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. 2010 Oct 21:5:825-37.
doi: 10.2147/IJN.S13482.

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

Sang Van  1 , Sanjib K Das, Xinghe Wang, Zhongling Feng, Yi Jin, Zheng Hou, Fu Chen, Annie Pham, Nan Jiang, Stephen B Howell, Lei Yu
Affiliations

"V体育官网" Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)- paclitaxel nanoconjugate

Sang Van et al. Int J Nanomedicine. .

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 VSports手机版. 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: anticancer; nanoconjugates; nanoparticles; poly(L-glutamic acid); poly(L-γ-glutamyl-glutamine)-paclitaxel. V体育安卓版.

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Figures

Figure S1
Figure S1
1H-NMR spectra of PGA-PGG, and PGG-PTX.
Figure S2
Figure S2
1H-NMR spectra of PGA, PGG, and PGG-PTX.
Figure S3
Figure S3
PGG and PGG-PTX chromatgrams using light scattering and refractive index detectors.
Figure S4
Figure S4
Red line came from light scattering detector. Blue line came from refractive index.
Figure S5
Figure S5
Size distribution of PGG-PTX in saline with various concentrations
Figure S6
Figure S6
PGG-PTX (2,000 μg/mL) in saline. Diameter = 13.7 nm; PDI = 0.404.
Figure S7
Figure S7
PGG-PTX (50 μg/mL) in saline. Diameter = 14.7 nm; PDI = 0.599.
Figure 1
Figure 1
Synthesis of PGG-PTX nanoconjugate. Abbreviations: HOBt, hydroxybenzotriazole; TFA, atrifluoroacetic acid; DMAP, 4-dimethylaminopyridine; NaHCO3, sodium bicarbonate; PGA, poly(L-glutamic acid); PGG, poly(L-γ-glutamyl-glutamine); PGG-PTX, poly(L-γ-glutamyl-glutamine)-paclitaxel conjugate.
Figure 2
Figure 2
SEC-HLPC chromatograms of PGA, PGG, and PGG-PTX. The chromatograms were recorded at 228 nm. A) PGA; B) PGG; C) PGG-PTX.
Figure 3
Figure 3
Critical micellar concentration of PGG-PTX nanoconjugate. The DLS could not detect the particle size of PGG-PTX solution below 25 μg/mL. The critical micellular concentration was assumed to be about 25 μg/mL in saline at 25°C. The results are expressed as means ± SD (n = 3). Abbreviation: DLS, dynamic light scattering.
Figure 4
Figure 4
Photographs of a solution of A) PGG-PTX (35% PTX loading) and B) PGA-PTX (32% PTX loading) in saline (0.9% NaCl). The polymer-PTX conjugates were dissolved in 0.9% NaCl at 50 mg/mL after sonication for 1 minute and allowed to stand for 20 minutes.
Figure 5
Figure 5
Inhibition of the growth of human lung cancer H460 cells as a function of concentration of PTX (O), PGA-PTX (■) and (▴) PGG-PTX. Note: Vertical bars, SEM.
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