Department of Bioengineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
ACS Nano. 2014 Jul 22;8(7):6724-38. doi: 10.1021/nn500498t. Epub 2014 Jun 13.
Supramolecular assemblies of amphiphilic block copolymers having polypeptide segments offer significant advantages for tailoring spatial arrangement based on secondary structures in their optically active backbones. Here, we demonstrated the critical effect of α-helix bundles in cisplatin-conjugated poly(L- (or D-)glutamate) [P(L(or D)Glu)-CDDP] segment on the packaging of poly(ethylene glycol) (PEG)-P(L(or D)Glu)-CDDP block copolymers in the core of polymeric micelles (CDDP/m) and enhanced micelle tolerability to harsh in vivo conditions for accomplishing appreciable antitumor efficacy against intractable pancreatic tumor by systemic injection. CDDP/m prepared from optically inactive PEG-poly(D,L-glutamate) (P(D,LGlu)), gradually disintegrated in the bloodstream, resulting in increased accumulation in liver and spleen and reduced antitumor efficacy. Alternatively, CDDP/m from optically active PEG-P(L(or D)Glu) maintained micelle structure during circulation, and eventually attained selective tumor accumulation while reducing nonspecific distribution to liver and spleen. Circular dichroism and small-angle X-ray scattering measurements indicated regular bundled assembly of α-helices in the core of CDDP/m from PEG-P(L(or D)Glu), which is suggested to stabilize the micelle structure against dilution in physiological condition. CDDP/m suffered corrosion by chlorides in medium, yet the optically active micelles with α-helix bundles kept the micelle structure for prolonged time, with slowly releasing unimers and dimers from the surface of the bundled core in an erosion-like process, as verified by ultracentrifugation analysis. This is in sharp contrast with the abrupt disintegration of CDDP/m from PEG-P(D,LGlu) without secondary structures. The tailored assembly in the core of the polymeric micelles through regular arrangement of constituting segments is key to overcome their undesirable disintegration in bloodstream, thereby achieving efficient delivery of loaded drugs into target tissues.
具有多肽段的两亲嵌段共聚物的超分子组装为基于其光学活性主链中的二级结构来定制空间排列提供了显著优势。在这里，我们证明了顺铂结合的聚（L-（或 D-）谷氨酸）[P（L（或 D）Glu）-CDDP]段中的α-螺旋束对聚乙二醇（PEG）-P（L（或 D）Glu）-CDDP 嵌段共聚物在聚合物胶束（CDDP/m）核心中的包装的关键影响，并增强了胶束对苛刻的体内条件的耐受性，从而通过系统注射对难治性胰腺肿瘤实现了可观的抗肿瘤功效。由非手性 PEG-聚（D，L-谷氨酸）（P（D，LGlu））制备的 CDDP/m 在血液中逐渐解体，导致在肝脏和脾脏中的积累增加，抗肿瘤功效降低。相比之下，来自手性 PEG-P（L（或 D）Glu）的 CDDP/m 在循环过程中保持胶束结构，最终实现了选择性肿瘤积累，同时减少了对肝脏和脾脏的非特异性分布。圆二色性和小角 X 射线散射测量表明，在来自 PEG-P（L（或 D）Glu）的 CDDP/m 的核心中存在规则的α-螺旋束的组装，这有助于在生理条件下稳定胶束结构。CDDP/m 会被介质中的氯化物腐蚀，但是具有α-螺旋束的手性胶束可以长时间保持胶束结构，通过在侵蚀样过程中从捆绑核心的表面缓慢释放单体和二聚体，通过超速离心分析得到验证。这与没有二级结构的 PEG-P（D，LGlu）的 CDDP/m 的突然解体形成鲜明对比。通过规则排列构成段的聚合物胶束的核心中的定制组装是克服其在血液中不可避免的解体的关键，从而实现将负载药物有效递送到靶组织中。
