2020-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/665375摘要：TPZ為一個缺氧活化前驅藥物，在臨床前和臨床一、二期有不錯的成效，但在臨床三期試驗中未能成功地增加腫瘤的療效。探究其原因，除了TPZ不易穿透到腫瘤內真正缺氧的組織外，腫瘤微環境抗拒TPZ的作用，以及免疫系統受到抑制，都和臨床試驗成果不理想有關。將藥物包埋於奈米粒子並藉由腫瘤的EPR效應已被證實可以增加藥物在組織的累積量。然而，因為TPZ本身特殊的物理化學性質而導致其在奈米粒子中的包覆率低，再加上腫瘤組織的缺氧狀態不一，因此文獻報導上以奈米粒子攜帶的TPZ療效一直相當有限。在這個研究計畫中我們將開發具有生物相容性且能同時攜帶光感物質Ce6及缺氧活化前驅藥物TPZ的脂質奈米粒子。我們計畫將這一雙效奈米粒子藉由光動力效應殺死腫瘤細胞，並破壞血管來促進腫瘤組織的缺氧狀態以提升後續TPZ之療效，之後再結合免疫檢查點抑制劑來進行原位腫瘤及轉移癌細胞的治療研究。為達成此目標我們擬定了下列研究目標：第一、開發同時包埋有TPZ和Ce6的脂質奈米粒子；第二、分析相關奈米粒子的穩定性、藥物釋放、細胞毒性及誘發細胞死亡模式；第三、藉由活體動物實驗探討其藥動、藥效和療效；第四、藉由雙效奈米粒子與免疫檢查點抑製劑的聯合使用，探討其對原位腫瘤和轉移癌細胞的治療成效並驗證於具有自發性腫瘤的病犬。綜合言之，這一研究計畫將自脂質奈米粒子藥物的開發，臨床前試驗的探討並藉由中繼動物的安全性及療效驗證來進行新劑型藥物開發相關的轉譯研究。<br> Abstract: Tumor hypoxia has been pursued as a target for tumor treatment by using hypoxia-activated prodrugs, such as TPZ that target the low-oxygen tumor compartments. Despite the promising results in preclinical and clinical phase I & II, the implementation of TPZ in the clinic has not been successful. Many factors could potentially affect the treatment outcome of TPZ, including its physicochemical properties and the tumor microenvironment. Therefore, there is a clear medical need to develop a more effective formulation for delivering TPZ. Nanoparticles have been reported to selectively accumulate in hypoxic tumor regions due to the EPR effects that not only can increase tumor-specific cytotoxicity and hypoxia sensitivity but also prevent drug degradation and side effects. Previously, we have demonstrated the possibility of using a dual-effect liposomal drug co-encapsulated with photosensitizer (Ce6) and chemotherapeutic agent (doxorubicin or cisplatin) for tumor treatment. The main objective of this research proposal is to develop a biocompatible dual-effect nanoparticle with a sequentially therapeutic efficacy, photodynamic therapy and following hypoxia-activated chemotherapy. After verifying its therapeutic efficacy, combination of dual-effect nanoparticle with immune checkpoint inhibitors will be used to induce a systemic therapeutic effect to treat primary tumors and disseminated cancer cells. Finally, the intermediate animals with naturally developed tumors will be used to verify the therapeutic efficacy. To fulfill these goals, we propose the following specific aims in this research project. Specific aim 1.Develop lipid-based nanoparticles encapsulated with TPZ and Ce6. Specific aim 2. Examine the release profile, stability, cytotoxic effect and cell death mode of the NP-TPZ-Ce6 in vitro. Specific aim 3. Studies of the pharmacokinetics, pharmacodynamics and therapeutic efficacy in vivo. Specific aim 4. Investigate the systemic antitumor effect by combining NP-TPZ-Ce6 with immune checkpoint inhibitors in tumor-bearing mice. Specific aim 5. Verify the therapeutic efficacy in intermediate animals, dogs with spontaneous tumor.光動力治療缺氧活化前驅藥物奈米粒子免疫療法Photodynamic therapyHypoxia-activated prodrugNanoparticleImmunotherapy