- 學位論文
設計新搭載化療藥物SN38之多功能奈米載體與其抗大腸癌療效評估
Efficacy Evaluation of Newly Designed Multifunctional Nanoagents with SN38 against Colorectal Cancer
摘要
Part I: 大腸癌的治療發展迄今，已經有許多專門提升化療藥物療效的奈米載體被研製出來，這些奈米載體不但能提升化療藥物於腫瘤的累積量，若被設計賦予其他特殊功能，則能夠更加提升化療藥物的療效；常賦予的功能中，標靶功能可增加腫瘤細胞的吞噬量，而藥物釋放功能則可有效地促使藥物從載體內釋放，提高藥物於細胞內的作用機率。有了以上文獻結果的借鏡，我們團隊針對大腸癌治療的研究，設計一新的多功能奈米載體，使其具有標靶作用與藥物釋放作用；此奈米載體富有雙硫鍵，能包覆大腸癌化療藥物－SN38，期望將來能成為臨床用大腸癌的化療候選藥。於此研究中，三種不同的奈米載體藥物被設計出來互相比較與評估，其分別為可分解型、不可分解型與葉酸標靶可分解型微胞；經評估後，葉酸標靶可分解型的奈米微胞可望成為一有效大腸癌化療的新劑型 Part II: 癌症研究中，熱療法與化療法並用已證實，用於近紅外線且具有特殊功能治療劑能抑制腫瘤生長，故此研究採用熱化療法以期能治癒大腸癌，利用尋找一新的策略，促使腫瘤能夠累積大量的化療藥物且在光熱療程中產生高溫，藉此得到最佳的療效。因此，我們設計一簡單且多功能近紅外線劑型，此劑型由近紅外線染劑、聚乙二醇、環狀胜肽－cRGD所組成，並搭載抗大腸癌化療藥物－SN38。劑型的每個組成皆有它特殊功能，都能夠提升熱化療法的療效。而從此篇研究結果顯示，這個新劑型所賦予的進紅外光顯影能力、光熱功能、高滲透長時間腫瘤滯留現象、躲避網狀內皮系統功能與新生血管標靶特性，能強化熱化療法對於大腸癌的效果。期望這新劑型有助於將來開發新的治療法用於大腸癌。
並列摘要
Part I: Several types of nano-sized anti-cancer agents that could increase the accumulation of drugs in the tumor site have been created and developed for enhancing efficacy of chemotherapeutic drugs in colon cancer treatment. In addition, to achieve the optimal cancer chemotherapeutic efficacy, nano-sized agents with specific functions were designed to efficiently kill cancer cells. The ideal nano-sized agent must be able to successfully release the drug and result in an increased cellular uptake of the chemotherapeutic drug. Our research team focused on two important functions, drug release and targeting functions, thus targeting functional micelles which were designed to possess disulfide bonds and entrapped much chemotherapeutic drug, 7-ethyl-10-hydroxy-camptothecin (SN38), which was created as a powerful candidate for an ideal anti-cancer drug for colon cancer treatment. In particular, Self-Breakable SN38-loaded micelles (SN/38 micelles), Non-Breakable micelles SN38-loaded (NB/38 micelles) and Folate-decorated Self-Breakable SN38-loaded micelles (FSB/38 micelles) were prepared and tested to the designed agents. The results showed that the folate-decorated functional micelles with disulfide bonds could be an effective chemotherapeutic agent for colon cancer treatment. Part II: Cancer researches regarding near-infrared(NIR) agents for chemothermal therapy(CTT) have shown that agents with specific functions are able to inhibit tumor growth. The aim of current study was to optimize CTT efficacy for treatment of colorectal cancer(CRC) by exploring strategies which can localize high temperature within tumors and maximize chemotherapeutic drug uptake. We designed a new and simple multifunctional NIR nanoagent composed of the NIR cyanine dye, polyethylene glycol, and a cyclic arginine-glycine-aspartic acid peptide and loaded with the anti-CRC chemotherapeutic agent, 7-ethyl-10-hydroxy-camptothecin(SN38). Each component of this nanoagent exhibited its specific functions that help boost CTT efficacy. The results showed that this nanoagent greatly strengthen the efficacy of SN38 and CTT againstCRC due to its NIR imaging ability, photothermal, enhanced permeability and retention(EPR) effect, reticuloendothelial system avoidance, and angiogenic blood vessel-targeting properties. This NIR nanoagent will help facilitate development of new strategies for treating CRC.