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Multi pH-sensitive polymer-drug conjugate mixed micelles for efficient co-delivery of doxorubicin and curcumin to synergistically suppress tumor metastasis.
Biomaterials Science ( IF 5.8 ) Pub Date : 2020-08-03 , DOI: 10.1039/d0bm00840k Yuanhang Zhou 1 , Chuhang Zhou , Yang Zou , Yao Jin , Shidi Han , Qi Liu , Xinping Hu , Leqi Wang , Yining Ma , Yan Liu
Biomaterials Science ( IF 5.8 ) Pub Date : 2020-08-03 , DOI: 10.1039/d0bm00840k Yuanhang Zhou 1 , Chuhang Zhou , Yang Zou , Yao Jin , Shidi Han , Qi Liu , Xinping Hu , Leqi Wang , Yining Ma , Yan Liu
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Combination therapy has been proved to be an effective strategy to inhibit metastasis, however, its efficacy is always compromised by the poor delivery efficiency of drugs. In this study, multi pH-sensitive polymer–drug conjugate mixed micelles were fabricated by the self-assembly of PEOz-PLA-ace-Cur, a conjugate of curcumin (Cur) with poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) through the linkage of the pH-cleavable acetal bond, and PEOz-PLA-imi-DOX, a conjugate of doxorubicin (DOX) with PEOz-PLA through the linkage of the pH-cleavable benzoic imine bond. The mixed conjugate micelles (PP-Cur/PP-DOX-Mix-PMs) with accurately and conveniently controlled mass ratio of the two drugs were demonstrated to have a small particle size (40–128 nm), high drug loading capacity and pH-dependent drug release behavior. Notably, PP-Cur5/PP-DOX1-Mix-PMs exhibited slower DOX release under physiological conditions compared with PEOz-PLA-imi-DOX micelles, resulting in deeply reduced side effects in vivo. Furthermore, the mixed conjugate micelles showed synergistically enhanced inhibition of MDA-MB-231 cell growth and metastasis evidenced by the results of in vitro anti-invasion, wound healing and anti-migration assessment, and in vivo bioluminescence imaging in nude mice, and significant reduction of the side effects of DOX compared with dual drug physically loaded polymeric micelles. Mechanistic studies demonstrated that the possible inhibitory mechanism of PP-Cur5/PP-DOX1-Mix-PMs on tumor metastasis could be assigned to their inhibition of the invasion, migration, intravasation and extravasation of tumor cells. In conclusion, the multi pH-sensitive polymer–drug conjugate mixed micelles with synergistically enhanced anti-tumor and anti-metastasis activity are potential candidates for safe and effective cancer combination therapy.
中文翻译：
多pH敏感的聚合物-药物偶联物混合胶束，可有效地共同递送阿霉素和姜黄素，以协同抑制肿瘤转移。
联合疗法已被证明是抑制转移的有效策略，但是，其疗效始终受到不良药物输送效率的损害。在这项研究中，通过自组装PEOz-PLA-ace-Cur（姜黄素（Cur）与聚（2-乙基-2-恶唑啉）-poly的共轭物）制备了多种pH敏感的聚合物-药物共轭混合胶束。 （D，L-丙交酯（PEOz-PLA）通过pH可裂解的乙缩醛键连接，以及PEOz-PLA-imi-DOX，阿霉素（DOX）与PEOz-PLA的共轭物通过pH可裂解的苯甲亚胺键连接。两种化合物的混合比率（PP-Cur / PP-DOX-Mix-PMs）具有精确且方便地控制的质量比，被证明具有较小的粒径（40-128 nm），高载药量和pH-依赖性药物释放行为。值得注意的是，与PEOz-PLA-imi-DOX胶束相比，PP-Cur5 / PP-DOX1-Mix-PMs在生理条件下显示出较慢的DOX释放，从而大大降低了体内的副作用。此外，混合缀合物胶束对MDA-MB-231细胞的生长和转移具有协同增强的抑制作用，体外结果证明了这一点。与双重药物物理负载的聚合物胶束相比，裸鼠体内的抗入侵，伤口愈合和抗迁移评估以及体内生物发光成像显着降低了DOX的副作用。机理研究表明，PP-Cur5 / PP-DOX1-Mix-PMs对肿瘤转移的可能抑制机制可能归因于它们对肿瘤细胞的侵袭，迁移，内渗和外渗的抑制。总之，具有协同增强的抗肿瘤和抗转移活性的多pH敏感的聚合物-药物缀合物混合胶束是安全有效的癌症联合治疗的潜在候选者。
更新日期：2020-09-15
中文翻译：
多pH敏感的聚合物-药物偶联物混合胶束，可有效地共同递送阿霉素和姜黄素，以协同抑制肿瘤转移。
联合疗法已被证明是抑制转移的有效策略，但是，其疗效始终受到不良药物输送效率的损害。在这项研究中，通过自组装PEOz-PLA-ace-Cur（姜黄素（Cur）与聚（2-乙基-2-恶唑啉）-poly的共轭物）制备了多种pH敏感的聚合物-药物共轭混合胶束。 （D，L-丙交酯（PEOz-PLA）通过pH可裂解的乙缩醛键连接，以及PEOz-PLA-imi-DOX，阿霉素（DOX）与PEOz-PLA的共轭物通过pH可裂解的苯甲亚胺键连接。两种化合物的混合比率（PP-Cur / PP-DOX-Mix-PMs）具有精确且方便地控制的质量比，被证明具有较小的粒径（40-128 nm），高载药量和pH-依赖性药物释放行为。值得注意的是，与PEOz-PLA-imi-DOX胶束相比，PP-Cur5 / PP-DOX1-Mix-PMs在生理条件下显示出较慢的DOX释放，从而大大降低了体内的副作用。此外，混合缀合物胶束对MDA-MB-231细胞的生长和转移具有协同增强的抑制作用，体外结果证明了这一点。与双重药物物理负载的聚合物胶束相比，裸鼠体内的抗入侵，伤口愈合和抗迁移评估以及体内生物发光成像显着降低了DOX的副作用。机理研究表明，PP-Cur5 / PP-DOX1-Mix-PMs对肿瘤转移的可能抑制机制可能归因于它们对肿瘤细胞的侵袭，迁移，内渗和外渗的抑制。总之，具有协同增强的抗肿瘤和抗转移活性的多pH敏感的聚合物-药物缀合物混合胶束是安全有效的癌症联合治疗的潜在候选者。
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