Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)- paclitaxel nanoconjugate.
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.
Nitto Denko Technical Corporation, Oceanside, CA 92058, USA.
Sang
S
Van
Sanjib K
SK
Das
Xinghe
X
Wang
Zhongling
Z
Feng
Yi
Y
Jin
Zheng
Z
Hou
Fu
F
Chen
Annie
A
Pham
Nan
N
Jiang
Stephen B
SB
Howell
Lei
L
Yu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D058726:Nanoconjugates / Q000737:chemistry*; D050997:Nanomedicine; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D010316:Particle Size; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D011506:Proteins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D012995:Solubility
D000972:Antineoplastic Agents, Phytogenic; D058726:Nanoconjugates; D011506:Proteins; C548171:poly(gamma-glutamylglutamine)paclitaxel; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex