天門冬胺酸修飾PLGA-g-PEG高分子作為骨標靶奈米載體之合成與性質研究

藥物控制釋放技術是現代醫藥科技最為重要的科學技術，藥物控制釋放技術目的在提高藥物的療效、降低藥物的副作用及減少病患的痛苦和麻煩，一般分為時間控制和分佈控制兩方法。目前臨床上有關骨疾病仍缺乏一種具有效標的骨組織的藥物載體，以致於藥物無法正確的傳遞至骨骼患部來達療效，更嚴重的問題是為了治療這些骨疾病卻常常引起許多不良的副作用；再者這類藥物往往是難溶於水的藥物，故一直以來無法以靜脈注射的方式給藥，而以口服方式給藥時，為達到有效的藥物劑量不得不提高服用的劑量，更是對於人體的代謝器官造成了負荷，還有慢性骨病的患者，往往需要每日的服藥，或長期的注射，對於患者的心理及生活品質上也受到極大的影響。本研究擬發展一種骨標的性的奈米藥物載體，使其可以包覆親脂性藥物並且比較有效率的傳遞到骨組織。這種具骨標的性的奈米載體設計是以線性聚乳酸聚甘醇酸(PLGA)生物高分子，末端修飾上具有親骨性質的胺基酸寡聚樹枝狀官能基(天門冬胺酸，Aspartic acid;(Asp)n n=1,3)以作為奈米高分子藥物載體。結果顯示本研究成功合成具有親骨性的分子如寡聚樹枝狀的Aspn (n=1,3)等。以此寡聚樹枝狀Aspn作為起始物，先接上甲氧基(-OMe)保護基，藉由保護基改變原本Aspn分子不溶於極性有機溶劑的特性，再與雙官能基的聚乙二醇(NH2-PEG-COOH)共價醯胺化鍵結，接著在鹼性環境下去除Aspn上胺基酸的甲氧基保護，最後再一次醯胺共價鍵結上PLGA，形成三段共聚高分子(triblock polymer , PLGA-PEG-(Asp)n) (n=1,3)。此PLGA-PEG-(Asp)n 三段共聚高分子的化學結構鑑定以FTIR、NMR、MASS評估，將共聚高分子以溶劑置換析出法製造的PLGA-PEG-(Asp)n奈米小球載體，其粒徑分佈在100-250nm之間。而此奈米藥物載體PLGA-PEG-(Asp)n所製造的奈米小球的再與骨組織之氫氧基磷灰石之親和實驗中，證實親骨性質比起PLGA-PEG高，顯示出當尾端的親骨性分子越多時，PLGA-PEG-(Asp)n 的親骨能力越優秀，因此本研究設計開發具骨標定性的藥物奈米載體，初步結果顯示具有骨標靶性治療骨疾病潛力。

關鍵字

骨標靶

並列摘要

Controlled drug delivery technology represents one of the most important areas of science in which chemists are contributing to human health. Its purpose is to improved efficacy, reduced toxicity, and improved patient compliance and convenience. Two types of control over drug release can be achieved, temporal and distribution control. Because of musculoskeletal diseases have lacked of targeting drug delivery systems, result in delivering the drug not on correct part to cure. Using this drug more often than not only to treatment of these disease but brings other side effect. And water-insoluble drug unable to intravenous (IV) injection. Using oral medicine, in order to reach effective drug concentration, high systemic doses of the therapeutic must often administered, which may lead to significant adverse systemic and side effect. Taking medicine every day or inject therapeutic agent to patients of chronic musculoskeletal diseases for a long time, which influenced patient’s body, mind and live quality. Therefore, the newly bone-targeting drug delivery systems had developed. The carrier will pack fat-soluble drug and delivery to bone tissues exactly. The bone-targeting nanoparticles prepared from liner biopolymer PLGA and the end group to modified aspartic acid which is an amino acid and bone-targeting characterization. Achievement of initial, bone-targeting moiety aspartic acid was synthesized. Aspartic acid as initiator, methoxy protection group was modified. By protecting group the material was changed property which was organic solvent-insoluble. The derivation was reacted with PEG. In alkaline to remove the methoxy group. And the copolymer was conjugated to PLGA. PLGA-PEG-Aspn (n=1,3) triblock polymer was synthesized. The bone-targeting polymer identified with NMR, MASS, UV and IR. Nanoparticles size were prepared by dialysis and had size spread from 100 to 250nm. In vitro HAp affinity assay, the nanoparticles displayed bone-targeting efficiency than unmodified PLGA nanoparticles. Therefore, the development of bone-targeting drug delivery should have significant potential for treating musculoskeletal diseases future.