RGD peptide-pegylated PLLA nanoparticles containing epirubicin hydrochloride exhibit receptor-dependent tumor trafficking in vitro and in vivo

Purpose: A novel hydrophilic conjugate of arginine-glycine-aspartic acid (RGD) and polyethylene glycol (PEG), i.e., RGD-PEG _Mw (M _W∈=∈300, 600, 1000 or 4000), was synthesized and employed in epirubicin (EPI) loaded poly L-lactic acid (PLLA) nanoparticles (NPs) to improve its tumor targeting effect. Methods: In vitro studies were performed to assess EPI release from NPs in tumor-mimic acidic medium, cytotoxicity and cell cycle assay in HepG2 cells, and cellular uptake kinetics in four types of tumor cells including A375 cells (high integrin receptor expression), HeLa cells (low integrin receptor expression), and metabolic HepG2/SMMC7721 cells. In vivo pharmacodynamics (PD) and pharmacokinetic (PK) studies were determined in a murine ascites tumor model. Results: Cellular uptake kinetics showed integrin receptor-dependent binding and internalization. In vitro release results showed that PLLA and PEG groups retarded EPI release from NPs and promoted drug release amount in acidic medium, which benefited in vivo trafficking to the acidic tumors. In vivo PD and PK studies revealed that RGD-PEG _Mw (M _W∈=∈600∈∼∈1000) improved tumor targeting capacity of NPs by ∼2.4-fold, compared to conventional EPI NPs. Conclusions: RGD-PEG _Mw (M _W∈=∈600∈∼∈1000) modified PLLA NPs provide a promising strategy to improve tumor selectivity in cancer treatment.