Dual-Modality Poly-L-histidine Nanoparticles to Deliver Peptide Nucleic Acids and Paclitaxel for In Vivo Cancer Therapy

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-coglycolic acid) (PLGA)-histidine-based nanoformulations for enhanced cytoplasmic delivery with minimal toxicity. PLGA/poly-Lhistidine nanoparticles show promising physico-biochemical features and transfection efficiency in a series of in vitro and cell culturebased 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 (similar to 6 fold) and paclitaxel (similar to 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.

Automated summary

Cationic polymeric nanoformulations based on PLGA and histidine were investigated for enhanced cytoplasmic delivery with minimal toxicity. The optimized formulation process using acetone/dichloromethane improved the morphology and size distribution of the nanoparticles. The nanoformulations showed promising results in in vitro and cell culture studies, and were safe and efficacious for delivering small molecules and synthetic nucleic acid analogs in vivo.