環境敏感性幾丁聚醣/嵌段共聚物奈米水膠顆粒的製備與其在藥物釋放的應用

Preparation of environmentally sensitive nanoparticles from chitosan/block copolymer and their application in drug release

林昱維(Yu-Wei Lin)

指導教授 ： 董崇民

淡江大學/工學院/化學工程與材料工程學系碩士班/碩士(2019年)

https://doi.org/10.6846/TKU.2019.00292

摘要

本研究利用丙烯酸(Acrylic acid, AA)與氮-異丙基丙烯醯胺 (N-isopropylamide, NIPAAm)以可逆加成-斷裂鏈轉移聚合(Reversible addition- fragmentation chain transfer polymerization，RAFT)活性自由基聚合方法合成出具環境應答性質的嵌段共聚物PAA-b-PNP，利用紅外線光譜儀(FTIR)及核磁共振光譜儀(1H-NMR)對產物作結構鑑定，分別求出共聚物的AA和NIPAAm的聚合度、轉化率及分子量。調整反應時間可使AA和NIPAAm的單體轉化率都可達到100%，並讓具有溫度及 pH 值雙重敏感性的PAA-b-PNP微胞複合載體，加入幾丁聚醣增加其生物相容性，得到具有溫度及 pH 值雙重敏感性質之PAA-b-PNP/CS奈米藥物載體(50~400 nm)。利用此藥物載體包覆疏水性藥物喜樹鹼(Camptothecin，CPT)，藥物包覆率(Encapsulation efficiency, EE)及 、藥物負載率(Loading capacity, LC)會根據不同的PAA-b-PNP/CS組成而有變化。最後本研究發現PAA-b-PNP/CPT/CS奈米顆粒於強酸環境下可以穩定的存在，而在人體體液(pH = 7.4)的環境下，其奈米水膠顆粒會不穩定而膨潤或是瓦解，PAA-b-PNP/CPT/CS奈米藥物載體可適用於口服藥物之遞送系統，亦即在胃酸(pH 2.0)裡面不會讓藥物釋出，並保護藥物不會在強酸環境下被破壞，最後可以在小腸(pH = 7.4)的環境下快速釋放藥物。

關鍵字

溫度敏感型 ； 可逆加成-斷裂鏈轉移聚合 ； 奈米藥物載體 ； 藥物釋放系統

並列摘要

In this study, acrylic acid (Arylic acid, AA) and N-isopropylamide (NIPAAm) were polymerized to prepare environmentally-responsive block copolymers using reversible addition-fragmentation chain transfer polymerization (RAFT) living radical polymerization. Structure of the prepared PAA-b-PNP block copolymers was identified by infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1H-NMR), as well as the polymerization, degree of conversion and molecular weight. Both monomer conversions of AA and NIPAAm could reach 100%. Furthermore, chitosan was added to PAA-b-PNP gel particals above its LCST to prepare environmentally-sensitive PAA-b-PNP/CS nano drug carrier (50~400 nm). For increasing biocompatibility, a hydrophobic drug camptothecin (CPT) was then encapsulated into the drug carrier, and the encapsulation efficiency (EE) the loading capacity (LC) according to different were varied formulations in PAA-b-PNP/CS. Finally, this study found that PAA-b-PNP/CPT/CS nanoparticles be stably present in a strong acid environment, while in the body fluid (pH = 7.4), the nano gel particles became unstable and swoiien or Is disintegrated, Therefore, PAA-b-PNP/CPT/CS nano drug carrier can be applied to the oral drug delivery system.The nano drug carrier would not allow the drug to be released in the stomach (pH 2.0), protecting the drug from being released in a strong acid environment. The drug would be finally released the drug rapidly in the environment of the small intestine (pH = 7.4).

並列關鍵字

thermal-responsive ； Reversible addition-fragmentation chain transfer polymerization ； Nano carrier ； Drug delivery system

參考文獻

[1] Ying Zhang Hon, Fai Chan Kam and W. Leong. Advanced materials and processing for drug delivery: The past and the future. Journal of Advanced Research; ,January 2013, Volume 65, Issue 1, Pages 104-120.

[2] Jayanta Kumar Patra, Gitishree Das, Leonardo Fernandes Fraceto, Estefania Vangelie Ramos Campos, Maria del Pilar Rodriguez‑Torres, Laura Susana Acosta‑Torres, Luis Armando Diaz‑Torres , Renato Grillo, Mallappa Kumara Swamy, Shivesh Sharma, Solomon Habtemariam and Han‑Seung Shin. Nano based drug delivery systems: recent developments and future prospects. Journal of Nanobiotechnology; September 2018, Number 71, ISSN: 1477-3155.-2

[3] Daniel J. Keddie, Graeme Moad, Ezio Rizzardo and San H. Thang. Raft Agent Design and Synthesis. American Chemical Society; July 2012, Volume 45, Issue 13, Pages 5321-5620.-3

[4] Graeme Moad, John Chiefari, (Bill) YK Chong, Julia Krstina, Roshan TA Mayadunne, Almar Postma, Ezio Rizzardo and San H Thang. Living free radical polymerization with reversible addition ? fragmentation chain transfer (the life od RAFT). Polymer International; September 2000, Pages 49:993-1001.-4

[5] Graeme Moad and Christopher Barner-Kowollik. The Mechanism and Kinetics of the RAFT Process: Overview, Rates, Stabilities, Side Reactions, Product Spectrum and Outstanding Challenges Stimuli-responsive polymers and their applications. Handbook of RAFT Polymerization; September 2008.-5