Academic literature on the topic 'Teranostica'

The functional optimization of the composition of radiopharmaceutical pairs based on the prostatespecific membrane antigen (PSMA) for the radionuclide theranostics of castration-resistant prostate cancer was carried out. The analysis of radiation-physical and dosimetric characteristics of 9 radionuclides for diagnostic components of theranostic pairs and 6 radionuclides for therapeutic components is carried out. It was shown that positron-emitting radionuclides 18F and 68Ga should be considered optimal for the diagnosis and monitoring of the effectiveness of theranostics, and 177Lu beta-emitting radionuclide and 225Ac alphabeta-emitting radionuclide should be considered as the radionuclide therapy. The values of the total and organ radiation risks of secondary radiation-induced cancers in patients who have completed several courses of theranostics are calculated. It is shown that for 2 teranostic pairs based on 177Lu‑PSMA the radiation risk is higher than significant, while for 2 teranostic pairs based on 225Ac the risk falls within the range of a significant level. The calculated radiological criteria for discharge of patients after a course of theranostics from nuclear medicine departments show the fundamental possibility of performing an outpatient treatment regimen using any of the 4 considered theranostic pairs.

XVII Zjazd Polskiego Towarzystwa Medycyny Nuklearnej odbył się w Białymstoku w dniach 26-28.05.2022r. Wykład inauguracyjny pt.: „Rozwój medycyny nuklearnej w Uniwersytecie Medycznym w Białymstoku dziś i jutro” wygłosił rektor białostockiej uczelni prof. Adam Krętowski. W zjeździe uczestniczyło 450 osób z kraju i zagranicy: pracowników nauki, specjalistów, klinicystów oraz przedstawicieli wszystkich grup zawodowych związanych z ośrodkami medycyny nuklearnej. Zjazd Polskiego Towarzystwa Medycyny Nuklearnej to największe w kraju wydarzenie skierowane bezpośrednio do tego środowiska. Wiodącym tematem spotkania była teranostyka nuklearna, czyli spersonalizowana terapia izotopowa. Oprócz innowacyjnego zastosowania medycyny nuklearnej w onkologii, endokrynologii, kardiologii, neurologii czy endokrynologii, ważne miejsce w programie zajmowały także sesje dotyczące roli sztucznej inteligencji w diagnostyce i terapii radioizotopowej, nowoczesnej radiofarmacji oraz przedklinicznych metod obrazowania nuklearnego, jako głównego narzędzia do opracowywania terapii molekularnych.

Nanopartikel Zink Oksid (ZnO-NP) merupakan suatu material yang dapat digunakan sebagai nanoplatform dalam sistem penghantaran obat sekaligus pencitraan biologis karena karakteristiknya yang unik. Penelitian ini bertujuan untuk mensintesis serta mengevaluasi pengaruh inkorporasi dua dopant (co-doping) magnesium (Mg2+) dan besi (III) (Fe3+) terhadap karakteristik optik dan struktur dari ZnO-NP. ZnO-NP (tanpa dopan, dengan dopan tunggal dan dengan dopan kombinasi) disintesis lewat jalur kimiawi dengan menggunakan metode ko-presipitasi sederhana. Larutan Zink Klorida dalam air digunakan sebagai material awal dan diendapkan dengan menambahkan Natrium Hidroksia dengan perbandingan molar 1:2. Sampel dikarakterisasi dengan menggunakan spektrofotometer UV-Visible dan Powder X-Ray Diffractometer (P-XRD). Hasil analisis sifat optik menunjukkan serapan maksimum sampel berada pada kisaran 361- 367 nm dan kalkulasi nilai bandgap berdasarkan data serapan tersebut berada pada rentang 3,09-3,23 eV. Difraktogram sampel menunjukkan sampel yang terbentuk adalah ZnO-NP dengan struktur kristal hexagonal wurtzite. Dari data difraktogram yang diperoleh, besar ukuran butir diestimasi dengan beberapa persamaan dan diketahui rentang diameter kristal berada pada kisaran 17,25 hingga 27,74 nm. Dari hasil penelitian ini dapat ditarik kesimpulan bahwa inkorporasi dopan Mg2+/Fe3+ mempengaruhi karakteristik ZnO-NP. Perubahan karakterisik ini dapat mempengaruhi performa nanomaterial ini sebagai agen teranostik.

Sisternografi radionuklida sering digunakan untuk membuktikan adanya kebocoran cairan serebrospinal dari hidung atau telinga serta melokalisasi lokasi kebocoran. Aktif tidaknya kebocoran pada saat pemeriksaan sangat mempengaruhi hasil pemeriksaan sisternogram radionuklida. Kami melaporkan kasus yang jarang dilakukan pemerikaan dengan menggunakan sisternografi radionuklida pada pasien wanita berumur 56 tahun. Pasien memiliki keluhan utama keluar cairan dari hidung, apatis dan lemas. Keluar cairan terutama dirasakan saat pasien duduk. Pasien memiliki riwayat operasi transsphenoid atas indikasi pengangkatan tumor di epifisis. Pemeriksaan sisternografi dilakukan di Departemen Kedokteran Nuklir dan Teranostik Molekuler untuk meyakinkan adanya kebocoran cairan liquor dan lokasi kebocoran pada pasien tersebut. Pencitraan dilakukan pada 1,3,6 jam setelah penyuntikan 99mTc-DTPA intratekal. Tampak penangkapan radioaktivitas yang meningkat pada area nasal terutama pada pencitraan jam ke 3. Pencitraan fusi SPECT/CT memberikan lokasi yang tepat kebocoran cairan liquor di area os sfenoid pada jam ke 3. Rasio tampon hidung dan serum darah adalah 4:1. Terapi bagi pasien adalah operasi penutupan kembali kebocoran.

The issue of improved diagnosis of both rheumatic diseases of the elderly and aortic diseases does not lose its relevance. In terms of aortic aneurysms, dissection and ruptures and their attended pathogenesis, both inflammation and structural wall damages may be detected with imaging methods whose role is vital. A number of international guidelines deal with the ma­nagement of polymyalgia rheumatica, giant cell arteritis, or aortic aneurysms. Aortitis is associated with up to 40 % of polymyalgia rheumatica’s cases. The clinical suspicion of aortitis is based on the detection of blood pressure and pulse asymmetry, aortic regurgitation murmur, vascular bruits, as well as persistent polymyalgia rheumatica or inflammatory dorsalgia, pelvis or leg pain. In 2020, the positron emission tomography/computed tomography’s use is approved by the Italian Society for Rheumatology for the diagnosis of vasculitis attended by polymyalgia rheumatica at the secon­dary healthcare level and by the European Headache Federation for the diagnosis of large vessel giant cell arteritis in the neurological practice. A review of the guideline by the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the American Society of Nuclear Cardiology (2018) was performed in terms of po­sitron emission tomography with fluorodesoxyglucose combined with computed tomography (angiography) imaging in large vessel vasculitis and polymyalgia rheumatica. It is further compared with the clinical guidelines, other guidelines by the societies of nuclear medicine and new scientific data. Both procedure and patient’s preparation for examination are decribed. The criteria for assessing vasculitis proposed for either clinical practice or cli­nical studies are consi­dered, as well as the factors influencing the test results and their interpretation (such as atherosclerosis, diabetes, age, body mass index, glucemia’s and acute phase markers’ levels). The guideline substantiates the benefit of both positron emission tomography’s use and its combination with computed tomography to detect extracranial vasculitis, as well as the va­lue of performing computed tomography-angiography at different stages of the disease. There is a need to strengthen evidence on both standard time of fluorodesoxyglucose exposure and the benefit of combining positron emission tomography with computed tomography-angiography, in particular for detection of vasculitis relapses. Finding a consensus for early test’s performing is nee­ded, as well as its score standardization, ensuring reimbursement and implementation of new imaging techniques for the cranial vessels. In the future, the evidence-based approach to managing vasculitis will be supplemented by teranostics.

In this work, hybrid magnetite-gold nanoparticles have been obtained, which have high contrast characteristics in magnetic resonance imaging and heat-release characteristics in magnetic particle hyperthermia, demonstrated in vitro.

La prospettiva della teranostica è quella di effettuare contemporaneamente diagnosi e cura, individuando le singole particelle tumorali. Questo è possibile grazie a nanoparticelle magnetiche, entità multifunzionali rivestite da un polimero, accompagnate nel luogo di interesse mediante un campo magnetico esterno. Per quanto riguarda la diagnosi possono essere utilizzate come agenti nella risonanza magnetica nucleare per aumentare il contrasto dell’immagine e consentire una migliore rivelazione del tumore. Per quanto riguarda la terapia esse sono utilizzate per l’ipertermia magnetica, tecnica basata sul riscaldamento mediante l’applicazione di un debole campo magnetico alternato dotato di un’opportuna frequenza. In questo modo le cellule tumorali, essendo più sensibili al calore rispetto a quelle sane, vengono distrutte, una volta raggiunta una temperatura locale tra i 41 e i 46°C. Un’altra grande applicazione terapeutica è il rilascio controllato e mirato dei farmaci (drug target delivery). Infatti un opportuno rivestimento polimerico consente di coniugare alla particella dei medicinali chemioterapici che, una volta raggiunta la zona tumorale, possono essere rilasciati nel tempo, permettendo dunque la somministrazione di una minor dose e un’azione più mirata rispetto ai classici trattamenti. I materiali maggiormente utilizzati per la sintesi delle nanoparticelle sono gli ossidi di ferro (come la magnetite Fe3O4 e la maghemite γ − Fe2O3) e l’oro. Tuttavia, nonostante i possibili vantaggi, questi trattamenti presentano degli effetti collaterali. Trattandosi infatti di particelle ultrafini, dell’ordine dei nanometri, possono migrare all’interno del corpo umano raggiungendo organi bersaglio e comprometterne il loro funzionamento. La teranostica, però, è una disciplina molto studiata e in via di sviluppo; si spera che da qui a breve sia possibile un utilizzo concreto di questi nuovi metodi, riducendo al minimo la tossicità per il corpo umano.

The research described in the present PhD Thesis has been conducted in the context of a multicenter FP7 European Project called THALAMOSS (THalassemia MOdular Stratification System), having as major objective the identification of molecular markers for the development of personalized therapies for hemoglobinopathies, in particular ß-thalassemia. The ß-thalassemias are an autosomal recessive genetic disorders caused by the absence or reduction of ß-globin chains of adult hemoglobin, for which targeted and definitive treatments are, at present, not available. In order to sustain project based on stratification of ß-thalassemia patients according to clinical, genetic and molecular features, we established a systematic collection of cellular samples, the cellular Biobank, containing hematopoietic stem cells isolated from the peripheral blood, expanded, freezed and cryopreserved. To this aim, 75 subjects comprising ß-thalassemia patients and healthy donors have been recruited up to now. They were all characterized for the genotype (in order to detect pathogenic mutations) and possible fetal hemoglobin (HbF)-associated polymorphisms. More importantly, new protocols to efficiently isolate, culture, freeze and thaw hematopoietic stem cells were developed. In particular, we demonstrated that freezing, cryopreservation and thawing steps do not affect the erythroid differentiation potential of the cells and the natural erythroid differentiation process, in terms of kinetics and types of hemoglobin produced by the cells of the same patient. Moreover, we found that the cells stored in the Biobank are responsive, once thawed and sub-cultured, to treatments with known HbF inducers, including mithramycin, resveratrol, butyric acid and hydroxyurea, and are therefore suitable for the identification and development of new HbF inducers to be used for experimental therapeutic strategy for ß-thalassemia. In this context, we demonstrated that the induction effects depend on the subject’s genotype, strongly suggesting that this approach could be very useful to develop personalized therapies. In conclusion, this research activity will allow patients stratification taking into account all the phenotypic/genotypic characteristics of the single individual, in association with in vitro HbF induction under treatment with effective inducers, providing an important opportunity for the research and development of novel therapeutic strategies for ß-thalassemia.

Lipid liquid crystalline nanoparticles can find application as nanocarriers in several fields of the daily life but, very likely, the pharmaceutical arena is the most relevant. Indeed, several problems encountered in drugs administration (e.g. critical sideeffects from antitumor drugs) require alternative, less invasive, but simultaneously efficient therapeutic routes to be explored. Novel fields of personalized nanomedicine are developing in this direction. One of the most interesting is theranostic, which calls for the design of platforms capable of combining therapeutic and diagnostic functionalities. In this optic, we explored the potential of monoolein-based cubosomes and hexosomes as nanocarriers for theranostic purposes. Our work focussed on the design of lipid nanoparticles able to deliver antineoplastic drugs and imaging probes for fluorescent optical in vitro and in vivo imaging. We developed cubosome formulations loaded with antineoplastic drugs and useful for the fluorescence imaging of cells. Such formulations were also actively targeted to cancer cells and coupled with a NIR-emitting fluorophore, which was the promise for in vivo applications. We also investigated hexosomes with encouraging results encapsulating in their lipid matrix a BODIPY derivative with solvatochromic properties, helpful for the understanding of the dye localization. Importantly, we reported (manuscript submitted) the first proof-of-principle for in vivo fluorescence optical imaging application using monoolein-based cubosomes in a healthy mouse animal model. Finally, since relatively little is known about the interaction of cubosomes with biological systems, their effects on lipid droplets, mitochondria and lipid profile of HeLa cells were deeply studied. This thesis is divided in two main parts. The introduction section reports on the essential background of the research field, and it is followed by the publications (published or submitted) resulting from these three years of work.

Master thesis deals with the use of bacteriophage as a theranostic drug nanocarrier. The term theranostics is used in recent years for systems that allow connecting of diagnostics, targeted drug delivery and monitoring of patient’s response to administered treatment in a single modality. These systems are very suitable especially with heterogeneous diseases, such as cancer. Nowadays, the treatment of cancer has often severe side effects to the patient’s body, which lowers his capability to fight the disease. Theoretical part of this work is focused on the properties of viral capsids, proteins and inorganic materials as drug nanocarriers. In practical part of this work, different methods for cultivation of bacteriophage are compared, both in liquid and solid medium and with different concentrations of the maltose, trough whose receptors bacteriophage is able to enter the host cell. Optimal was cultivation with 0.2% maltose in solid medium. Practical part is focused mainly on the use of bacteriophage as a nanocarrier for cytotoxic drug doxorubicin. Bacteriophage was able to encapsulate all applied concentrations of doxorubicin (0; 12.5; 25; 50; 100 and 200 g/ml), which was proved using fluorescent detection. Different times of encapsulation (2; 4; 8 and 12 hours) were studied. Optimal time was 2 hours. Encapsulation properties of bacteriophage were compared to apoferritin. Bacteriophage was able to encapsulate 4× higher concentrations of doxorubicin and its release during rinsing with water was 10× lower compared to apoferritin. This work concludes that bacteriophage is a very suitable platform for targeted drug delivery in theranostics.

Se opportunamente sfruttata, l'emissione radioattiva di radioisotopi metallici può essere utilizzata per la diagnosi, il trattamento e il monitoraggio del cancro. La combinazione di imaging e terapia in una ‘coppia abbinata’ di radioisotopi dà origine al concetto di ‘teranostico’, un paradigma di gestione clinica emergente in cui il trattamento del paziente è pianificato secondo un regime terapeutico personalizzato. Mentre nei decenni passati venivano impiegati solo pochi radiometalli, a causa della difficoltà insita nella loro produzione, oggigiorno è disponibile una varietà sempre più ampia di radionuclidi metallici rari, che offrono una scelta più varia di energie e proprietà di decadimento, e quindi hanno il potenziale di migliorare i percorsi diagnostici e terapeutici secondo le esigenze del paziente, così come definito dal principio della medicina personalizzata. Queste coppie teranostiche includono i radionuclidi esotici, argento-103/104/111 (103/104/111Ag) e mercurio-197m/g (197m/gHg) e quelli non-standard, piombo-203/212 (203/212Pb) e rame-64/67 (64/67Cu). Per indirizzare con successo la radiazione al bersaglio molecolare desiderato, gli ioni radiometallici devono essere fortemente legati da un chelante coniugato ad una molecola biologicamente attiva. Tuttavia, ad oggi, non esistono chelati stabili in vivo per [103/104/111Ag]Ag+ e [197g/mHg]Hg2+ che consentano di sfruttare il loro potenziale teranostico. Inoltre, i leganti esistenti non sono adatti in vivo per 64/67Cu poiché la stabilità dei complessi di [64/67Cu]Cu2+ è compromessa dalla riduzione di Cu2+ a Cu+, innescata biologicamente, che può portare a processi di demetallazione. Di conseguenza, il radiometallo non legato può diffondersi attraverso il corpo portando a una perdita di selettività per il sito target che dev’essere visualizzato o trattato. Analogamente, restano irrisolti i problemi della dissociazione di [203/212Pb]Pb2+ combinati con il complessamento stabile del suo radionuclide figlio bismuto-212. Lo scopo di questa tesi è quello di esplorare nuovi agenti chelanti per le coppie teranostiche borderline-soft Ag+, Cu2+/+, Pb2+ e Hg2+, per risolvere i problemi legati al loro complessamento non sufficientemente stabile e per facilitare la loro traslazione clinica. A tale scopo è stata progettata e sintetizzata una famiglia di poliazamacrocicli contenenti donoratori solforati. Per ottimizzare le proprietà di coordinazione dei chelanti sono stati variati diversi parametri strutturali come le catene laterali, ed è stata considerata un'ampia gamma di scaffold macrociclici. La chimica di coordinazione acquosa dei complessi metallici corrispondenti è stata studiata valutandone la stabilità termodinamica, la cinetica di formazione e dissociazione e le proprietà strutturali. Sono stati eseguiti esperimenti di radiomarcatura con i radioisotopi corrispondenti per valutare l'efficienza di complessamento in condizioni estremamente diluite. Come valutazione finale del potenziale dei leganti proposti per applicazioni teranostiche, sono stati eseguiti saggi di stabilità in vitro dei complessi radiometallici risultanti.
When appropriately harnessed the radioactive emission of metallic radioisotopes can be exploited to image, treat and monitor cancer. The combination of imaging and therapy in a ‘matched pair’ of radioisotopes gives rise to the concept of ‘theranostic’, an emerging clinical management paradigm where patient treatment is planned according to an individually tailored therapeutic regime. Although in past decades only a few radiometals were employed due to the difficulty inherent to their production, nowadays an increasingly wide variety of rare metallic radionuclides are available, providing larger choice among decay energy and properties, and thus having the potential to improve diagnostic and therapeutic routes according to patient needs, as defined by the principle of personalized medicine. These theranostic pairs include the exotic silver-103/104/111 (103/104/111Ag) and mercury-197m/g (197m/gHg) and the non-standard lead-203/212 (203/212Pb) and copper-64/67 (64/67Cu). To successfully deliver the radiation to the desired molecular target, radiometal ions need to be securely bound by a chelator coupled to a biologically active molecule. However, to date, no in vivo stable [103/104/111Ag]Ag+ and [197g/mHg]Hg2+ chelates exist to harness their theranostic power. Moreover, existing ligands do not perform well in vivo for 64/67Cu as the stability of [64/67Cu]Cu2+-complexes is thwarted by the biologically triggered redox switching between Cu2+ and Cu+ that may bring to demetallation processes. As a consequence, the unbound radiometal can spread through the body leading to a loss of selectivity for the target to be imaged or treated. Analogously, the issues of the [203/212Pb]Pb2+-dissociation combined with the stable complexation of its daughter radionuclide bismuth-212 remain unsolved. The aim of this thesis is to explore novel chelating agents for the borderline-soft theranostic couples Ag+, Cu2+/+, Pb2+ and Hg2+, to circumvent the shortcomings in their stable complexation and to facilitate their clinical translation. For this purpose, a family of polyazamacrocycles bearing sulphanyl arms were designed and synthesized. To optimize the coordination properties of the chelators several structural parameters were tuned such as different pendant coordinating arms and a wide range of macrocyclic scaffolds rings. The aqueous coordination chemistry of the corresponding metal complexes was investigated assessing their thermodynamic stability, formation and dissociation kinetics and structural properties. Radiolabeling experiments were performed with the corresponding radioisotopes to evaluate the complexation efficiency in extremely diluted conditions. As a final assessment of the potential of the proposed ligands for theranostic applications, in vitro stability assays were executed with the resultant radiometal complexes.

This diploma thesis focuses on the preparation of the liposomes, containing lipids with gadolinium, which are used for a contrast magnetic resonance imaging. The liposomes were prepared by the lipid film hydration followed by an extrusion and also by a new nanofluid mixing method on the NanoAssemblr Benchtop. The preparation technology has been optimized for parameters such as the composition of lipids, the flow rate ratio and total flow rate. The method of modification of the liposomes surface by gadolinium complexes has been developed. This method is using a conjugation reaction between the lipids containing cyanuric acid and Gd-DOTA. Prepared Gd-liposomes, which contain gadolinium, were complexly defined by the characterization techniques of DLS and NTA. The morphology of liposomes was observed by TEM and cryo-TEM. Methods for the determination of phospholipid content (Stewart test) and residual water in the lyophylisates of liposomes (Karl-Fischer titration) were used. Gadolinium in liposomal preparations was determined by ICP-OES. Using MR, the concept of gadolinium liposomes was verified and designed for MRI imaging of thrombi. The concept describing the mechanism of liposomes formation based on the experimentally proven existence of a phospholipid bilayer fragment has been developed. This concept is based on the experimentally proven existence of a phospholipid bilayer fragment.

Il lavoro di ricerca si è occupato della sintesi, caratterizzazione e studio delle proprietà antitumorali in vitro e in vivo di un sistema ibrido inorganico-organico, costituito da una nanoparticella magnetica di magnetite e la proteina umana ferritina. La tesi descrive le procedure sintetiche che hanno permesso la realizzazione di una piattaforma dalle applicazioni teranostiche, lo studio delle caratteristiche e degli utilizzi in nanomedicina, ed infine la verifica delle proprietà antitumorali sia in vitro che in vivo. I risultati ottenuti dimostrano l'efficacia del sistema realizzato nell'uccidere le cellule tumorali in vitro e nel ridurre la crescita della massa tumorale in vivo. This research present the synthesis, characterization and study of antitumoral effectiveness both in vitro and in vivo of an inorganic-organic hybrid system, composed by a magnetic nanoparticle of magnetite and the human protein ferritin. The thesis describes the procedures followed to create the theranostic platform, the study of its characteristics and its uses in nanomedicine, and finally the verification of the antitumor properties by both in vitro and in vivo analysis. The obtained results demonstrate the effectiveness of the system in killing tumor cells in vitro and in reducing the growth of tumor mass in vivo.

Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...

Theranostics is connecting two medical branches, diagnostic and therapy. It enables transport of drugs and diagnostic imaging in one step. Nanoparticles, nanotubes, lipozomes or apoferritin can be used as platform for targeted transport. Apoferritin (APO) is a protein from ferritin family, which is characterized by an empty cavity. Is possible encapsulate some cargo (e.g., drug) into this cavity. Encapsulation is done by pH change. There is a possibility to modify APO surface. It causes targeted transport to for example cancer cells. In this study, process of preparation of targeted nanotransporter based on APO is described; next, its characterization by in vitro experiments is shown. The prepared targeted nanotransporter delivered drug to cancer cells and in the same time was decreased toxicity on surrounding tissue and organs.