PLGA奈米球結合玻尿酸水膠作為長效複合藥物劑型於濕性老年性黃斑部病變治療上之應用

Abstract

濕性老年性黃斑部病變是由於脈絡膜層的血管往上新生到視網膜層，破壞了視網膜上的感光細胞導致視力受損的疾病。目前現行主要治療方式是透過玻璃體內注射抗血管新生因子的蛋白質藥物，藉此抑制脈絡膜血管生長，以達到治療目的，然而由於蛋白質藥物在玻璃體內的半衰期極短，導致患者必須每個月接受一次玻璃體內注射，才足以維持有效的藥物治療濃度，不僅會造成眼內發炎或視網膜剝離等副作用，對患者的心理與經濟上也帶來一大負擔。本研究透過結合PLGA奈米球粒與化學交聯型玻尿酸水膠，製作出包覆模型藥物牛血清白蛋白的可注射式複合型藥物傳輸系統，探討其在體外控制釋放藥物的能力。研究結果顯示，化學交聯型玻尿酸水膠可以在pH 7.4的生理環境下自發反應成膠並同時包覆含有BSA之PLGA奈米球粒，形成可注射式的複合型藥物傳輸系統，且此傳輸系統在37°C的環境下放置6週後仍保有六成以上的重量。體外試驗中，透過MTT試驗與Live/Dead染色證明此複合型藥物傳輸系統對於人類視網膜色素上皮細胞並沒有表現出明顯之細胞毒性，也不會對細胞型態有所影響，顯示材料擁有良好的生物相容性。最後，透過結合兩種藥物傳輸系統的方式，本研究可以將BSA之釋放時間從原本的一個禮拜延長到一個月以上，且所釋放出的藥物濃度依舊維持在有治療意義的濃度之上，顯示出此複合型藥物傳輸系統在濕性老年性黃斑部病變治療上，可以改善注射頻率並表現出一個更好的藥物釋放曲線的能力。

Wet age-related macular degeneration is mainly caused by the development of choroidal neovascularization, which penetrates the fibrous barrier between choroid and retina and damages the photoreceptor cells. The current treatment for wet AMD is monthly intravitreal injection of anti-vascular endothelium growth factor protein drugs. The monthly intravitreal injection increases the risks of adverse effects including endophthalmitis and retinal detachment; moreover, the psychological and economic burdens further reduce patient compliance. In the current study, we combine PLGA nanospheres with chemically crosslinked hyaluronic acid hydrogel to create an injectable composite drug delivery system encapsulating model drug bovine serum albumin and evaluate its capability of extending BSA release in vitro. The results suggest that the modified HA polymer can gel at phycological condition and encapsulate the drug-laden PLGA nanosphere upon injection. The in situ forming injectable composite DDS can maintain more than 60% of its wet weight at 37°C for more than six weeks. According to in vitro studies, the composite DDS have no cytotoxicity on human retinal pigmented epithelium cells (ARPE-19). Finally, the composite DDS can maintain BSA at the therapeutically relevant concentration for more than one month which is much longer than encapsulating BSA in chemically crosslinked HA hydrogel only. These outcomes show that the injectable composite drug delivery system can be a potential replacement for the treatment of wet AMD.