A size switchable nanoplatform for targeting the tumor microenvironment and deep tumor penetration
A size switchable nanoplatform for targeting the tumor microenvironment and deep tumor penetration
复制标题
用于靶向肿瘤微环境和深度肿瘤渗透的尺寸可切换纳米平台
DOI：
10.1039/c8nr00640g
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发表时间：
2018-06-07
期刊：
影响因子：
6.7
通讯作者：
He, Qin
中科院分区：
文献类型：
--
作者：
Cun, Xingli;Li, Man;He, Qin
实体瘤中复杂的肿瘤微环境（TME）对纳米药物的有效递送形成生理屏障，导致治疗效果有限。在此，为了克服这些生理障碍并提高治疗效果，我们构建了一种新型的尺寸可调节的纳米平台，用于有效地将药物递送到实体肿瘤中。通过基质金属蛋白酶2（MMP-2）敏感肽将小树枝状接枝聚-l-赖氨酸（DGL）缀合到聚（乙二醇）-聚（己内酯）胶束上制备了智能尺寸可切换纳米平台（DGL/DOX@PP）。DGL/DOX@PP具有100 nm的初始尺寸和接近中性的电荷，使得系统能够利用增强的渗透性和保留效果。在从肿瘤血管外渗后，响应于TME中的MMP-2，小的DGL/DOX纳米颗粒（约30 nm）从DGL/DOX@PP中快速释放。这种颗粒尺寸改变的过程大大增强了纳米颗粒渗透到多细胞球体（MCS）和实体瘤中。体内结果表明，与小的和不可切换的纳米颗粒相比，来自尺寸可切换的纳米平台的颗粒在4 T1荷瘤小鼠中实现了优异的抗肿瘤功效。这种尺寸可调节的纳米平台为TME调节和肿瘤渗透提供了多功能策略。
The complex tumor microenvironment (TME) in solid tumors forms physiological barriers to the efficient delivery of nanomedicine, leading to limited therapeutic efficacy. Herein, to overcome these physiological barriers and improve the therapeutic effect, we constructed a novel size-adjustable nanoplatform for efficient drug delivery into solid tumors. The smart size-switchable nanoplatform (DGL/DOX@PP) was prepared by conjugating small dendrigraft poly-l-lysine (DGL) to poly(ethylene glycol)-poly(caprolactone) micelles via a matrix metalloproteinase 2 (MMP-2)-sensitive peptide. DGL/DOX@PP had an initial size of 100 nm and a nearly neutral charge, rendering the system able to take advantage of the enhanced permeability and retention effect. After extravasation from the tumor vessels, small DGL/DOX nanoparticles (approximate to 30 nm) were rapidly released from DGL/DOX@PP in response to MMP-2 in the TME. This process of particle size alteration greatly enhanced the nanoparticle penetration into both multicellular spheroids (MCSs) and solid tumors. In vivo results demonstrated that compared with small and non-switchable nanoparticles, particles from the size-switchable nanoplatform achieved excellent antitumor efficacy in 4T1 tumor-bearing mice. This size-adjustable nanoplatform provides a multifunctional strategy for TME modulation and tumor penetration.