Tumor Microenvironment Stimuli-Responsive Nanoparticles for Programmed Anticancer Drug Delivery
Tumor Microenvironment Stimuli-Responsive Nanoparticles for Programmed Anticancer Drug Delivery
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DOI：
10.1021/acs.molpharmaceut.9b01189
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发表时间：
2020-05-04
影响因子：
4.9
通讯作者：
Hu, Haiyang
中科院分区：
文献类型：
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作者：
Jia, Nan;Li, Wenpan;Hu, Haiyang
众所周知，大尺寸纳米颗粒在循环系统中停留时间较长，但组织渗透性差，细胞摄取低。为了协调对延长循环时间、广泛的肿瘤组织渗透和增强细胞摄取纳米片递送系统的矛盾需求，我们设计了含有DOX的超敏纳米粒，它响应肿瘤微环境进行程序化DOX递送。合成了一种超灵敏聚合物材料聚(2-乙基-2-恶唑啉)-聚(甲基丙烯酰磺胺二甲氧基)(PEOz-b-PSD，pK(A)=6.96)。在生理环境中，PEOz-b-PSD和聚酰胺胺/DOX(PAMAM/DOX)可通过静电吸附形成纳米粒子PEOz-b-PSD/PAMAM/DOX(PEPSD/PAM/DOX)。PEPSD/PAM/DOX具有完整的结构，可以延长循环时间。而在肿瘤环境中，PEOz-b-PSD被快速质子化并表现出电荷反转，导致PEOz-b-PSD从纳米粒子中脱落；然后带有负电荷的大尺寸纳米粒子(PEPSD/PAM/DOX)瞬间转变为带正电荷的超细纳米粒子。大小和电荷的突然反转可以有效地改善肿瘤的聚集和内穿透。在进入肿瘤细胞后，纳米粒子可以通过PAMAM质子海绵的作用快速释放药物，从而增强对肿瘤的抑制。结果表明，程序化纳米粒能显著提高DOX的体内抗肿瘤活性，降低其心脏毒性。本研究在肿瘤微环境中设计了超灵敏的纳米粒子，这似乎有利于提高DOX在实体瘤中的治疗效果。
It is well-known that large size nanoparticles stay for a long time in the circulation system, but show poor tissue penetration and low cellular uptake. In order to reconcile the conflicting needs for extended circulation time, extensive tumor tissue penetration, and enhanced cellular uptake for nanodrug delivery systems, we designed DOX-containing hypersensitive nanoparticles that responded to the tumor microenvironment for programmed DOX delivery. A supersensitive polymer material, poly(2-ethyl-2-oxazoline)-poly(methacryloyl sulfadimethoxine), was synthesized (PEOz-b-PSD, pK(a) = 6.96). At the physiological environment, PEOz-b-PSD and polyamidoamine/DOX (PAMAM/DOX) can form nanoparticles, PEOz-b-PSD/PAMAM/DOX (PEPSD/PAM/DOX), via electrostatic adsorption. The PEPSD/PAM/DOX has an intact structure, which can prolong circulation time. While in the tumor environment, the PEOz-b-PSD was rapidly protonated and showed charge reversal, leading the detachment of PEOz-b-PSD from the nanoparticles; then the large size nanoparticles with a negative charge (PEPSD/PAM/DOX) instantaneously turn into positively charged ultrafine nanoparticles. The sudden inversion of size and charge can effectively improve tumor accumulation and internal penetration. After entering tumor cells, nanoparticles can release drugs quickly through the action of a PAMAM proton sponge, resulting in enhanced tumor inhibition. Our results proved that the programmed nanoparticles could remarkably enhance the in vivo antitumor efficacy and reduce cardiotoxicity of DOX. This study designed ultrasensitive nanoparticles in the tumor microenvironment, which appear to be beneficial for enhancing the treatment efficacy of DOX in solid tumors.