Hierarchical responsive micelle facilitates intratumoral penetration by acid-activated positive charge surface and size contraction
Hierarchical responsive micelle facilitates intratumoral penetration by acid-activated positive charge surface and size contraction
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DOI：
10.1016/j.biomaterials.2021.120741
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发表时间：
2021-03-10
期刊：
影响因子：
14
通讯作者：
Zhang, Xingdong
中科院分区：
文献类型：
--
作者：
Ma, Mengcheng;Chen, Yafang;Zhang, Xingdong
将酸激活的带正电表面和尺寸收缩的这些特征整合到单个纳米颗粒中将是增强细胞摄取、瘤内渗透和积累的有效策略。在此，通过 RAFT 反应开发了分层响应胶束 (HVDM) 作为多功能聚合物-药物缀合物，通过将带正电荷的表面与尺寸收缩相结合，最大限度地提高对 MCF-7 肿瘤的渗透和治疗效果：通过 PHEME 质子化和尺寸收缩（类似于 81-类似于 41 nm）实现表面 zeta 电位反转（2 至 +12 mV） 同时疏水/亲水转化（pH值约6.7）；疏水性PVB和DOX之间腙键的分解引发药物释放（pH值接近5.0）。在pH 6.7下，体外结构稳定性、细胞摄取和抗增殖效率显着高于其他对照组（CVDM和HSDM）。在pH 6.7的3D MCS球体中证实了显着增加的渗透深度、细胞内化和抗肿瘤效率，并且离体DOX荧光图像进一步证实了在实体瘤内部区域的明显渗透和积累。体内抗肿瘤作用表明HVDMs加速肿瘤萎缩，诱导瘤内细胞凋亡并减轻系统毒性。
Integrating these features of acid-activated positively charged surface and size contraction into single nanoparticle would be an effective strategy for enhancing cellular uptake, intratumoral penetration and accumulation. Here, hierarchical responsive micelle (HVDMs) was developed via RAFT reaction as multifunctional polymer-drug conjugate for maximizing penetration and therapeutic effect against MCF-7 tumor by combining positively charged surface with size contraction: surface zeta-potential reversal ( 2 to +12 mV) by protonation of PHEME and size contraction (similar to 81-similar to 41 nm) by simultaneous hydrophobic/hydrophilic conversion (pH approximate to 6.7); the disintegration of hydrazone bond between hydrophobic PVB and DOX triggered drug release (pH approximate to 5.0). The in vitro structural stabilization, cellular uptake and anti-proliferative efficiency were significantly higher than other control groups (CVDMs and HSDMs) at pH 6.7. The markedly increased penetration depth, cellular internalization and anti-tumor efficiency were confirmed in 3D MCSs spheroids at pH 6.7, and the ex vivo DOX fluorescence images further verified obvious penetration and accumulation in internal region of solid tumor. The antitumor effect in vivo demonstrated that HVDMs accelerated tumor atrophy, induced intratumoral cells apoptosis and alleviated system toxicity.