Dissertations / Theses on the topic 'Peptide receptor radiolabelled therapy'

Depuis plusieurs années, la radiothérapie interne vectorisée (RIV) est devenue une thérapie efficace dans la prise en charge des cancers de la prostate métastatique résistant à la castration, forme rare au pronostic très péjoratif. Cette approche théranostique se repose sur l'administration d'un médicament radiopharmaceutique (MRP), molécule vectrice radiomarquée qui cible spécifiquement l'antigène membranaire spécifique de la prostate (PSMA) surexprimée à la surface des cellules cancéreuses. Le MRP peut être à visée diagnostique permettant une imagerie TEP (tomographie par émission de positons) ou à visée thérapeutique délivrant localement un rayonnement ionisant, initiant des dégâts irréversibles au niveau de l'ADN des cellules tumorales et induisant leur mort. Malgré des résultats cliniques prometteurs, l'accès à la RIV reste limité et son application est réservé à des patients porteurs de tumeurs à un stade avancé de la pathologie. De plus, une accumulation non négligeable du MRP dans les organes d'élimination (e.g., rein, foie) et les organes du système immunitaire induit des effets indésirables impactant le bien être du patient. L'un des défis consiste à assurer une diffusion rapide dans toute la tumeur des agents de liaison tout en maintenant ou améliorant la fixation spécifique à la tumeur, afin de réduire les doses injectées. L'émission d'ondes ultrasonores combinée à l'injection intravasculaire de microbulles de gaz fournit des alternatives sans précédent comme méthode adjuvante pour la délivrance locale de molécules thérapeutiques. En effet, la vibration des microbulles sous l'effet des ultrasons entraîne une perméabilisation transitoire des barrières biologiques (e.g., barrière hémato-tumorale). Cette technique, appelée sono-perméabilisation potentialise l'extravasation de molécules thérapeutiques dans la région d'intérêt en augmentant leur biodisponibilité uniquement dans la zone où les ondes sont focalisées. L'objectif de la thèse est d'optimiser par TEP, la délivrance locale du MRP au sein de la tumeur de la prostate par sono-perméabilisation. Cette approche permettra de répondre aux questions cruciales de la diminution de la dose d'injection et donc de la radiotoxicité sur les organes sains pour aller vers une médecine du futur personnalisée et moins délétère pour le patient. Pour cela, des études in vitro ont été réalisées afin d'évaluer l'impact de la sono-perméabilisation sur la perméabilité membranaire. Les protocoles ultrasonores ont ainsi été validées sur deux modèles cellulaires : un modèle en suspension de cancer de la prostate métastatique (LNCaP) et un modèle perméabilité épithéliale (MDCKII-MDR1). L'impact de la sono- perméabilisation a été ensuite évaluée dans un modèle préclinique murin sous cutanée du cancer de la prostate. Cette étude in vivo a permis d'évaluer la biodistribution d'un MRP à usage diagnostique dans un premier temps ([¹⁸F]F-PSMA-1007), utilisé en routine clinique au sein de notre laboratoire par imagerie TEP/tomodensitométrie (TDM). Le dernier axe actuellement en cours est d'évaluer l'efficacité thérapeutique de la sono-perméabilisation combinée avec le MRP thérapeutique ([¹⁷⁷Lu]Lu-PSMA-617). Cet axe permettra de calculer par la suite la posologie optimale afin d'atteindre la dose thérapeutique efficace tout en minimisant l'accumulation du MRP dans les tissus sains. Ce projet pourrait ouvrir la voie à des études combinant la sono-perméabilisation avec d'autres traitements comme l'immunothérapie sur les tumeurs prostatiques ou encore des études cliniques pour évaluer l'efficacité de cette technique chez les patients
For several years, peptide receptor radiolabelled therapy (PRRT) has become an effective therapy for managing metastatic castration-resistant prostate cancer, a rare form with a very poor prognosis. This theranostic approach relies on the administration of a radiopharmaceutical (RP), a radiolabelled vector molecule that specifically targets the prostate-specific membrane antigen (PSMA) overexpressed on the surface of cancer cells. The RP can be diagnostic, allowing for PET imaging (positron emission tomography), or therapeutic, delivering ionizing radiation locally, causing irreversible damage to the DNA of tumor cells and inducing their death. Despite promising clinical results, access to VIRT remains limited, and its application is reserved for patients with advanced-stage tumors. Additionally, a significant accumulation of the RP in elimination organs (e.g., kidneys, liver) and immune system organs induces adverse effects impacting the patient's well-being. One challenge is ensuring rapid diffusion of binding agents throughout the tumor while maintaining or improving specific tumor binding to reduce injected doses. The emission of ultrasound waves combined with the intravascular injection of gas microbubbles provides unprecedented alternatives as an adjunctive method for the local delivery of therapeutic molecules. Indeed, the vibration of microbubbles under ultrasound induces transient permeabilization of biological barriers (e.g., the blood-tumor barrier). This technique, called sonopermabilization, enhances the extravasation of therapeutic molecules in the region of interest by increasing their bioavailability only where the waves are focused. The aim of the thesis is to optimize the local delivery of the RP within the prostate tumor using sonopermabilization through PET. This approach will address crucial questions regarding the reduction of injected doses and thus radiotoxicity to healthy organs, moving towards a future of personalized medicine that is less harmful to the patient. To achieve this, in vitro studies were conducted to evaluate the impact of sonopermabilization on membrane permeability. Ultrasound protocols were validated on two cellular models: a suspension model of metastatic prostate cancer (LNCaP) and an epithelial permeability model (MDCKII-MDR1). The impact of sonopermabilization was then evaluated in a preclinical murine subcutaneous model of prostate cancer. This in vivo study allowed for the assessment of the biodistribution of a diagnostic RP initially ([¹⁸F]F- PSMA-1007), routinely used in our laboratory for PET/computed tomography (CT) imaging. The latest focus is to evaluate the therapeutic efficacy of sonopermabilization combined with the therapeutic RP ([¹⁷⁷Lu]Lu-PSMA-617). This will subsequently allow for the calculation of the optimal dosage to achieve an effective therapeutic dose while minimizing accumulation of RP in healthy tissues. This project could pave the way for studies combining sonopermabilization with other treatments such as immunotherapy for prostate tumors, or clinical studies to evaluate the effectiveness of this technique in patients

O câncer de próstata é considerado o segundo mais comum na população masculina em todo o mundo e ocupa a 15ª posição em mortes por câncer, em homens, representando cerca de 6% do total de mortes por câncer no mundo. O antígeno de membrana prostático específico (PSMA) é uma glicoproteína tipo II transmembrânica superexpressa no câncer de próstata, suas metástases e em neovascularizações relacionadas a tumores sólidos, que tem estimulado o desenvolvimento de pequenas moléculas inibidoras do receptor de PSMA, que carreguem agentes terapêuticos. Este trabalho pretendeu estudar de forma inédita a marcação e estabilidade radioquímica do Glu-NH-CO-NH-Lys(Ahx)-DOTA com 177Lu (PSMA-DOTA-177Lu) e avaliar seu potencial para a terapia do câncer de próstata. O radiofármaco foi obtido com pureza radioquímica elevada (PR > 95%) em todas as condições estudadas e permaneceu inalterada em ≤ - 20 °C até 48 horas, mesmo em atividade específica alta (74 MBq/μg). O ensaio de ligação específica do PSMADOTA- 177Lu mostrou que a fração do peptídeo que se ligou às células LNCaP de tumor de próstata foi de 1,79 ± 0,21 %, 2,47 ± 0,03 %, 3,07 ± 0,01 % e 4,13 ± 0,27%, para as concentrações de 0,15 x 106, 0,3 x 106, 0,5 x 106 e 1 x 106 células, respectivamente. O ensaio de internalização do PSMA-DOTA-177Lu sugere que o maior percentual da ligação específica do radiofármaco às células LNCaP corresponde à fração da ligação de superfície (99,03 ± 0,84 %). Os parâmetros farmacocinéticos determinados no estudo in vivo em camundongos Balb/c são compatíveis com o rápido clareamento sanguíneo e excreção renal, além de apresentar apreciável captação tumoral in vivo (2,76 ± 1,21 % Al/g) após 4 horas de administração do radiofármaco. Os estudos em estabilidade em soro humano demonstram estabilidade alta do radiofármaco PSMA-DOTA-177Lu por um período de até 24 horas, que foi confirmada pela baixa captação óssea demonstrada nos estudos in vivo de biodistribuição. O estudo de variação da atividade possibilitou estabelecer a atividade específica ideal (MBq/μg), que será extrapolada para um piloto de produção do radiofármaco. Os resultados favoráveis deste estudo encorajam a perspectiva de realização de ensaio clínico controlado deste novo radiofármaco, avaliando seu potencial para aplicação no tratamento do câncer de próstata.
Prostate cancer is the second most frequently worldwide diagnosed cancer among males and ranks the 15th common cause of death from cancer in men, comprising 6% of the world\'s total cancer deaths. The prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein, which is overexpressed in prostate cancer as well as in the neovasculature of solid tumors and metastasis. These features render PSMA an ideal target for developing small molecules inhibitors of PSMA and therapeutic approaches to targeted drugs delivery. This work intended to study in an unprecedented way the radiochemical labeling and stability of Glu-NHCO- NH-Lys (Ahx)-DOTA with 177Lu (177Lu-PSMA-DOTA) and its potential anti-tumor effects in prostate cancer. The radiopharmaceutical PSMA-177Lu was obtained with high radiochemical purity (RP > 95%) under all studied conditions and remained unchanged up to 48 hours (high at ≤ -20 °C), even at high specific activity (74 MBq / μg). The cellular uptake of PSMA-DOTA-177Lu was determined using PSMAexpressing LNCaP cells and showed a binding of 1.79 ± 0.21%, 2.47 ± 0.03%, 3.07 ± 0.01% and 4.13 ± 0.27%, to 0.15 × 106, 0.3 × 106, 0.5 × 106 and 1 × 106 LNCaP cells, respectively. The PSMA-DOTA-177Lu internalization assay revealed that the membrane-bound activity (non-internalized peptide) to LNCap cells, was 99.03 ± 0.84%. Moreover, the pharmacokinetic in vivo studies performed in Scid mice resulted in a rapid blood clearance and renal excretion, and showed significant tumor uptake (2.76 ± 1.21% lA/g) 4 hours after PSMA-DOTA-177Lu administration. Stability studies in human serum demonstrated high PSMA-DOTA-177Lu stability over 24 hours, which is in agreement with the low bone uptake obtained in the in vivo biodistribution studies. Furthermore, the comparative study aiming to establish the ideal PSMA-DOTA-177Lu specific activity (MBq / μg) will be considered for further radiopharmaceutical production. The pre-clinical data obtained from this study suggested a great potential for PSMA-DOTA-177Lu to be included in clinical trials and to make a major contribution to the treatment of prostate cancer.

Les médicaments radiopharmaceutiques ciblant les récepteurs peptidiques tels que les analogues de la somatostatine ont un réel potentiel et un fort intérêt pour à la fois le diagnostic et le traitement des tumeurs neuroendocrines (TNE) non-opérables, par radiothérapie interne vectorisée (RIV). La toxicité des traitements par radiopeptides analogues de la somatostatine limite leur développement clinique. Le développement de nouveaux peptides ciblant d'autres types de récepteurs tels que le ceux de la cholécystokinine (CCK) est une solution dont l'intérêt a été montré par les travaux de notre équipe, basés sur un analogue CCK novateur. Ce travail en trois volets décrit dans un premier temps le radiomarquage de l'analogue CCK, par des radionucléides émetteurs - tels que l'yttrium 90 et le lutétium 177 adaptés à la thérapie, en plus de l'indium 111 pour le diagnostic, les capacités de complexation et la stabilité de ce nouvel analogue peptidique CCK. Une étude in vivo préliminaire sur modèle murin a permis d'étudier la faisabilité d'un traitement de RIV. Une troisième étude a été réalisée in vitro sur deux lignées cellulaires tumorales par le traitement à l'aide d'une molécule antitumorale caractérisée dans notre équipe, à travers la réexpression d'une voie de signalisation cellulaire. Ce travail a permis de montrer l'intérêt potentiel de l'utilisation des analogues CCK en RIV en association thérapeutique pour la prise en charge de certaines TNE
Les médicaments radiopharmaceutiques ciblant les récepteurs peptidiques tels que les analogues de la somatostatine ont un réel potentiel et un fort intérêt pour à la fois le diagnostic et le traitement des tumeurs neuroendocrines (TNE) non-opérables, par radiothérapie interne vectorisée (RIV). La toxicité des traitements par radiopeptides analogues de la somatostatine limite leur développement clinique. Le développement de nouveaux peptides ciblant d'autres types de récepteurs tels que le ceux de la cholécystokinine (CCK) est une solution dont l'intérêt a été montré par les travaux de notre équipe, basés sur un analogue CCK novateur. Ce travail en trois volets décrit dans un premier temps le radiomarquage de l'analogue CCK, par des radionucléides émetteurs - tels que l'yttrium 90 et le lutétium 177 adaptés à la thérapie, en plus de l'indium 111 pour le diagnostic, les capacités de complexation et la stabilité de ce nouvel analogue peptidique CCK. Une étude in vivo préliminaire sur modèle murin a permis d'étudier la faisabilité d'un traitement de RIV. Une troisième étude a été réalisée in vitro sur deux lignées cellulaires tumorales par le traitement à l'aide d'une molécule antitumorale caractérisée dans notre équipe, à travers la réexpression d'une voie de signalisation cellulaire. Ce travail a permis de montrer l'intérêt potentiel de l'utilisation des analogues CCK en RIV en association thérapeutique pour la prise en charge de certaines TNE

Targeted radionuclide therapy is becoming a widely used cancer treatment strategy. By radiolabeling receptor-specific peptides, cancer cells overexpressing the receptor can be selectively targeted, and the cytotoxic radionuclide can be delivered to the target cell or tissue for therapeutic or diagnostic purposes. Bombesin analogues have been previously developed and utilized to target the gastrin-releasing peptide receptor (GRPR), a receptor commonly overexpressed in prostate cancer cells. The RM26 analogue derived from the native bombesin is an antagonistic ligand of GRPR and a possible candidate for targeted radiotherapy. Prolonging the half-life of the molecule is an important aspect of developing a new protein therapeutic. Using albumin binding domain (ABD) for this purpose is an emerging strategy in recent years. ABD is able to bind to serum albumin and thus remains in the blood circulation for a long period of time. It is also a scaffold for protein engineering efforts and by coupling receptor-specific ligands to ABD, the target-specific binding along with extended in vivo halflife can be achieved. In this project, an RM26 analogue with a PEG linker and ABD with a DOTA chelator for future radiolabeling were synthesized with solid phase peptide synthesis (SPPS), conjugated, purified by RP-HPLC and analyzed by mass spectrometry. The binding properties of the conjugate were evaluated by SPR-based biosensory studies, and further experiments are planned for the testing the product and its potential application in radionuclide therapy.
Riktad radioterapi är en allt vanligare metod för behandling av cancer. Genom att radioinmärka receptor-specifika peptider kan dessa selektivt levereras till tumörceller som uttrycker receptorn. Radioterapi kan användas för diagnostik eller terapi, beroende på kopplad radionuklid. Bombesinanaloger har utvecklats och använts för att selektivt binda gastrinfrisättande peptidreceptor (gastrin-releasing peptide receptor, GRPR), en receptor som ofta är överuttryckt i prostatacancer. Bombesinanalogen RM26, som har sitt ursprung från nativt bombesin, är en antagonist till GRPR och kan möjligen användas för riktad radioterapi av prostatacancer. Vid utvecklingen av nya proteinläkemedel är halveringstiden i serum en viktig aspekt. En nyligen utvecklad strategi för att förlänga halveringstiden i serum är fusion av det  tumörspecifika proteinet till en albumin-bindande domän (ABD). ABD binder till albumin, ochsåledes kan fusionsproteinet bevaras i blodcirkulationen under en längre tid. I detta projekt, har både RM26 med en PEG-linker, och ABD med en DOTA kelator syntetiserats med fastfaspeptidsyntes (solid phase peptide synthesis, SPPS). RM26-PEG och DOTA-ABD har därefter konjugerats, renats med RP-HPLC och analyserats med massspektrometri. Bindning till albumin har utvärderats med ytplasmonresonans (surface plasmon resonance, SPR). Vidare studier planeras för att utvärdera peptid-proteinkonjugatet och dess potential för riktad radioterapi.

Les substances addictives détournent les apprentissages par la récompense en augmentant la dopamine (DA) dans le système mésolimbique, en particulier dans le striatum, où elle module durablement la transmission glutamatergique excitatrice et contribue à la mise en place d’altérations comportementales persistantes. L’intégration des signaux dopaminergique et glutamatergique au sein du striatum est réalisée par les neurones moyen épineux du striatum (MSN), qui forment deux populations majoritairement distinctes : les MSN de la « voie directe » exprimant les récepteurs D1 de la DA (D1R-MSN) et ceux de la « voie indirecte » qui expriment les récepteurs D2 de la DA (D2R-MSN). Une hypothèse qui prévaut à l’heure actuelle est que la libération de DA induite par les drogues active les D1R-MSN, ce qui promeut le renforcement, alors qu’elle inhibe les D2R-MSN, diminuant ainsi leurs fonctions « anti-renforcement ». Les travaux du laboratoire ont montré que l’interaction physique (i.e. hétéromérisation) entre le D1R et le récepteur NMDA (NMDAR) du glutamate était nécessaire à la facilitation de la transmission glutamatergique par la DA dans les D1R-MSN. À l'inverse, d'autres travaux ont montré que l'interaction D2R / NMDAR sous-tend l'effet inhibiteur de DA sur la signalisation NMDAR dans les D2R-MSN. Toutefois, la modulation et la fonction de ces hétéromères in vivo dans les réponses induites par la cocaïne sont encore inconnues. À l'aide du test de « proximity ligation assay », nous avons montré que la sensibilisation locomotrice induite par des expositions répétées à la cocaïne est associée à la formation d'hétéromères D1R/NMDAR dans le Noyau Accumbens (NAc) et le Striatum Dorsal, tandis que l'hétéromérisation D2R/GluN2B est majoritairement observée au sein du NAc. Pour identifier les rôles des hétéromères DAR / NMDAR dans les différentes phases des adaptations moléculaires, morphologiques et comportementales induites par la cocaïne in vivo, nous avons conçu une approche virale pour perturber les hétéromères DAR / NMDAR de manière contrôlée dans le temps grâce à un promoteur dépendant de la doxycycline. Nous avons constaté que la perturbation de l'interaction D1R / NMDAR dans le NAc bloque la mise en place des altérations synaptiques induites par la cocaïne dans les D1R-MSN ainsi que le développement de la sensibilisation locomotrice et de la préférence de lieu conditionné par la cocaïne (CPP). A l’inverse, le blocage de l'interaction D2R / NMDAR interfère avec le maintien de la sensibilisation psychomotrice et de la CPP à la cocaïne. L’observation d’un rôle préférentiel des hétéromères D2R/GluN2B dans la maintenance des réponses comportementales à la cocaïne et leur absence d’effet dans le cas d’une récompense naturelle suggèrent que ce sous-type d’hétéromère pourrait être une cible thérapeutique à envisager. J’ai donc mis au point la détection des complexes D2R / NMDAR à partir des tissus striataux humains post-mortem issus d’individus avec un historique de dépendance aux psychostimulants ou des sujets sains. Ceci m’a permis de montrer, qu’en dépit d’une forte baisse de l’expression du D2R, la proportion de D2R formant des hétéromères avec les NMDAR est trois fois supérieure chez les sujets dépendants par rapport au sujets sains. Ce travail renforce donc les évidences en faveur d’un rôle central des interactions entre les systèmes dopaminergique et glutamatergiques dans les réponses aux drogues et identifie les hétéromères DAR / NMDAR comme des cibles moléculaires avec un potentiel thérapeutique non seulement dans la dépendance aux drogues mais également pour les nombreux troubles psychiatriques associés à un déséquilibre entre les transmissions dopaminergiques et du glutamatergiques
Addictive substances hijack reward-dependent learning by increasing dopamine (DA) in the mesolimbic system, in particular in the striatum, where it modulates durably excitatory glutamatergic transmission and contributes to the establishment of persistent behavioral alterations. The integration of dopaminergic and glutamatergic signals within the striatum is achieved by the medium-size spiny neurons of the striatum (MSN), which form two mostly segregated populations: the MSN of the "direct pathway" expressing DA D1 receptors (D1R-MSN) and those of the "indirect pathway" which express the DA D2 receptors (D2R-MSN). A prevailing hypothesis is that the surge of DA evoked by drugs of abuse facilitates D1R-MSN activation through the stimulation of D1R, which promotes reinforcement, whereas the D2R-mediated inhibition of D2R-MSN prevent their so-called anti-reward action. Our laboratory has previously shown that the physical interaction (i.e. heteromerization) between D1R and the NMDA glutamate receptor (NMDAR) was necessary for the facilitation of glutamatergic transmission by DA in D1R-MSN. Conversely, others have shown that the D2R/NMDAR interaction underlies the inhibitory effect of DA on NMDAR signaling in D2R-MSN.However, the modulation and function of these heteromers in vivo in responses to cocaine are still unknown. Using the “proximity ligation assay” technique, we found that locomotor sensitization induced by repeated exposure to cocaine is associated with the formation of D1R/NMDAR heteromers in the Nucleus Accumbens (NAc) and the Dorsal Striatum, while the D2R/GluN2B heteromerization is mainly observed within the NAc. To identify the roles of the DAR/NMDAR heteromers in the different phases of the molecular, morphological and behavioral adaptations induced by cocaine in vivo, we designed a viral-based approach to disrupt the DAR/NMDAR heteromers in a controlled manner over time owing to a doxycycline-dependent promoter. We found that the disruption of the D1R/NMDAR interaction in the NAc blocks cocaine-evoked long-term synaptic plasticity in D1R-MSN and the development of both psychomotor sensitization and conditioned place preference (CPP). By contrast, blocking the D2R/NMDAR interaction interferes with the maintenance of cocaine psychomotor sensitization and CPP. The observation of a preferential involvement of the D2R/GluN2B heteromers in the maintenance of behavioral responses to cocaine and their lack of effect in natural reward suggests that this subtype of heteromers could be a promising therapeutic target. Based on this hypothesis, we developed the detection of D2R/NMDAR complexes from human post-mortem striatal tissues prepared from individuals with a history of psychostimulants dependence or healthy subjects. This allowed us to show that, despite a sharp decrease in D2R expression, the proportion of D2R forming heteromers with NMDAR is three-fold higher in addict subjects compared to healthy controls. This work therefore reinforces the evidence of the central role of interactions between the dopaminergic and glutamatergic systems in drug responses and identifies the DAR/NMDAR heteromers as molecular targets with therapeutic potential not only in addiction but also for the numerous psychiatric disorders associated with an imbalance between dopaminergic and glutamatergic transmissions

This dissertation provides a detailed exploration and valuable insights of type 2 diabetes management in the real-world setting. Incretin-based therapies and thiazolidinedione were found to provide higher chances of sustainable glycaemic and cardiovascular risk factor control, compared to older anti-diabetic treatment options. The project highlights alarming rates of the existing cardio-metabolic burden at the population level. Proper control in terms of timely intensification with anti-hyperglycaemic, anti-hypertensive, and anti-dyslipidemic therapies when needed, remains a key aspect to improve long-term outcomes in patients with type 2 diabetes.

碩士
國立陽明大學
微生物及免疫學研究所
101
Colorectal cancer (CRC) has became the most frequently encountered cancer and the third most common cause of cancer-related death in Taiwan since 2007. The cause of CRC mortality is mainly due to the resistance to treatment and the occurrence of distant metastasis, Unfortunately, proximately 45% CRC patients are diagnosed after metastasis. Recent evidences suggest that circulating tumor cell or cancer stem cells could contribute to tumor initiation and metastasis, and confers to drug resistance. Therefore, specifically targeting and killing of these cells could reduce the probability of recurrence. Previous studies have shown that Atherosclerotic plaque-specific peptide-1 (AP1) can high affinity bind to interleukin-4 receptor (IL-4R that is a tumor-promoting molecule and overexpress on CRC tissues. In this study, we used a novel doxorubicin-loaded liposome nanoparticle conjugated with AP1(Lipo-Dox-AP1) and established the IL-4Rstable expression cells (CT26-IL4R) and control cells (CT26-ctrl) to evaluate the treatment efficacy of novel nanoparticle in vitro and in vivo. First of all, immunohistochemistry analysis revealed that IL-4Rα were highly expressed in colorectal cancer tissue compared to normal tissue. Moreover, the AP1 peptide exhibited more bound to and be internalized into CT26-IL4R than CT26-ctrl. Furthermore, Lipo-Dox-AP1 showed a selective cytotoxicity to CT26-IL4R than CT26-ctrl. The Lipo-Dox-AP1 showed higher survival rate than Lipo-Dox or free doxorubicin though tumor inhibition ability was not significantly different in mice bearing CT26 cells. However, the Lipo-Dox-AP1 exhibited better tumor suppression ability than Lipo-Dox or free doxorubicin in mice bearing CT26-IL4R cells. Blood chemical analysis revealed that Lipo-DOX-AP1 was less toxic to kidney. In conclusion, we evaluate the AP1 is an excellent conjugated molecule that can enhance specifically binding to and uptake in cells and showed better therapeutic efficacy in tumor-bearing mice. Inhibition of CRC metastasis using Lipo-DOX-AP1 will be further investigated in orthotopic animal model.

Lu, Zengbing.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 206-217).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Fan, Rongrong.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 130-150).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Trabalho de Projeto do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
Introdução: Os tumores neuroendócrinos constituem um tipo raro de neoplasias caracterizadas pelo seu metabolismo endócrino, padrão histológico único e heterogeneidade biológica. Apesar da progressão insidiosa, uma grande percentagem de doentes desenvolve doença metastática irressecável principalmente a nível hepático, ósseo e ganglionar. Nestes casos, a Terapêutica Radiometabólica com 177Lu-[DOTA0,Tyr3]-octreotate(DOTA-TATE) constitui uma opção terapêutica promissora devido à eficácia limitada das atuais opções terapêuticas disponíveis. Apesar da eficácia e segurança da Terapêutica Radiometabólica terem sido demonstradas, a inexistência de protocolos ou orientações clínicas transversais a todas as instituições constitui uma limitação à sua implementação. Objetivo: Com o intuito de melhorar o planeamento, pretendemos avaliar a toxicidade e perfil farmacocinético da captação de 177Lu-DOTA-TATE quando usado em esquemas de Terapêutica Radiometabólica para tratamento de tumores neuroendócrinos. Materiais e Métodos: 16 Dezasseis doentes multimetastizados foram progressivamente selecionados, entre Julho julho de 2013 e Maio maio de 2016. 10 Dez homens e 6 mulheres (67.,6±13.,4 anos) foram submetidos a 3 ciclos de Terapêutica Radiometabólica com 177Lu-DOTA-TATE (17.,9±6.,5 GBq) para tratamento de 57 metástases (33 hepáticas e 22 ósseas). A variação da intensidade de captação doe 177Lu-DOTA-TATE nas lesões foi avaliada ao longo de todo o tratamento. Os parâmetros de toxicidade incluíram hemograma com fórmula leucocitária, função hepática e renal antes, durante e após tratamento. A análise estatística incluiu a comparação de variáveis pelo teste de Wilcoxon e a determinação do coeficiente de Spearman para avaliar a existência de correlação entre variáveis. Resultados: As metástases hepáticas e ósseas apresentaram um perfil de captação semelhante, com redução da captação de 177Lu-DOTA-TATE do primeiro para o terceiro ciclo. Mielotoxicidade aguda (Grau I e II) foi observada 5 semanas após cada ciclo sem toxicidade medular, hepática ou renal significativa após o tratamento. Conclusão: Os nossos resultados demonstraram um perfil de toxicidade adequado com mielotoxicidade mínima após cada ciclo e sem nefrotoxicidade significativa após 3 ciclos. Os estudos de correlação mostraram que as avaliações laboratoriais pré-tratamento podem servir como ponto de partida para a seleção de doentes. Por fim, propusemos um esquema de dosimetria clinicamente exequível e capaz de determinar o perfil de captação de 177Lu-DOTA-TATE intra e inter-ciclos.
Introduction: Neuroendocrine tumors (NETs) constitute a particularly rare type of tumors characterized by their endocrine metabolism, unique histological pattern and biological heterogeneity. Despite their indolent course, many patients develop multiple unresectable metastatic disease affecting mainly the liver, bones and lymph nodes. In those cases, current therapeutic options have a limited efficacy. Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-[DOTA0,Tyr3]-octreotate(DOTA-TATE) constitutes a promising new treatment modality for inoperable metastatic NETs. Notwithstanding being proved effective and safe, PRRT still struggles with the lack of established protocols and guidelines. Aim: The main goal of this study was to contribute to improve PRRT planning by providing insight about the safety and pharmacokinetic profile of 177Lu-DOTA-TATE when used on current therapeutic protocols for NET. Materials and Methods: Sixteen patients with progressive multi-metastatic disease were consecutively enrolled from July 2013 to May 2016. Ten males men and six females women (67.6 ± 13.4 years) received three cycles of PRRT with 177Lu-DOTA-TATE (17.9 ± 6.5 GBq) for treatment ofto treat 57 metastatic lesions (33 in the liver and 22 in the bones metastases). Individual lesion 177Lu-DOTA-TATE uptake was evaluated trough treatment. Toxicity parameters assessed included full blood count, liver and renal function before, during and after treatment. Data analysis comprised a Wilcoxon test for variable comparison and linear regression using Spearman’s coefficient. Results: A similar uptake profile for liver and bone metastases was found with an overall reduction on 177Lu-DOTA-TATE uptake from the first to the third cycle. Regarding safety, acute myelotoxicity (Grade I and II) was found five weeks after each cycle without significant bone marrow, hepatic or nephrotoxicity after treatment. Conclusion: Our results demonstrate that Peptide Receptor Radionuclide TherapyPRRT with 177Lu-DOTA-TATE has a tolerable safety profile, with minimum acute myelotoxicity after each cycle and minimum nephrotoxicity after the entire treatment. Our correlation studies revealed that pre-treatment laboratorial evaluation constitutes a reliable starting point for patients’ selection and extrapolation of toxicity outcomes. Moreover, we proposed a feasible approach to dosimetry that established an intra and inter-cycle variation profile for 177Lu-DOTA-TATE uptake.