Enhanced thrombolysis using tissue plasminogen activator (tPA)-loaded PEGylated PLGA nanoparticles for ischemic stroke

Abstract Conventional thrombolytic therapy of ischemic stroke by tPA shows sometimes complications or insufficient therapeutic effects due to limitations of tPA. To prolong the circulating time and the thrombolytic activity of tPA as well as augmenting the capacity of self-targeting of tPA, we aimed to engineer tPA-loaded biodegradable and biocompatible polymeric nanoparticles (NPs). The PEG (polyethylene glycol) attached to the poly(lactic-co-glycolic acid) (PLGA) through carbodiimide/N-hydroxysuccinimide chemistry and then the PEG-PLGA NPs containing tPA was formulated using single emulsion solvent diffusion/evaporation technique. The physicochemical and morphological properties of NPs and functional release profile were investigated and the thrombolytic activity of NPs was evaluated using in vitro models. The engineered NPs showed a smooth spherical shape with a mean size of 250–280 nm, PDI of 0.1–0.2, and zeta potential of −7 mV and −12 mV for PLGA and PEG-PLGA NPs, respectively. Drug entrapment efficiencies were 80–100% and the functional release studies showed decreasing the thrombolytic activity of NPs during the experiment time. Thrombolytic activity measurements revealed that the engineered NPs presented an enhanced thrombolytic activity compared to the plain tPA. Based on these findings, the tPA-PEG-PLGA NPs could be a robust nanomedicine for enhanced thrombolytic therapy.