Polymer-polymer conjugation to fabricate multi-block polymer as novel drug carriers: poly(lactic acid)-poly(ethylene glycol)-poly(L-lysine) to enhance paclitaxel target delivery.

Abstract

Multifunctional nanoparticles assembled from multi-block polymers are now one of the most convenient and convincing carriers for target drug delivery. Multi-block polymers could provide multi-functions such as sufficient drug loading capability and efficient target ligand coupling potency. In this article, novel multi-block polymer poly(lactic acid)-poly(ethylene glycol)-poly(L-lysine) (PLA-PEG-PLL) with relatively precise block molecular weight were synthesized by new method which we called polymer-polymer conjugation. This method conjugated different polymer blocks by reactions between the terminal active groups of different blocks, thus simplified the synthesis procedure. The obtained PLA-PEG-PLL was characterized by 1H NMR and gel permeation chromatography. The controlled drug delivery capability and the target ligand coupling potency of PLA-PEG-PLL were verified using paclitaxel (PTX) as model drug and vascular endothelial growth factor (VEGF) antibody as target ligand. The PTX-loaded PLA-PEG-PLL nanoparticles (PNP) and VEGF antibody modified PTX-loaded PLA-PEG-PLL nanoparticles (VPNP) were prepared using solvent diffusion methods. The two nanoparticles showed spherical or ellipsoidal shapes with uniform particle size distribution (190.1 +/- 1.27 nm and 203.6 +/- 4.10 nm for PNP and VPNP, respectively) and positive zeta potential (23.76 +/- 0.72 mv and 20.76 +/- 0.34 mv for PNP and VPNP, respectively). The cellular cytotoxicity, cellular uptake, in vivo therapeutic effects of the two nanoparticles were investigated. Cytotoxicity of VPNP against HepG2 cells was superior to that of PNP and Taxol. The VPNP and PNP showed better antitumor efficacy in a murine model bearing H22 compared with Taxol and VPNP was the best. The study on cellular uptake indicated that the better antitumor efficacy of VPNP was attributed to the increased uptake of drug by tumor cells. These results demonstrated that PLA-PEG-PLL was a favorable multifunctional material for drug target delivery and polymer-polymer conjugation was a promising method to fabricate novel multi-block polymers.