by post-insertion technique. Cytotoxic effect and VEGF gene suppression were studied in vitro in two different cell lines, MCF7 (breast adenocarcnioma) and PC3 (prostatic adenocarcinoma), after treatment with liposomal vesicles. Analytical procedures were developed with isocratic elution, 6,5 minutes runs, with linearity, specificity, precision and accuracy. Quantification limit was 750 Ng/mL and 1000 Ng/mL for IB and PTX, respectively. After extrusion, liposomes had mean diameter close to 100 nm and low polidispersion index. Post-insertion of folic acid attached to lipid anchor procedure increased polidispersion, because the procedure lasted 24h. Drug to lipid ratios were 1:26 and 1:27 (IB and PTX respectively). Lyophilized formulations containing trehalose remained stable after 60 days of storage in terms of %EE. Synthesis of DSPE-PEG(2000)-FA was confirmed by RMN, FT-IR and ESIMS techniques. Liposomal PTX was more cytotoxic (p<0,05) than free drug in MCF7 cell line, after both 24h and 48h of exposion, for all tested concentrations. Targeted formulation containing folic acid ligand, had more impact on cell viability reduction (p<0,05) than non targeted liposomes (LPIP), also after 24h. On PC3 cell line cell viability reduction was greater (p<0,01) when the cells were exposed to targeted vesicles loaded with 1 and 10 Ng/mL of IB and PTX, after 24 and 48h. VEGF gene expression was reduced in MCF7 and PC3 (p<0,05), and once more targeted vesicles showed better results than non-targeted liposomes. It is, thus, plausible to conclude, through in vitro experiments results, that the attachment of folic acid to liposomal formulations, resulting in multi-functional liposomes, is an interesting strategy to achieve enhanced internalization and accumulation of drugs in targeted cells. This was observed by the enhancement of cytotoxic and antiangiogenic effects in breast and prostate cell lines.
A nanotecnologia tem ganhado cada vez mais destaque em várias áreas da ciência, no sentido de desenvolver novos produtos que possam trazer benefícios em comparação com alternativas já existentes no mercado. Uma série de vantagens emergem da nanoencapsulação de fármacos quimioterápicos, principalmente, a possibilidade de diminuição da dose administrada através de estratégias de direcionamento. Dentre elas, podem ser citadas a vetorização passiva, relacionada ao aumento da permeabilidade vascular em regiões tumorais, e a vetorização ativa, que significa o uso de ligantes específicos, cujos receptores são superexpressos em células tumorais, e que ficam ancorados na superfície de nanoestruturas. A coencapsulação de fármacos antitumorais é altamente relevante, uma vez que permite a utilização de diferentes abordagens para eliminação de tumores e a sincronização da farmacocinética dos agentes coencapsulados. No caso deste trabalho, o objetivo foi a associação do efeito citotóxico do paclitaxel (PTX) ao efeito antiangiogênico do imatinibe (IB), encapsulados no mesmo lipossoma direcionado para o receptor folato, superexpresso em vários tumores sólidos. Foi desenvolvido e validado novo método analítico para quantificação simultânea do IB e do PTX. Os lipossomas foram desenvolvidos usando fosfatidilcolina de soja (PC) como lipídio estrutural, colesterol e DSPE-mPEG(2000), este último para conferir efeito de longa circulação. Foi desenvolvido método inédito de síntese da molécula DSPEPEG( 2000)-AF, âncora lipídica ligada ao ácido fólico destinada a biorreconhecimento. Essa molécula foi adicionada à formulação por pós-inserção. Os nanossistemas obtidos foram testados in vitro quanto à citotoxicidade e quanto à inibição da expressão gênica de VEGF em células de adenocarcinoma mamário (MCF7) e de próstata (PC3). O método analítico foi isocrático, com corrida de apenas 6,5 minutos, linear, seletivo, preciso e exato, com limite de quantificação 750 Ng/mL para o IB e 1000 Ng/mL para o PTX. Os lipossomas tiveram diâmetro médio próximo de 100 nm e baixo índice de polidispersão. Apenas após a inserção da âncora ligada ao ácido fólico as amostras ficaram mais polidispersas, devido ao tempo de agitação desse processo (24 h). O IB foi encapsulado na razão molar fármaco:lipídio 1:26 e o PTX na razão 1:27. As formulações liofilizadas, usando o crioprotetor trealose, mantiveram a estabilidade em termos de %EE após 60 dias de armazenamento. O método desenvolvido para síntese do componente DSPEPEG( 2000)-AF foi bem sucedido, o que pôde ser verificado através dos espectros de RMN, FT-IR e IES-EM, que evidenciam a formação de uma nova substância a partir dos reagentes, que tem as características químicas esperadas. O paclitaxel lipossomal foi mais citotóxico (p<0,05) para a linhagem MCF7, tanto em 24h como em 48h, em comparação com o fármaco livre, em todas as concentrações testadas. A formulação vetorizada com a âncora ligada ao ácido fólico, com IB e PTX coencapsulados, foi mais citotóxica (p<0,05) que a não vetorizada (LPIP) nas concentrações testadas, no tempo 24 h. Na linhagem PC3 a redução da viabilidade celular causada pela vetorização ativa, em comparação com o resultado da formulação não vetorizada, foi ainda maior (p<0,01) tanto em 24 como em 48h, nas concentrações 1 e 10 Ng/mL. Houve redução, nas linhagens MCF7 e PC3, da expressão gênica de VEGF, e também nesse caso o tratamento com a formulação vetorizada causou maior efeito em comparação com a não vetorizada (p<0,05). É razoável chegar-se à conclusão, através dos testes in vitro, de que o direcionamento de fármacos nanoencapsulados ao receptor folato, através do emprego de lipossomas multi-funcionais, é uma estratégia interessante no sentido de aumentar a quantidade de fármaco que entra nas células, o que pôde ser observado através do aumento dos efeitos citotóxico e anti-angiogênico em linhagens tumorais de mama e próstata.
43
Polak, Roberta. "Desenvolvimento e fabricação de filmes ultra-finos, obtidos pela técnica layer-by-layer, para aplicações na entrega direcionada de fármacos e na captura seletiva de bio-marcadores." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/9/9135/tde-27042015-152718/.
Full textAbstract:
O objetivo geral deste trabalho foi explorar a versatilidade de filmes multicamadas de polieletrólitos (PEM) e suas aplicações em sistemas de entrega de drogas e como filmes funcionais para aplicações biomédicas. Filmes PEM montados pela técnica de camada por camada (layer-by-layer, LbL), foram explorados em três aplicações principais. Na primeira, foi explorado o desenvolvimento de um protocolo de funcionalização em filmes de poli(alilamina)/poli (estireno sulfonato), PAH/SPS. Os parâmetros de construção do filme para biotinilação dos grupamentos amina do PAH foram otimizados e aplicados na captura e detecção do antígeno específico da próstata (PSA), na concentração de 100 a 0,1 ng/mL, usando pontos quânticos (Qdots). Em comparação com outros trabalhos, este sistema apresentou uma boa sensibilidade na detecção de PSA, dentro do limite de detecção clínica de 0,4 a 0,1 ng/mL. A segunda aplicação envolveu o desenvolvimento de filmes de sacrifício baseados nas interações naturais da mucina submandibular bovina e da lectina, jacalina (BSM/JAC). Filmes de BSM/JAC apresentaram estabilidade quando submetidos a uma ampla faixa de pH (pH 3--9) e em solução de alta força iônica (5 M NaCl). A dissolução dos filmes BSM/JAC pôde ser seletivamente desencadeada mediante à incubação em solução de melibiose, 37 °C, pH 7,4, sem apresentar citotoxicidade às células. Na última parte deste trabalho, a incorporação de lipossomos ecogênicos (ELIP) em mochilas celulares foi investigada. Mochilas celulares são \"patches\" de 7-10 µm de diâmetro que podem ser fabricados por meio de deposição alternada de polímeros utilizando--se a técnica de LbL, sobre uma matriz pré-moldada obtida por fotolitografia, a fim de criar um sistema composto por três multicamadas estratificadas: uma região de liberação, para promover o destacamento do substrato, uma região de carga de droga, e uma região adesiva às células. O uso de ELIP permitiu incorporação de até 9x mais doxorrubicina (DOX) se comparado com o fármaco livre em solução absorvido pelos dos filmes. A liberação de DOX pelos filmes foi monitorado por 25 dias. Mochilas contendo ELIP-DOX foram então aderidos a monócitos, e sua viabilidade monitorados por 72h. Mochilas vazias mostraram diminuir a proliferação de monócitos ao longo das 72 horas, enquanto mochilas carregadas com ELIP-DOX mostraram uma diminuição dramática na população celular, apontando uma potencialização dos efeitos da droga pela sua proximidade com as células.The overall goal of this thesis was to exploit the versatility of polyelectrolite multilayers (PEM) to be applied in drug delivery systems and biofunctionalizable films for biomedical applications. PEM films assembled by the layer-by-layer technique were explored in three main applications. In the first part of this work, the development of a functionalization protocol of poly(allylamine)/poly(styrene sulfonate), PAH/SPS was explored. The optimal film parameters to the use of biotinylated multilayers were applied for the capture and detection of prostate specific antigen (PSA) protein in the range of 100 to 0.1 ng/mL, by using quantum dots. Compared to previous work, this system presented a good sensitivity for PSA detection that is within the clinical limit range of 0.4 to 0.1 ng/mL. The second application involved the creation of a novel sacrificial multilayer film. Films based in natural interactions of bovine submaxillary mucin and the lectin jacalin, BSM/JAC were assembled. BSM/JAC films showed stability when underwent a wide rage of pH (pH 3 to 9) and high ionic strength (5 M NaCl) solutions. BSM/JAC dissolution could be triggered released by incubation in melibiose at 37 °C in pH 7.4 buffer, without cytotoxicity. In the last part of this work the incorporation of echogenic liposomes (ELIP) into cell backpacks was investigated. Cell backpacks are 7-10 µm diameter patches that can be fabricated through LbL polymer deposition onto a photopatterned array to create a stacked composite of three stratified multilayer systems: a releasable region for easy detachment from the substrate, a drug payload region, and a cell adhesive region. The use of ELIP allowed up to 9x more doxorubicin (DOX) loading when compared to free drug in solution adsorbed through the films. DOX release from films was monitored for over 25 days. ELIP-DOX backpacks were then attached to mouse monocytes and their viability monitored by 72h. Empty backpacks showed to decrease monocytes proliferation over the course of 72h, while ELIP-DOX backpacks showed a dramatic decrease in cell population, showing that DOX effects were enhancement in drug potency by its proximity.
44
Tseng, Yun-Long, and 曾雲龍. "Targeted Cancer Therapy with Liposomal Doxorubicin." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/36883455445417114939.
Full textAbstract:
博士國立臺灣大學
生化學研究所
87
Steric stabilization by polyethylene glycol (PEG) can reduce opsonization of the liposome by plasma proteins. It has a higher plasma area under the concentration-time curve (AUC), which is believed to correlate with better therapeutic efficacy. However, the presence of large molecules on the liposomal surface may reduce interactions of liposomes with cells and hinder the entry of liposomes into the tumor tissue. Using a stable liposomal system composed of distearoyl phosphatidylcholine (DSPC)/cholesterol, we examined the effect of PEG (mol. wt.: 2000) on the pharmacokinetics and on the efficacy of liposomal doxorubicin with C-26 syngeneic tumor model in the BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol % PEG-modified distearoylphosphatidylethanolamine (PEG-DSPE) was about twice that of liposomal doxorubicin without PEG at various dosages, regardless of tumor bearing or not. Paradoxically, the tumor concentration of liposomal doxorubicin without PEG was higher. The 72-hour tumor AUC was 1.44 times that of liposomal doxorubicin with 6% PEG-DSPE. The tumor-accumulation efficiency (Te=AUCTumor/AUCPlasma) of liposomal doxorubicin without PEG was 0.87 and this was more than twice that of the liposomal doxorubicin with 6% PEG-DSPE (0.31). At the dose of 10 mg/kg, although both liposomal groups were better than free drug group in terms of clinic-relevant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between two liposomal drug groups. In this stable liposome system, surface coating with PEG (PEGylation) offered no benefit for liposomal doxorubicin in the C-26 tumor model. To enhance the therapeutic index of liposomal doxorubicin, just increasing plasma AUC by PEGylation may not be satisfactory. Pegylated liposomes results in smaller distribution volume and longer circulation time in blood and thus may improve drug targeting. The characteristics and therapeutic efficacy of immunoliposomes with similar liposomal formulation have never been studied in lymphoma models. We have developed immunoliposomes conjugated with S5A8 monoclonal antibody (MAb), an anti-idiotype antibody to 38C13 murine B-cell lymphoma, and loaded them with doxorubicin using an ammonium sulfate gradient. Purified antibodies were covalently coupled to the termini of PEG on the surface of small unilamellar liposomes. Cell binding and internalization ability of these immunoliposomes was estimated by a fluorescence assay using a pH-sensitive fluorescent dye (HPTS). In vitro cytotoxicity of doxorubicin encapsulated in immunoliposomes was greater for idiotype-positive 38C13 cells than that for idiotype-negative variant (V1-1) of this cell line. In syngeneic C3H/HeN mice, doxorubicin encapsulated in immunoliposomes exhibited long circulation time and was more effective in prolonging survival of mice bearing 38C13 tumor than non-targeted liposomal doxorubicin or free doxorubicin plus empty immunoliposomes. Our results demonstrate the superiority of targeted therapy with these immunoliposomes, and may have potential in cancer treatment.
45
Narainpersad, Nicolisha. "Cationic liposome mediated targeted gene delivery with and without pegylated accessories." Thesis, 2009. http://hdl.handle.net/10413/8352.
Full textAbstract:
As a consequence of safety issues encountered by the use of viral vectors in gene therapy,
there has been a steady increase in the development and application of non-viral vectors,
especially liposomes. Cationic liposome mediated delivery is one of the most promising nonviral
delivery methods. These liposomes are prepared from synthetic lipids, are positively
charged and interact favourably with DNA through electrostatic interactions. Cationic
liposomes have also shown immense potential in the targeting of specific cell types such as
HepG2 (hepatocellular carcinoma) cells, a model in vitro gene delivery system for the study
of hepatocyte function. However, these liposomes also have a number of limitations in vivo.
In an attempt to overcome these restrictions, a hydrophilic polymer, polyethylene glycol
(PEG) is incorporated into the cationic liposome. This covalent attachment of (PEG) to the
liposomal surface is thought to sterically stabilise liposomes, promote biological stability,
inhibit aggregation, decrease toxicity and immunogenicity, prevent interaction with serum
proteins and complement and thus prolonging the circulation time of liposomes in vivo. The
versatility and simplicity of cationic liposomes have made them vitally significant non-viral
gene delivery vehicles for human gene therapy.
In this investigation novel untargeted and targeted glycosylated liposomes with and without
PEG were synthesised to evaluate their gene transfer activities in vitro to potentially develop a
suitable gene delivery system for future in vivo applications. A constant molar quantity of the
cationic cholesterol derivative, 3 [N-(N’, N’-dimethylaminopropane)-carbamoyl]
cholesterol (CHOL-T) was mixed with dioleoylphosphatidylethanolamine (DOPE) and a
galactose/glucose derivative to produce targeted cationic liposomes. PEG liposomes were
prepared in the same way with the addition of distearoylphosphoethanolamine polyethylene
glycol 2000 (DPSE-PEG2000), 2% on a molar basis.
Supported by transmission electron microscopy characterisation, we present evidence that the
pegylation of liposomes affects the DNA binding capability and transfection efficiencies of
the cationic liposomes in addition to protecting the plasmid DNA in lipoplexes from serum
nuclease degradation. Optimal DNA : liposome binding ratios were obtained from gel
retardation studies and confirmed by ethidium bromide intercalation assays. These complexes
were then tested on the human hepatoma cell line, HepG2, to determine toxicity and assess
transfection efficiencies. From results obtained in this study, it appears that both cationic and
pegylated cationic liposomes are well tolerated by cells in vitro. The results further suggest
that targeting by use of glycolipids incorporated into the structure of the liposome increases
transfection, while pegylation of cationic liposomes marginally decreases the transfection
efficiency of the lipoplexes to HepG2 cells in vitro.Thesis (M.Sc.)-University of KwaZulu-Natal, 2009.
46
Dunne, Michael. "Quantitative In Vivo Assessment of Tumour Vasculature-targeted Liposomes." Thesis, 2010. http://hdl.handle.net/1807/30116.
Full textAbstract:
Targeting angiogenic vasculature has been validated as a viable approach for cancer imaging and therapy. The tumour vasculature-specific ligand asparagine-glycine-arginine (NGR) peptide targets the isoform of aminopeptidase N (CD13) expressed on endothelial cells lining angiogenic vessels. CD13 has become widely recognized as a rational target for therapeutic development and several NGR-conjugated agents are now in pre-clinical and clinical development. In the current study, a CT image-based approach is used to evaluate the in vivo performance of several NGR-conjugated liposome formulations that vary in terms of NGR density and PEG spacer arm length. Indeed, for the first time it is demonstrated that CT imaging can be used for quantitative and longitudinal assessment of the pharmacokinetics and biodistribution of an actively targeted liposome formulation. In comparison to conventional methods, CT imaging enables visualization of the intratumoural distribution of liposomes and quantification of the fraction of tumour occupied by the vesicles over time.
47
Nogueira, Eugénia Sofia Costa. "Development of folate-targeted liposomes for rheumatoid arthritis therapy." Doctoral thesis, 2015. http://hdl.handle.net/1822/40446.
Full textAbstract:
Tese de Doutoramento em Biologia Molecular e Ambiental (área de especialização em Biologia Celular e Saúde).Rheumatoid arthritis is a common, chronic inflammatory and destructive arthropathy with considerable personal, social and economic implications. Although the etiology of rheumatoid arthritis remains controversial, the hallmark of the disease is characterized by symmetrical inflammation of the synovial membrane of freely moveable joints, massive synovial proliferation and influx of inflammatory cells. Methotrexate is the first line therapy, but in intolerant patients biologic agents should be used. The development and clinical use of highly effective biological substances for standard treatment guidelines of rheumatic conditions treatment is a health economic problem due of being exceedingly costly. Activated macrophages are critical in the pathogenesis of rheumatoid arthritis and specifically express folate receptor β, a receptor for the vitamin folic acid. This receptor allows internalization of coupled cargo to folic acid by folate receptor-mediated endocytosis. Liposomes have gained extensive attention as carriers for a wide range of therapeutic agents because of being both nontoxic and biodegradable. This work aims to exploit the potential of folate-targeted liposomal nanoparticles as effective drug delivery systems for therapies directly targeting activated macrophages, reducing long term effects in rheumatoid arthritis patients. Specific targeting of activated macrophages is an important research challenge because they are phagocytic cells capable of internalizing any foreign particle. A complete stealth degree is needed to avoid the clearance of nanoparticles by macrophages of the reticuloendothelial system. Chapter II reports the study of surface modification of liposomes with the glycolipid monosialoganglioside and the polymer polyethylene glycol to improve stealth and decrease their clearance. Liposomes prepared with the monosialoganglioside clearly reduced macrophage uptake, but not to the same extent as liposomes prepared with 10% polyethylene glycol which ensure a proper stealth degree of the nanoparticles. The preparation of folate receptor-targeted liposomes, is typically performed by covalently attaching folic acid to a phospholipid or cholesterol anchor with polyethylene glycol and subsequent incorporation in the bilayer. Although these folic acid conjugates were shown to successfully target folate receptor α, there are some concerns regarding their use, namely chemical stability and self-aggregation at the liposome surface. Chapter III describes an innovative strategy for targeted liposomal delivery that uses a hydrophobic fragment of pulmonary surfactant protein D conjugated to a linker and folic acid. The peptide conjugate inserts deeply into the lipid bilayer without affecting liposomal integrity. The novel liposomal constructs are highly stable, specific for folate receptor α – expressing cells, and promote a more efficient liposomal membrane disruption than classic systems. The capacity of targeted liposomes to encapsulate and specifically deliver either hydrophobic or hydrophilic drugs into targeted cells was also demonstrated. The combination of all these characteristics of the new liposomes led us to evaluate its the efficiency to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages. Chapter IV reports the encapsulation of methotrexate in the new liposomal formulation, to enhance its tolerance and efficacy. The presence of 10% polyethylene glycol in the liposomes greatly improved the stealth degree, promoting the specificity of folic acid-mediated targeting. Liposomes strongly accumulated in the joints of arthritic mice, demonstrating their specificity in vivo. Furthermore, this liposomal formulation significantly increases the clinical benefit and complete prophylactic efficacy of methotrexate in an animal model. Chapter V reports a preliminary study on the use of the optimized liposome nanoparticles as siRNA carriers. Myeloid cell leukaemia-1 protein is essential for synovial macrophage survival. This study demonstrated that neutral liposomal formulation derived from DOPE phospholipid ensures that siRNAs molecules, are encapsulated inside the core of the liposomes with high polyethylene glycol content, reducing the toxicity associated to cationic liposomes. Chapter VI describe the establishments of a method to assess the disruption of nanoparticle drug delivery system in vitro using Hoechst 34580 a DNA binding dye, as a drug mimicker. This approach enables to correlate the intensity of a fluorescent dye with the nanoparticle disruption and consequent drug delivery in the cytoplasm of the cell. In summary, this work reports the use of liposomes prepared with a novel peptide conjugate for folic acid-mediated delivery, what creates new opportunities for the treatment of human diseases, namely rheumatoid arthritis and cancer.
A artrite reumatoide é uma artropatia inflamatória crónica comum e destrutiva, com consideráveis implicações pessoais, sociais e económicas. Embora a etiologia da artrite reumatoide permaneça controversa, a doença é caracterizada por inflamação simétrica da membrana sinovial de articulações móveis, intensa proliferação sinovial e influxo de células inflamatórias. O metotrexato é a terapia de primeira linha mas, em doentes intolerantes, devem ser usados agentes biológicos. O desenvolvimento e uso clínico de agentes biológicos altamente efetivos nas diretrizes de tratamento padrão de doenças reumáticas é um problema económico de saúde por serem altamente dispendiosos. Deste modo, estratégias mais eficazes têm de ser identificadas. Os macrófagos ativados têm papel vital na patogénese da artrite reumatoide e tem sido demonstrado que expressam especificamente o recetor de folato β, o recetor para a vitamina ácido fólico. Este recetor permite a internalização de ácido fólico acoplado a carga por endocitose. Os lipossomas são altamente atrativos como transportadores de vários agentes terapêuticos por serem não tóxicos e biodegradáveis. Este trabalho visa explorar o potencial dos lipossomas com folato como um sistema de libertação de fármacos eficaz para terapias direcionadas diretamente para macrófagos ativados, reduzindo efeitos a longo prazo em pacientes com artrite reumatoide. O direcionamento específico de macrófagos ativados é um importante desafio na investigação, porque estas células fagocíticas são capazes de internalizar qualquer partícula estranha. É necessário um grau de invisibilidade total, para evitar a remoção das nanopartículas por macrófagos do sistema reticuloendotelial. O Capítulo II reporta o estudo da modificação da superfície de lipossomas com o glicolípido monossialogangliosídeo e o polímero polietileno glicol para aumentar o grau de invisibilidade e diminuir a sua remoção. Os lipossomas preparados com o monossialogangliosídeo apresentam uma reduzida remoção pelos macrófagos, contudo não com a mesma extensão que lipossomas preparados com 10% de polietileno glicol, o qual assegura um grau de invisibilidade adequado nestas nanopartículas. A preparação de lipossomas direcionados para recetores de folato envolve normalmente a ligação covalente do ácido fólico a uma âncora de fosfolípido ou colesterol com polietileno glicol e sua incorporação na bicamada. Embora estes conjugados de folato tenham mostrado direcionar o vetor para o recetor de folato α, existem algumas preocupações subjacentes ao seu uso, nomeadamente estabilidade química e auto-agregação na superfície do lipossoma. O Capítulo III descreve uma estratégia inovadora para o direcionamento lipossomal que utiliza um fragmento hidrofóbico de proteína surfactante pulmonar D conjugada a um ligante e ácido fólico. O conjugado peptídico insere-se profundamente na bicamada lipídica sem afetar a integridade lipossomal. Estas novas construções são altamente estáveis, específicas para células que expressam o recetor de folato α e promovem a rutura da membrana lipossomal de forma mais eficiente do que o sistema clássico. Além disso, foi também demonstrada a capacidade destes lipossomas para encapsular e libertar especificamente nas células-alvo tanto fármacos hidrofóbicos como hidrofílicos. A combinação de todas estas características dos novos lipossomas levou-nos a avaliar a sua eficácia para o tratamento de artrite reumatoide, por direcionamento do recetor de folato β, presente na superfície de macrófagos ativados. O Capítulo IV relata o encapsulamento do metotrexato na nova formulação lipossomal para melhorar a sua tolerância e eficácia. A presença de 10% de polietileno glicol nos lipossomas melhorou significativamente o grau de invisibilidade, promovendo a especificidade de direcionamento mediada pelo ácido fólico. Os lipossomas acumulam-se fortemente nas articulações de ratinhos com artrite, demonstrando a sua especificidade in vivo. Além disso, esta formulação lipossomal aumenta significativamente o benefício clínico e apresenta uma total eficácia profilática do metotrexato num modelo animal. O Capítulo V reporta um estudo preliminar sobre a utilização dos lipossomas como transportadores de siRNA. A proteína myeloid cell leukaemia-1 é essencial para a sobrevivência de macrófagos do sinóvio. Este estudo demonstra que é possível utilizar uma formulação lipossomal neutra derivada do fosfolípido DOPE assegurando que os siRNAs são encapsulados no interior central dos lipossomas com concentração elevada de polietileno glicol, reduzindo a toxicidade associada aos lipossomas catiónicos. O Capítulo VI descreve o estabelecimento de um método para avaliar a disrupção de lipossomas como sistemas de libertação de fármacos in vitro, utilizando o Hoechst 34580, um corante que se liga ao DNA, para simular o fármaco. Esta abordagem permite correlacionar a intensidade de um corante fluorescente com a rutura das nanopartículas e consequente libertação da droga no citoplasma da célula. Em resumo, este trabalho reporta a utilização de lipossomas preparados com o novo conjugado peptídico, para direcionamento mediada por ácido fólico, abrindo novas oportunidades para o tratamento de doenças humanas, como artrite reumatoide e cancro.
Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/81269/2011 e UID/BIA/04050/2013.
48
Chen, Jung-Ying, and 陳容瑩. "The study of antisense oligonucleotides delivery by Tf-targeted liposomes." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/47554709606269818458.
Full textAbstract:
碩士臺北醫學大學
藥學研究所
97
Antisense oligonucleotides (ODN) are attractively therapeutic agents for cancer therapy. They are short fragments of nucleic acids and designed to target the complementary mRNA sequence to specifically interfere with gene expression and inhibit encoded protein production. Apoptosis is a physiological mechanism for selective elimination of cells, and regulated by the balance between many proteins during this process, such as Bcl-2, an essential inhibitory protein to apoptosis. Many cancer cells proliferate abnormally due to overexpression of Bcl-2. Therefore, to down-regulate the Bcl-2 expression, it is a potential strategy that delivered a phosphorothioate ODN (G3139) to Bcl-2 in targeting cells. However, ODN are easily destroyed by enzymes and nucleases in vivo and negtive charged molecules with high molecular weight make them the ability across cell membranes is poor. In this study, to improve antisense delivery, we developed a cationic lipid system, encapsulating ODN in lipid vesicles. The liposomes made up of DC-Chol/egg-PC/ PEG-DSPE (22.5:76:1.5 mol%) containing G3139 with a mean diameter of 190.94±11.13nm, a zata potential of 4.07±3.18mV and showed colloidal stability can maintain up to 11 weeks. Encapsulation efficiency of ODN in the liposomes was up to 70%. In order to enhance the targeting effect, transferrin (Tf)-PEG-DSPE was inserted into the lipid bilayer by post-insertion. Cell uptake of different formulations of liposomal ODN/FITC were observed by flow cytometry. The amount of ODN/FITC entering cells corresponds with the initial amount of ODN/FITC. In competition study, uptake of Tf-conjugated liposomes could be inhibited, when pre-treating free holo-transferrin 100μM to K562 cells, that were TfR positive . In the meantime, Bcl-2 protein level was evaluated by western blot to confirm G3139 work in selective cancer cells. The Bcl-2 protein level was down-regulation by G3139.
49
Yang, Tzu-Sheng, and 楊子聖. "Evaluation of multi-targeted and single-targeted liposomal drug treating for gastric cancer." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/27x48f.
Full textAbstract:
碩士國立臺北科技大學
生物科技研究所
95
Liposome as a carrier encapsulate anti-cancer drugs has always regard as an interesting topic in clinical research. In this study, we develop a targeting anti-cancer liposome that has a specific target molecule by synthesis, which has potential to directly target to the specific cancer. First, we made Octreotide and RGD respectively conjugated with DSPE-PEG, and then we made DSPE-PEG-Octreotide and DSPE-PEG-RGD integrated to lipid bilayer, which is called Octreotide(RGD)-PEG-liposome, also we encapsulated dihydrotanshinone I as the anti-cancer drug.The results showed that the graft density of DSPE-PEG-Octreotide and DSPE-PEG-RGD was 69% and 85%. In addition, we made liposome with different composition (Octreotide-PEG-liposome, RGD-PEG-liposome, PEG-liposome, and Octreotide/RGD-PEG-liposome, with 10mM lipid concentration). The anti-cancer activity was investigating by in virto and in vivo test. The in vitro study we used different liposomes treat with AGS human gastric adenocarcinoma. Cytotoxicity effect showed that Octreotide/RGD-PEG-liposome is obviously superior to other component (the survival rate of Octreotide：12.8%, RGD：20.1%, PEG：15.7% and Octreotide/RGD：2.3%, respectively) after 24 hours treatment. Also in vivo study result showed that tumor bearing mice i.v. injected with Octreotide/RGD-PEG-liposome also evident to inhibit growth of tumor size (the tumor volume after treatment/original volume of Octreotide：64.8%, RGD：102.9%, PEG：92.8%, Octreotide/RGD：61.2%, respectively). In these results, multi-targeted liposomal drug has better potential to inhibit tumor cell proliferation than single-targeted liposomal drug, it may be a new direction of liposomal development in the future.
50
Cheng, Yu Hsin, and 鄭宇欣. "Cetuximab-conjugated thermo-sensitive magnetic liposome for targeted delivery of Irinotecan in glioma treatment." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/22960061794700763749.
Full text