Cationic polymeric nanoformulations have been explored to increase the transfection efficiency of small molecules and nucleic acid-based drugs. However, an excessive positive charge density often leads to severe cell and tissue-based toxicity that restricts the clinical translation of cationic polymeric nanoformulations. Herein, we investigate a series of cationic poly(lactic-co-glycolic acid) (PLGA)-histidine-based nanoformulations for enhanced cytoplasmic delivery with minimal toxicity. PLGA/poly-l-histidine nanoparticles show promising physico-biochemical features and transfection efficiency in a series of in vitro and cell culture-based studies. Further, the use of acetone/dichloromethane as a solvent mixture during the formulation process significantly improves the morphology and size distribution of PLGA/poly-l-histidine nanoparticles. PLGA/poly-l-histidine nanoformulations undergo clathrin-mediated endocytosis. A contrast-matched small-angle neutron scattering experiment confirmed poly-l-histidine’s distribution on the PLGA nanoformulations. PLGA/poly-l-histidine formulations containing paclitaxel as a small molecule-based drug and peptide nucleic acids targeting microRNA-155 as nucleic acid analog are efficacious in in vitro and in vivo studies. PLGA/poly-l-histidine NPs significantly decrease tumor growth in PNA-155 (∼6 fold) and paclitaxel (∼6.5 fold) treatment groups in a lymphoma cell line derived xenograft mice model without inducing any toxicity. Hence, PLGA/poly-l-histidine nanoformulations exhibit substantial transfection efficiency and are safe to deliver reagents ranging from small molecules to synthetic nucleic acid analogs and can serve as a novel platform for drug delivery.

中文翻译：

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双模态多聚-l-组氨酸纳米颗粒为体内癌症治疗提供肽核酸和紫杉醇

已探索阳离子聚合物纳米制剂以提高小分子和基于核酸的药物的转染效率。然而，过多的正电荷密度通常会导致严重的细胞和组织毒性，从而限制阳离子聚合物纳米制剂的临床转化。在此，我们研究了一系列基于阳离子聚（乳酸-共-乙醇酸）（PLGA）-组氨酸的纳米制剂，用于增强细胞质递送，且毒性最小。PLGA/poly -l-组氨酸纳米粒子在一系列基于体外和细胞培养的研究中显示出有前景的物理生化特征和转染效率。此外，在配制过程中使用丙酮/二氯甲烷作为溶剂混合物显着改善了 PLGA/聚-L-组氨酸纳米颗粒的形态和尺寸分布。PLGA/聚-L-组氨酸纳米制剂经历网格蛋白介导的内吞作用。对比匹配的小角中子散射实验证实了聚L-组氨酸在PLGA纳米制剂上的分布。PLGA/poly -l含有作为小分子药物的紫杉醇和作为核酸类似物的靶向microRNA-155的肽核酸的组氨酸制剂在体外和体内研究中是有效的。在淋巴瘤细胞系衍生的异种移植小鼠模型中， PLGA/聚L-组氨酸 NP 显着降低 PNA-155（~6 倍）和紫杉醇（~6.5 倍）治疗组的肿瘤生长，而不会引起任何毒性。因此，PLGA/聚-l-组氨酸纳米制剂表现出显着的转染效率，并且可以安全地递送从小分子到合成核酸类似物的试剂，并且可以作为药物递送的新平台。