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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers
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Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers

机译：使用自组装生物集成嵌段共聚物对目标纳米颗粒进行精确工程设计

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摘要

There has been progressively heightened interest in the development of targeted nanoparticles (NPs) for differential delivery and controlled release of drugs. Despite nearly three decades of research, approaches to reproducibly formulate targeted NPs with the optimal biophysicochemical properties have remained elusive. A central challenge has been defining the optimal interplay of parameters that confer molecular targeting, immune evasion, and drug release to overcome the physiological barriers in vivo. Here, we report a strategy for narrowly changing the biophysicochemical properties of NPs in a reproducible manner, thereby enabling systematic screening of optimally formulated drug-encapsulated targeted NPs. NPs were formulated by the self-assembly of an amphiphilic triblock copolymer composed of end-to-end linkage of poly(lactic-co-glycolic-acid) (PLGA), polyethyleneglycol (PEG), and the A10 aptamer (Apt), which binds to the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer (PCa) cells, enabling, respectively, controlled drug release, "stealth" properties for immune evasion, and cell-specific targeting. Fine-tuning of NP size and drug release kinetics was further accomplished by controlling the copolymer composition. By using distinct ratios of PLGA-b-PEG-b-Apt triblock copolymer with PLGA-b-PEG diblock copolymer lacking the A10 Apt, we developed a series of targeted NPs with increasing Apt densities that inversely affected the amount of PEG exposure on NP surface and identified the narrow range of Apt density when the NPs were maximally targeted and maximally stealth, resulting in most efficient PCa cell uptake in vitro and in vivo. This approach may contribute to further development of targeted NPs as highly selective and effective therapeutic modalities.
机译：人们越来越关注用于差异递送和药物控释的靶向纳米颗粒（NP）的开发。尽管进行了近三十年的研究，但仍难以确定具有最佳生物物理化学性质的可重复配制目标NP的方法。一个主要的挑战是确定参数的最佳相互作用，以赋予分子靶向，免疫逃逸和药物释放以克服体内的生理障碍。在这里，我们报告了一种策略，用于以可再现的方式狭窄地改变NP的生物物理化学特性，从而能够系统地筛选最佳配制的药物封装的靶向NP。 NP是通过两亲性三嵌段共聚物的自组装而形成的，该两亲性三嵌段共聚物由聚乳酸-乙醇酸（PLGA），聚乙二醇（PEG）和A10适体（Apt）的端对端连接组成。与前列腺癌（PCa）细胞表面上的前列腺特异性膜抗原（PSMA）结合，从而分别控制药物的释放，免疫逃逸的“隐身”特性和细胞特异性靶向。 NP尺寸和药物释放动力学的微调通过控制共聚物组成进一步完成。通过使用不同比例的PLGA-b-PEG-b-Apt三嵌段共聚物与缺乏A10 Apt的PLGA-b-PEG二嵌段共聚物，我们开发了一系列具有增加Apt密度的靶向NP，这反过来影响了PEG在NP上的暴露量当NP被最大程度地靶向并最大程度地隐身时，表面可以识别出Apt密度的狭窄范围，从而在体外和体内都能最有效地吸收PCa细胞。这种方法可能有助于靶向NP进一步发展为高度选择性和有效的治疗方式。

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