Co-delivery systems with programmed release of combined drugs are of great value for combination cancer therapy. However, design of such co-delivery systems for potent synergistic cancer therapy is still a great challenge. In the present work, dimethylcurcumin (DMC) and docetaxel (DTX) co-loaded branched worm-like nanoparticles (NPs) with programmed release of DMC and DTX were developed for potent synergistic castration-resistant prostate cancer (CRPC) therapy. (2-Hydroxypropyl)-β-cyclodextrin-retinoic acid (HP-β-CD-RA) conjugates with different molar ratios of RA to HP-β-CD were synthesized and used for the preparation of DMC and DTX co-loaded NPs. The as-prepared DMC and DTX co-loaded NPs ( D h 170–190 nm) have branched worm-like morphologies, and DMC/DTX@HP-β-CD-RA 3.0 NPs show the highest drug loading content and encapsulation efficiency. DMC/DTX@HP-β-CD-RA 3.0 NPs exhibit programmed drug release patterns with DTX released much faster than DMC, which could be ascribed to the difference between DMC and DTX in the interaction with HP-β-CD-RA 3.0 as analyzed by molecular simulation, phase solubility method, and fluorescence spectra. DMC/DTX@HP-β-CD-RA 3.0 NPs exhibit enhanced cellular uptake as compared to DMC/DTX. Mechanism dissection reveals that the cellular uptake of DMC/DTX@HP-β-CD-RA 3.0 NPs is energy-dependent in which macropinocytosis and clathrin- and caveolae-independent endocytosis pathways are involved. Benefited from their enhanced cellular uptake and programmed drug release, DMC/DTX@HP-β-CD-RA 3.0 NPs exhibit significantly enhanced antitumor effect as compared to DMC/DTX. Such mechanisms for potent synergistic antitumor effect, by enhancing cellular uptake of DMC and DTX together with programmed drug release, may provide new therapeutic options for CRPC.

中文翻译：

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具有程序化药物释放的分支蠕虫状纳米粒子用于协同去势抵抗性前列腺癌治疗

具有组合药物程序释放的共递送系统对于组合癌症治疗具有重要价值。然而，设计用于有效协同癌症治疗的这种共递送系统仍然是一个巨大的挑战。在目前的工作中，二甲基姜黄素 (DMC) 和多西紫杉醇 (DTX) 共同负载的分支蠕虫状纳米粒子 (NPs) 与 DMC 和 DTX 的程序释放被开发用于有效的协同去势抵抗前列腺癌 (CRPC) 治疗。合成了具有不同 RA 与 HP-β-CD 摩尔比的 (2-羟丙基)-β-环糊精-视黄酸 (HP-β-CD-RA) 缀合物，并将其用于制备 DMC 和 DTX 共载 NP。制备的 DMC 和 DTX 共载 NPs (D h 170–190 nm) 具有分支蠕虫状形态，DMC/DTX@HP-β-CD-RA 3.0 NPs 显示出最高的载药量和封装效率。DMC/DTX@HP-β-CD-RA 3.0 NPs 表现出程序化的药物释放模式，其中 DTX 的释放速度比 DMC 快得多，这可以归因于 DMC 和 DTX 在与 HP-β-CD-RA 3.0 相互作用方面的差异：通过分子模拟、相溶解度法和荧光光谱分析。与 DMC/DTX 相比，DMC/DTX@HP-β-CD-RA 3.0 NPs 表现出增强的细胞摄取。机制剖析表明，DMC/DTX@HP-β-CD-RA 3.0 NPs 的细胞摄取是能量依赖性的，其中涉及巨胞饮作用和网格蛋白和小窝独立的内吞作用途径。得益于其增强的细胞摄取和程序化药物释放，与 DMC/DTX 相比，DMC/DTX@HP-β-CD-RA 3.0 NPs 表现出显着增强的抗肿瘤作用。这种有效协同抗肿瘤作用的机制，