Smart Superstructures with Ultrahigh pH-Sensitivity for Targeting Acidic Tumor Microenvironment: Instantaneous Size Switching and Improved Tumor Penetration
Smart Superstructures with Ultrahigh pH-Sensitivity for Targeting Acidic Tumor Microenvironment: Instantaneous Size Switching and Improved Tumor Penetration
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DOI：
10.1021/acsnano.6b02326
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发表时间：
2016-07-01
期刊：
影响因子：
17.1
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Li, Hong-Jun;Du, Jin-Zhi;Wang, Jun
目前，纳米粒子的低递送效率和有限的肿瘤穿透仍然是癌症纳米医学的两个主要挑战。在这里，我们报告了一类pH响应纳米粒子超结构，在酸性肿瘤微环境中具有超灵敏的尺寸切换，以改善肿瘤渗透和有效的体内药物递送。超结构由两亲聚合物引导的铂-前药共轭聚酰胺-胺（PAMAM）树枝状聚合物组装而成，其中两亲聚合物含有用于快速pH响应的可电离叔胺基团。这些超结构在中性pH下具有类似于80 nm的初始尺寸（例如，在血液循环中），但是一旦沉积在微酸性肿瘤微环境（pH类似于6.5-7.0）中，它们在非常窄的酸度范围内（小于0.1-0.2 pH单位）经历了剧烈和急剧的尺寸转变，并瞬间解离成树枝状聚合物结构单元（直径小于10 nm）。这种快速的尺寸转换特征不仅可以通过增强的渗透性和保留效应促进纳米颗粒外渗和积聚，而且还允许更快的纳米颗粒扩散和更有效的肿瘤渗透。我们进一步在多细胞球体和渗透性差的BxPC-3胰腺肿瘤模型中对具有相似尺寸、表面电荷和化学组成的pH敏感和不敏感纳米结构进行了比较研究，其结果表明pH触发的尺寸转换是改善药物渗透和治疗效果的可行策略。
The currently low delivery efficiency and limited tumor penetration of nanoparticles remain two major challenges of cancer nanomedicine. Here, we report a class of pH-responsive nanoparticle superstructures with ultrasensitive size switching in the acidic tumor microenvironment for improved tumor penetration and effective in vivo drug delivery. The superstructures were constructed from amphiphilic polymer directed assembly of platinum-prodrug conjugated polyamido-amine (PAMAM) dendrimers, in which the amphiphilic polymer contains ionizable tertiary amine groups for rapid pH-responsiveness. These superstructures had an initial size of similar to 80 nm at neutral pH (e.g., in blood circulation), but once deposited in the slightly acidic tumor microenvironment (pH similar to 6.5-7.0), they underwent a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units) and dissociated instantaneously into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature not only can facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention effect but also allows faster nanoparticle diffusion and more efficient tumor penetration. We have further carried out comparative studies of pH-sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition in both multicellular spheroids and poorly permeable BxPC-3 pancreatic tumor models, whose results demonstrate that the pH-triggered size switching is a viable strategy for improving drug penetration and therapeutic efficacy.