Cell-penetrating Peptide-modified PLGA Nanoparticles For Enhanced Doxorubicin Delivery For Overcoming Drug-resistant Cancer

Objective: To explore the CPP-modified nano-drug delivery system for enhanceddoxorubicin delivery for overcoming Multidrug-resistant (MDR) cancer. TheDox-loaded LMWP-modified PLGA nanoparticles (LMWP/PLGA/Dox NP) wereprepared. The anti-tumor activity and anti-MDR effect were evaluated both in vitroand in vivo.Methods: An alkyl-chained LMWP hybrid peptide was synthesized bysolid-phase peptide synthesis. The alkyl chain of the hybrid peptide can anchor ontothe surface of Dox-loaded PLGA nanoparticles through hydrophobic interaction. Theparticle size and zeta potential of the LMWP/PLGA/Dox NP were measured by aparticle analyzer. The morphology of nanoparticles were determined by transmissionelectron microscopy (TEM); In vitro drug release was investigated using dialysismethod. The fluorescence imaging and flow cytometry were performed to determinecellular uptake efficiency. The proliferation inhibitory effect on the sensitive andresistant tumor cells was determined by the MTT method. The treatment efficacy andtoxicity were evaluated on the nu/nu mice bearing drug-resistant breast tumor.Result: The LMWP/PLGA/Dox NP with diameter about200nm and zetapotential about27mV was obtained through formulation optimization. The TEMshowed uniform spherical morphology. The particles remained stable in thephysiological PBS containing10%serum. The hemolysis test revealed the bloodbiocompatibility of the LMWP/PLGA/Dox NP. The in vitro experiments indicated thesignificiant anit-MDR effect on the resistant MCF-7/ADR and A549/T cells. Animalexperiments demonstrated the treatment efficacy in the mice bearing MCF-7/ADRbreast tumor. The LMWP/PLGA/Dox NP was found to be able to penetrate into thetumor tissue. Moreover, the LMWP/PLGA/Dox NP displayed reduced side effectcompared to the free Dox. No observable side toxicity effect was found in the micetreated with the LMWP/PLGA/Dox NP.Conclusions: The LMWP-modified Dox-loaded PLGA nanoparticles showed the enhanced anti-tumor activity both in vitro and in vivo. Modification of LMWP couldimprove the penetration ability of nanoparticles into the MDR tumor cells andenhance the intratumoral delivery. The CPP-modified nanoparticles could be apotential method for the treatment of breast resistant cancer.