多功能奈米載體在藥物傳輸上之應用(光動力治療合併化學療法與抑制血管新生對腫瘤治療之評估)

近年來奈米載體作為藥物傳輸的研究與臨床應用極為熱門且具前瞻性。而合併不同療法，如光動力治療、化學療法、與抗血管新生療法等，也成為腫瘤治療上的新趨勢。為藉由奈米藥物載體整合不同療法，故本論文的架構先由小分子光感藥物有機合成推向高分子奈米載體的製備；由單一治療推向多療法的合併；由細胞實驗推向動物實驗的評估多功能奈米載體在藥物傳輸上與合併抗腫瘤治療上的應用。本論文分為三的部分，第一部分是光感藥物的合成與鍵結在光動力治療上的評估。此部分有兩個研究主題，一是非對稱卟啉類光感藥物的合成與抗癌評估。二是鍵結光感藥物與樹枝狀高分子應用於光動力治療與基因轉植的載體的評估。本研究合成一系列非對稱卟啉類光感藥物，並針對其在腫瘤細胞所表現的特殊胞器標的特性與光動力效果家以評估。研究中所得知的卟啉結構與生物交互作用的特性關係，可作為未來光感藥物設計的借鏡。進一步利用所合成出的卟啉與樹枝狀高分子鍵結，提升其在藥物傳輸與基因治療的應用性。第二部分是製備雙效的奈米微胞作為合併光動力療法與化學療法的藥物載體。此部分有兩個研究主題。首先是合成以光感藥物為中心的放射狀雙性高分子，其可在水相環境中自組形成奈米微胞，包覆輸水性化療藥物。以紫杉醇為標的藥物作為乳癌合併療法的評估。進一步包覆喜樹鹼類藥物SN-38於大腸直腸癌症動物模式評估本載體合併治療的效果。結果顯示，有六成的老鼠腫瘤經過重覆的合併治療後完全消失。而治療對於腫瘤細胞的複製與血管密度均有抑制的效果。第三部分是評估合併抗血管新生對於光動力治療與奈米藥物在腫瘤治療上的影響。在合併光動力治療部分，發現抗血管新生藥物-癌思停(抗血管內皮生長因子抗體, Bevacizumab)可增加光動力治療的的效果，尤其是以先光動力後再給與抗血管內皮生長因子抗體的效果較具有統計上的加成效果。所給予的抗體可有效降低光動力治療後所產生的血管內皮生長因子含量，抑制血管再生、降低腫瘤復發。抗血管內皮生長因子抗體對於奈米藥物在腫瘤上的累積量與治療效果的評估。以喜樹鹼微胞為測試奈米藥物，以大腸直腸癌的動物模型進行測試。初步結果顯示，抗血管內皮生長因子抗體對於較大尺寸的喜樹鹼微胞的腫瘤累積量與抗癌效果並不影響，對於一百奈米左右的顆粒較具有統計意義的累積量抑制。

關鍵字

光動力治療；化學療法；抑制血管新生；奈米藥物；奈米微胞；光感藥物；癌症

並列摘要

In recent years, the nanomaterials, such as polymer-drug conjugates, nanoparticles, and polymeric micelles, have been considered as potential carriers for hydrophobic drug delivery that may resolve the mentioned problems. The combination of photodynamic therapy, chemotherapy, or anti-angiogenesis had been a development tendencies for the cancer treatments. This dissertation was divided into three parts. The first part is synthesis of photosensitizers and their conjugates for photodynamic therapy. There are two topics of research in this part. The first topic is to synthesis and evaluate the asymmetric porphyrins on intracellular uptake, subcellular localization and phototoxicity in cancer cells. The second topic is synthesis and evaluate of PAMAM- porphyrin conjugates for photodynamic therapy and gene transfection. In first study, we prepared a series of asymmetric porphyrins with varying proportion of substituents, such as 4-hydroxyphenyl, 4-aminophenyl, and 4-pyridine, with a varied degree of hydrophobic/hydrophilic substitution as model compounds for localization studies of photosensitizers and its photodynamic activity in tumor cells. In addition, we conjugated photosensitizers (TAMCPP, P35) with PAMAM dendriers to increase the hydrophilicity for clinical applicaion. And G4-TAMCPP became less aggregation, more photocytotoxitic efficacy, and lysosomal targeting that could be applied on delivery system for the photochemical internalization. The second part is to prepare the dual functionalized micellar delivery system for the combination of photodynamic therapy and chemotherapy. This part has two topics of research, the first is to synthesis and evaluate the self-assembled chlorin-cored poly(ε-caprolactone)-poly(ethylene glycol) diblock copolymer (CSBC) micelles for paclitaxel-based chemotherapy combinated with photodynamic therapy in MCF-7 breast cancer cells. The second topics is to use CSBC micelles for SN-38 delivery and evaluate its combination efficacy effects in a HT-29 human colon cancer xenograft model. Combined SN-38/CSBC-mediated PDT synergistically inhibited tumor growth, resulting in up to 60% complete regression of well-established tumors after 3 treatments. These treatments also decreased the microvessel density (MVD) and cell proliferation within the subcutaneous tumors. The third part is Anti-angiogenesis therapy combinated with photodynamic therapy or nanomedicines. The first topic is anti-angiogenic treatment (Bevacizumab) enhances the responsiveness of photodynamic therapy in a HT-29 human colon cancer xenograft mode. Our results demonstrated that combination therapy protocol of PDT then bevacizumab exhibited greater tumor response in comparison with other treatment protocols. The last topic is to investigate the relationship between angiogenesis and nanomedicines on the therapeutic efficacy in colon cancer. The vascular-targeting PDT induce the loss of vascular barrier function and increase in vascular permeability. In this study, we demonstrated that alteration in tumor vascular barrier by vascular-targeting PDT, which enhances the delivery of macromolecules. It also demonstrated whether pretreatment with bevacizumab (anti-angiogenesis) or vascular-targeting PDT (pro-angiogenesis) influence the efficacy of systemically administered nanomedicines in mice bearing human colon HT-29 adenocarcinoma, and to investigate the optimal conditions (time window, particle size) of anti-angiogenesis and pro-angiogenesis and their effects on the delivery and efficacy of nanomedicines. Bevacizumab had been shown to decrease microvessel density (MVD) and vascular perfusion in solid tumours. However, the effects of bevacizumab on the delivery of micellar SN-38 formulations therapeutic efficacy are not effected, because of the larger size of SN-38/micelles.

並列關鍵字

Photodyamic therapy ； chemotherapy ； anti-angiogenesis ； photosensitizers ； micelles ； nanomedicine ； cancer

參考文獻

Chapter 1 General Introduction

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多功能奈米載體在藥物傳輸上之應用(光動力治療合併化學療法與抑制血管新生對腫瘤治療之評估)

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