Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration

Abstract

Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely used as systemic gene vectors.

Novel Polymeric Hybrid Nanocarrier for Curcumin and Survivin shRNA Co-delivery Augments Tumor Penetration and Promotes Synergistic Tumor Suppression

“…Meanwhile, COOH-PEG 2K -COOH (CPC) was synthesized according to our previous paper (Yu et al, 2016 ). Briefly, PEG 2K , succinic anhydride, and 4-dimethylaminopyridine (DMAP) were dissolved in dichloromethane (DCM) solution and stirred at room temperature (RT) over 24 h. Thereafter the solvent was evaporated, and the crude product CPC was purified by the recrystallization process from isopropyl alcohol.…”

Colorectal Cancer from Molecular Pathways to Gene Therapy

“…al. [63] a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed. In this study this construction was capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based non-viral carriers.…”

“…D-NPs offer an innovative strategy for gene therapy delivery by intravenous injection and this delivery system might be a potential therapeutic approach for various cancers. [63] Future studies will elucidate probably a combination of injectable non-specific cytotoxic drugs with pill as gene inhibitors making CRC treatment more efficient.…”