製備聚乳酸-甘醇酸(PLGA)奈米粒子作為藥物載體之生醫應用

The formulation of poly(lactic-co-glycolic acid) nanoparticles as drug carriers for biomedical applications

朱志航(Chih-Hang Chu)

指導教授 ： 吳立真

共同指導教授 ： 楊重熙

國立暨南國際大學/科技學院/應用化學系/博士(2011年)

摘要

A部分: 一步製備表面覆蓋聚乙二醇的聚乳酸-甘醇酸奈米粒子在生醫上的應用

利用乳化溶劑揮發法發展出創新的一步合成表面覆蓋乙二醇的聚乳酸-甘醇酸奈米粒子(PEGPE-PLGA)，而cetyltrimethylammonium bromide (CTAB) 或是poly(ethylene glycol)- distearyl phosphoethanolamine (PEGPE)被當作在製備過程中的油相乳化劑，合成出小於50 nm的PLGA奈米粒子，這是從未被報導過的。PEGPE-PLGA的產率是隨著PEGPE/PLGA的重量比增加而提高，當PEGPE/ PLGA達到3:1時，產率可達相對的大量約為85%。PEGPE-PLGA和傳統的PLGA奈米粒子做比較可以發現有較高的藥物包覆率、降低快速的藥物釋放、好的血清穩定性及快速的細胞吸收能力，所以小於50 nm的PEGPE-PLGA展示出未來在活體上的藥物投遞應用之潛力。
我們實際利用克拉霉素(Clarithromycin)來包覆PEGPE-PLGA中做相關的研究，CL是一種半合成的大環內酯類抗生素，是被用來處理各式各樣的傳染性疾病，CL有很多劑型例如:錠劑、膠囊、內服懸浮液和靜脈注射型。然而靜脈注射的主要問題是會引起發炎並產生嚴重的疼痛；所以我們實驗室利用PEGPE- PLGA包覆CL來改善靜脈注射的問題，並且研究CL包覆在PEGPE-PLGA中的物理性質、體外藥物釋放和藥物動力學相關實驗。

B部分: 利用近紅外光照射聚乳酸-甘醇酸奈米粒子包覆奈米棒: 主動控制的藥物釋放系統

利用聚乳酸-甘醇酸(PLGA)奈米粒子同時包覆奈米金棒和代表性釋放物質如: phosphatidylethanolamine-rhodamine (PE-Rh)或是bovine serum albumin (BSA)，利用近紅外光雷射(808 ± 3 nm)照射奈米粒子，造成奈米金棒的斷裂並產生熱量，同時也使得PE-Rh、BSA從奈米粒子中釋放出來。本研究對於近紅外光照射造成藥物釋放機制加以研究外，也利用水浴溫度超過PLGA的玻璃相轉移溫度做藥物釋放實驗，來探討熱對於PLGA奈米粒子藥物釋放的影響，我們也成功利用原子力顯微鏡觀察到奈米金棒的形狀和PLGA奈米粒子表面性質改變，而推論可能是因為奈米金棒的形變和放熱而造成奈米粒子包覆的藥物釋放。發展出利用非侵入式的近紅外光雷射光源照射，來控制PLGA/奈米金棒的複合奈米粒子可以主動的藥物釋放；這種的複合奈米粒子是具有應用在活體上藥物投遞治療的潛力。

關鍵字

奈米粒子 ； 聚乳酸-甘醇酸 ； 奈米金棒 ； 藥物釋放

並列摘要

Part A : One-step preparation of PEG-coated poly(lactic-co-glycolic acid) nanoparticle for biomedical application

A novel method was developed for the one-pot synthesis of ultrafine poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), using an emulsion solvent evaporation formulation method. Using either cetyltrimethylammonium bromide (CTAB) or poly(ethylene glycol)-distearyl phosphoethanolamine (PEGPE) as an oily emulsifier during the emulsion process, produced PLGA particle sizes of less than 50 nm, constituting a breakthrough in emulsion formulation methods. The yield of ultrafine PLGA NPs increased with PEGPE/PLGA ratio, reaching a plateau at around 85%, when the PEGPE/PLGA ratio reached 3:1. The PEGPE–PLGA NPs exhibited high drug loading content, reduced burst release, good serum stability, and enhanced cell uptake rate compared with traditional PLGA NPs. Sub-50 nm diameter PEG-coated ultrafine PLGA NPs show great potential for in vivo drug delivery systems.
Clarithromycin (CL), a semisynthetic macrolide antibiotic, is indicated for the treatment of various infectious diseases. Many dosage forms of CL, such as tablets, capsules, dry suspensions and intravenous injectable CL. However, the main problem associated with its use is that the intravenous injectable dosage form causes venous irritation which results in serious pain. For this reason, it is of great importance to develop a new formation form for CL with improved intravenous administration. Therefore, CL loaded with PEGPE-PLGA for physical property and pharmacokinetics was investigated in this study. Furthermore, PEGPE-PLGA is evaluated in many pharmaceutical applications such as drug and protein delivery systems in the future.

Part B : Surface Deformation of Gold Nanorods-Loaded poly(lactic-co-glycolic acid) Nanoparticles After Near Infrared Irradiation: An Active and Controllable Drug Release System

Gold nanorods (GNRs) with either phosphatidylethanolamine-rhodamine (PE-Rh) or bovine serum albumin (BSA) were co-loaded in poly(lactic-co-glycolic acid) (PLGA) nanoparticles. PE-Rh or BSA was released from PLGA nanoparticles (NPs) after near infrared (NIR) laser irradiation (808 ± 3 nm) which made GNRs fragment and produce heat. This NIR-triggered release mechanism was investigated. Heating the PLGA NPs above PLGA’s glass temperature could not induce similar release behavior, whereas deformation and property change on PLGA NPs surface was observed by atomic force microscope. The PLGA matrix might loosened, which was caused by the mechanical agitation of the GNRs fragmentation, resulting in an active controllable release of the entrapped molecules in PLGA NPs upon NIR irradiation. The NIR thus acts as a non-invasive external light source for active and controllable drug release from the PLGA/GNR composite NPs. This type of drug delivery system may be of value in in vivo target delivery in the future.

並列關鍵字

Nanoparticles ； Poly(lactic-co-glycolic acid) ； Gold nanorods ； Drug release

參考文獻

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