Su Zhihui, Liang Yanchao, Yao Yao, Wang Tianqi, Zhang Na
Department of Pharmaceutics, School of Pharmaceutical Science, Shandong University, 44 West Culture Road, Ji'nan 250012, Shandong Province, China.
J Mater Chem B. 2016 Feb 14;4(6):1122-1133. doi: 10.1039/c5tb02188j. Epub 2016 Jan 12.
Stimuli-triggered drug release and improved drug loading are two key prerequisites in the preparation of nano-drug delivery systems. Herein, we constructed the first pluronic P123-double (d)-hydrazone bond (hyd)-docetaxel (DTX)/DTX complex micelles (P123-d-hyd-DTX/DTX) which integrated the highly pH-sensitive strategy and the dual drug-loading pattern in one platform. We synthesized pluronic P123-double (d)-hydrazone bond (hyd)-docetaxel (DTX) conjugates (P123-d-hyd-DTX) by conjugating DTX to the PEO chains of P123 via two hydrazone linkages in the backbone for the first time. An increase in the number of hydrazone linkages within the unimolecular conjugate was conducive to improve the pH sensitivity of conjugated-based micelles. Besides, aiming at improving drug loading, the dual drug-loading strategy (chemical conjugation and physical encapsulation) was adopted. Namely, pH-sensitive P123-d-hyd-DTX was used as a vehicle to further encapsulate DTX for preparing P123-d-hyd-DTX/DTX complex micelles. The resulting P123-d-hyd-DTX/DTX micelles exhibited intact spherical shape, uniform particle size distribution (110.37 nm) and higher drug loading (12.64%). The release study in vitro confirmed that P123-d-hyd-DTX/DTX micelles and P123-d-hyd-DTX micelles (as a control) showed highly pH-responsive release properties. In particular at pH 6.5, almost 90.9% and 75% of DTX was released within 48 h, respectively. Compared to P123-d-hyd-DTX micelles, P123-d-hyd-DTX/DTX complex micelles exhibited higher proliferation inhibition effects on B16F10 cells (p < 0.01), while the cytotoxicity of P123-d-hyd-DTX/DTX complex micelles was slightly inferior to that of free DTX (p < 0.05). In the xenograft B16F10 melanoma model, P123-d-hyd-DTX/DTX complex micelles suppressed tumor growth more effectively than Duopafei® (p < 0.01) and P123-d-hyd-DTX micelles (p < 0.05), without causing obvious adverse effects. Overall, the novel polymeric complex micelle based on double-hydrazone bond and dual drug-loading strategies was a promising delivery platform to improve therapeutic efficiency and decrease side effects in cancer treatments.
刺激触发的药物释放和提高药物负载量是制备纳米药物递送系统的两个关键前提条件。在此，我们构建了首个普朗尼克P123 - 双（d）腙键（hyd）- 多西他赛（DTX）/DTX复合胶束（P123 - d - hyd - DTX/DTX），该复合胶束在一个平台上整合了高度pH敏感策略和双重药物负载模式。我们首次通过在主链中经由两个腙键将DTX与P123的PEO链共轭，合成了普朗尼克P123 - 双（d）腙键（hyd）- 多西他赛（DTX）共轭物（P123 - d - hyd - DTX）。单分子共轭物中腙键数量的增加有利于提高基于共轭的胶束的pH敏感性。此外，为了提高药物负载量，采用了双重药物负载策略（化学共轭和物理包封）。即，使用pH敏感的P123 - d - hyd - DTX作为载体进一步包封DTX以制备P123 - d - hyd - DTX/DTX复合胶束。所得的P123 - d - hyd - DTX/DTX胶束呈现出完整的球形、均匀的粒径分布（110.37 nm）以及更高的药物负载量（12.64%）。体外释放研究证实，P123 - d - hyd - DTX/DTX胶束和P123 - d - hyd - DTX胶束（作为对照）表现出高度pH响应性的释放特性。特别是在pH 6.5时，在48小时内分别有近90.9%和75%的DTX释放。与P123 - d - hyd - DTX胶束相比，P123 - d - hyd - DTX/DTX复合胶束对B16F10细胞表现出更高的增殖抑制作用（p < 0.01），而P123 - d - hyd - DTX/DTX复合胶束的细胞毒性略低于游离DTX（p < 0.05）。在异种移植B（16）F10黑色素瘤模型中，P123 - d - hyd - DTX/DTX复合胶束比多帕菲®（p < 0.01）和P123 - d - hyd - DTX胶束（p < 0.05）更有效地抑制肿瘤生长，且未引起明显的不良反应。总体而言，基于双腙键和双重药物负载策略的新型聚合物复合胶束是一个有前景的递送平台，可提高癌症治疗中的治疗效率并减少副作用。
