Efficient Co-delivery of Doxorubicin and Methotrexate by pH-Sensitive Dual-Functional Nanomicelles for Enhanced Synergistic Antitumor Efficacy,ACS Applied Bio Materials

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Efficient Co-delivery of Doxorubicin and Methotrexate by pH-Sensitive Dual-Functional Nanomicelles for Enhanced Synergistic Antitumor Efficacy
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2019-05-06 , DOI: 10.1021/acsabm.9b00230
Youmei Li ₁ , Shu Chen ₁ , Xiupeng Chang ₁ , Feng He ₁ , Renxi Zhuo ₁

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Combination therapy by co-delivering multiple drugs using a single delivery carrier is a promising strategy to achieve a synergistic antitumor effect. In this study, a novel dual-functional block copolymer mPEG-b-poly(TAC-co-ATMC-g-S(CH₂)₁₀COOH) was designed and synthesized for co-delivering two kinds of anticancer drugs, methotrexate (MTX) and doxorubicin (DOX). This biodegradable amphiphilic copolymer could spontaneously self-assemble into electronegative nanomicelles with higher micelle stability and lower hemolysis ratio. Besides hydrophobic interactions, electrostatic interactions between the carboxyl groups of 5-allyloxy-1,3-dioxan-2-one (ATMC) with amine groups of DOX, as well as complementary multiple hydrogen-bonding interactions between thymine groups of thymine-functional six-membered cyclic carbonate (TAC) and 2,6-diaminopyridine (DAP) groups of MTX, could contribute to co-delivering DOX/MTX simultaneously with high-efficiency loading without interference with each other. For comparison, DOX alone and MTX alone were also encapsulated into mPEG-b-poly(TAC-co-ATMC-g-S(CH₂)₁₀COOH) nanomicelles. All drug-loaded nanomicelles exhibited sustained release properties with a pH sensitivity. Confocal laser scanning microscopy revealed an efficient cell uptake of DOX and MTX delivered by mPEG-b-poly(TAC-co-ATMC-g-S(CH₂)₁₀COOH) nanomicelles, while DOX mainly accumulated in nuclei and MTX in cytoplasm after 8 h of incubation. MTT assay further demonstrated an enhanced synergistic antitumor efficacy of DOX/MTX co-loaded nanomicelles. Therefore, DOX/MTX co-loaded mPEG-b-poly(TAC-co-ATMC-g-S(CH₂)₁₀COOH) nanomicelles might have attractive potentials in clinical implications for efficient combination chemotherapy.

中文翻译：

通过 pH 敏感双功能纳米胶束有效共同递送多柔比星和甲氨蝶呤以增强协同抗肿瘤功效

通过使用单一递送载体共同递送多种药物的联合治疗是实现协同抗肿瘤作用的有前景的策略。在本研究中，一种新型双功能嵌段共聚物 mPEG- b -poly (TAC- co -ATMC- g -S(CH ₂ ) ₁₀COOH) 被设计和合成用于共同递送两种抗癌药物，甲氨蝶呤 (MTX) 和多柔比星 (DOX)。这种可生物降解的两亲共聚物可以自发地自组装成具有较高胶束稳定性和较低溶血率的负电纳米胶束。除疏水相互作用外，5-烯丙氧基-1,3-二恶烷-2-酮 (ATMC) 的羧基与 DOX 的胺基之间的静电相互作用，以及胸腺嘧啶官能团 6 的胸腺嘧啶基团之间的互补多重氢键相互作用MTX 的 - 元环状碳酸酯 (TAC) 和 2,6-二氨基吡啶 (DAP) 基团有助于在高效负载的同时共同递送 DOX/MTX，而不会相互干扰。为了比较，单独的 DOX 和单独的 MTX 也被封装到 mPEG- b-poly (TAC- co -ATMC- g -S(CH ₂ ) ₁₀ COOH) 纳米胶束。所有载药纳米胶束均表现出具有pH敏感性的缓释特性。共聚焦激光扫描显微镜显示通过 mPEG- b -poly (TAC- co -ATMC- g -S(CH ₂ ) ₁₀ COOH) 纳米胶束传递的 DOX 和 MTX 有效的细胞摄取，而 DOX 主要在细胞核和 MTX 后积累在细胞质中8小时的孵化。MTT 测定进一步证明了 DOX/MTX 共负载纳米胶束的协同抗肿瘤功效增强。因此，DOX/MTX 共载 mPEG- b -poly (TAC- co -ATMC- g-S(CH ₂ ) ₁₀ COOH) 纳米胶束在有效联合化疗的临床意义方面可能具有吸引人的潜力。

更新日期：2019-05-16

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