J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida.
Department of Biomedical Engineering, University of California, Davis, Davis, California.
J Biomed Mater Res A. 2018 Apr;106(4):1022-1033. doi: 10.1002/jbm.a.36298. Epub 2017 Dec 21.
Poly(lactic-co-glycolic acid) (PLGA) is widely used as a vehicle for delivery of pharmaceutically relevant payloads. PLGA is readily fabricated as a nano- or microparticle (MP) matrix to load both hydrophobic and hydrophilic small molecular drugs as well as biomacromolecules such as nucleic acids and proteins. However, targeting such payloads to the cell cytosol is often limited by MP entrapment and degradation within acidic endolysosomes. Poly(propylacrylic acid) (PPAA) is a polyelectrolyte polymer with the membrane disruptive capability triggered at low pH. PPAA has been previously formulated in various carrier configurations to enable cytosolic payload delivery, but requires sophisticated carrier design. Taking advantage of PPAA functionality, we have incorporated PPAA into PLGA MPs as a simple polymer mixture to enhance cytosolic delivery of PLGA-encapsulated payloads. Rhodamine loaded PLGA and PPAA/PLGA blend MPs were prepared by a modified nanoprecipitation method. Incorporation of PPAA into PLGA MPs had little to no effect on the size, shape, or loading efficiency, and evidenced no toxicity in Chinese hamster ovary epithelial cells. Notably, incorporation of PPAA into PLGA MPs enabled pH-dependent membrane disruption in a hemolysis assay, and a three-fold increased endosomal escape and cytosolic delivery in dendritic cells after 2 h of MP uptake. These results demonstrate that a simple PLGA/PPAA polymer blend is readily fabricated into composite MPs, enabling cytosolic delivery of an encapsulated payload. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1022-1033, 2018.
聚（丙交酯-乙交酯）（PLGA）广泛用作药物相关有效载荷的递送载体。PLGA 很容易被制成纳米或微颗粒（MP）基质，以负载疏水性和亲水性小分子药物以及生物大分子，如核酸和蛋白质。然而，将这些有效载荷靶向到细胞质中通常受到 MP 在内体酸性环境中的包埋和降解的限制。聚（丙稀酸）（PPAA）是一种聚电解质聚合物，在低 pH 值时具有膜破坏能力。PPAA 以前曾在各种载体构型中进行配方设计，以实现细胞质内有效载荷的递送，但需要复杂的载体设计。利用 PPAA 的功能，我们将其掺入 PLGA MPs 中作为一种简单的聚合物混合物，以增强 PLGA 包封有效载荷的细胞质内递送。通过改良的纳米沉淀法制备了负载罗丹明的 PLGA 和 PPAA/PLGA 共混 MPs。PPAA 掺入 PLGA MPs 对其大小、形状或载药效率几乎没有影响，并且在仓鼠卵巢上皮细胞中没有表现出毒性。值得注意的是，PPAA 掺入 PLGA MPs 可在溶血试验中导致 pH 依赖性的膜破坏，并且在 MPs 摄取 2 小时后，树突状细胞中内体逃逸和细胞质内递送增加了三倍。这些结果表明，简单的 PLGA/PPAA 聚合物共混物可轻松制成复合 MPs，从而实现包封有效载荷的细胞质内递送。© 2017 Wiley Periodicals, Inc. J 生物材料研究杂志 A 部分：106A:1022-1033，2018。
