Centre for Nanoscience and Nanotechnology, Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
ACS Nano. 2010 Mar 23;4(3):1653-63. doi: 10.1021/nn9014278.
We report the modular assembly of a polymer-drug conjugate into covalently stabilized, responsive, biodegradable, and drug-loaded capsules with control over drug dose and position in the multilayer film. The cancer therapeutic, doxorubicin hydrochloride (DOX), was conjugated to alkyne-functionalized poly(l-glutamic acid) (PGA(Alk)) via amide bond formation. PGA(Alk) and PGA(Alk+DOX) were assembled via hydrogen bonding with poly(N-vinyl pyrrolidone) (PVPON) on planar and colloidal silica templates. The films were subsequently covalently stabilized using diazide cross-linkers, and PVPON was released from the multilayers by altering the solution pH to disrupt hydrogen bonding. After removal of the sacrificial template, single-component PGA(Alk) capsules were obtained and analyzed by optical microscopy, transmission electron microscopy, and atomic force microscopy. The PGA(Alk) capsules were stable in the pH range between 2 and 11 and exhibited reversible swelling/shrinking behavior. PGA(Alk+DOX) was assembled to form drug-loaded polymer capsules with control over drug dose and position in the multilayer system (e.g., DOX in every layer or exclusively in layer 3). The drug-loaded capsules could be degraded enzymatically, resulting in the sustained release of active DOX over approximately 2 h. Cellular uptake studies demonstrate that the viability of cells incubated with DOX-loaded PGA(Alk) capsules significantly decreased. The general applicability of this modular approach, in terms of incorporation of polymer-drug conjugates in other click multilayer systems, was also demonstrated. Biodegradable click capsules with drug-loaded multilayers are promising candidates as carrier systems for biomedical applications.
我们报告了一种将聚合物-药物偶联物组装成共价稳定、响应性、可生物降解且载药胶囊的方法，可控制多层膜中的药物剂量和位置。抗癌药物盐酸多柔比星（DOX）通过酰胺键形成与炔基功能化聚（L-谷氨酸）（PGA（Alk））偶联。PGA（Alk）和 PGA（Alk+DOX）通过氢键与平面和胶体二氧化硅模板上的聚（N-乙烯基吡咯烷酮）（PVPON）组装。然后使用叠氮交联剂共价稳定薄膜，并通过改变溶液 pH 值破坏氢键从多层中释放 PVPON。去除牺牲模板后，获得单一组分 PGA（Alk）胶囊，并通过光学显微镜、透射电子显微镜和原子力显微镜进行分析。PGA（Alk）胶囊在 pH 值为 2 至 11 之间稳定，表现出可逆的溶胀/收缩行为。PGA（Alk+DOX）被组装成具有控制多层系统中药物剂量和位置的载药聚合物胶囊（例如，每个层中的 DOX 或仅在第 3 层中的 DOX）。载药胶囊可以通过酶降解，导致活性 DOX 持续释放约 2 小时。细胞摄取研究表明，与载有 DOX 的 PGA（Alk）胶囊孵育的细胞的活力显着降低。这种模块化方法的通用性，在将聚合物-药物偶联物纳入其他点击多层系统方面，也得到了证明。具有载药多层的可生物降解点击胶囊是生物医学应用中载体系统的有前途的候选物。
