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.