新型骨標的性奈米高分子藥物傳遞系統之合成與特性研究

目前臨床上有關骨質疏鬆及骨癌等骨科疾病仍缺乏一具有效標的性的藥物載體，以致於藥物無法正確的傳遞至患部來達療效，更嚴重的問題是為了治療這些疾病卻常常引起許多不良的副作用；再者這類藥物往往是油脂性藥物，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精確的傳遞到骨組織。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=3,7)以作為奈米高分子藥物載體。初步結果顯示本研究成功合成具有親骨性的分子如Bisphosphonates (n-Amino-1-hydroxybutane-1,1-diyldiphosphonic acid；n=4, 8, 12)、以及寡聚樹枝狀的Aspn(n=3,7)等。其中以寡聚樹枝狀Aspartic acid 作為起始物，接上甲氧基(-OMe)保護基，藉由保護基改變原本分子不溶於有機溶劑的特性，先與聚乙二醇鍵結，在鹼性環境下去除胺基酸上的甲氧基保護，最後再鍵結上PLGA，形成三段共聚高分子(triblock polymer , PLGA-PEG-(Asp)n) (n=3,7)。此PLGA-PEG-(Asp)n 三段共聚高分子的粒徑大小及體外親骨性質研究結果顯示，以透析法製造的PLGA-PEG-(Asp)n奈米小球載體，其粒徑分佈在160-230nm之間。而此奈米藥物載體PLGA-PEG-(Asp)n所製造的奈米小球的親骨性質比起未接枝的PLGA高了2-3倍，因此本研究開發具骨標定性的藥物奈米載體初步顯示具有骨標靶性治療骨疾病潛力。

關鍵字

骨標的；藥物傳輸系統

並列摘要

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 everyday 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 removed the methoxy group. And the copolymer was conjugated to PLGA. PLGA-PEG-Aspn (n=3,7) 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 160 to 230nm. In vitro HAp affinity assay, the nanoparticles displayed 2-3 fold bone-targeting efficiency than unmodified PLGA nanoparticles. Therefore, the development of bone-targeting drug delivery should have significant potential for treating musculoskeletal diseases future.