Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

Sang Van¹, Sanjib K Das¹, Xinghe Wang¹, Zhongling Feng¹, Yi Jin¹, Zheng Hou¹, Fu Chen¹, Annie Pham¹, Nan Jiang¹, Stephen B Howell², Lei Yu^1
1Nitto Denko Technical Corporation, Oceanside, CA, USA; ²Moores Cancer Center, University of California, La Jolla, San Diego, CA, USA

Abstract: The purpose of this study was to develop a novel, highly water-soluble poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate (PGG-PTX) that would improve the therapeutic index of paclitaxel (PTX). PGG-PTX is a modification of poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX) in which an additional glutamic acid has been added to each glutamic side chain in the polymer. PGG-PTX has higher water-solubility and faster dissolution than PGA-PTX. Unlike PGA-PTX, PGG-PTX self-assembles into nanoparticles, whose size remains in the range of 12–15 nm over the concentration range from 25 to 2,000 µg/mL in saline. Its critical micellar concentration in saline was found to be ~25 µg/mL. The potency of PGG-PTX when tested in vitro against the human lung cancer H460 cell line was comparable to other known polymer-PTX conjugates. However, PGG-PTX possesses lower toxicity compared with PGA-PTX in mice. The maximum tolerated dose of PGG-PTX was found to be 350 mg PTX/kg, which is 2.2-fold higher than the maximum tolerated dose of 160 mg PTX/kg reported for the PGA-PTX. This result indicates that PGG-PTX was substantially less toxic in vivo than PGA-PTX.

Keywords: nanoconjugates, poly(L-glutamic acid), poly(L-γ-glutamyl-glutamine)-paclitaxel, nanoparticles, anticancer