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Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane.

Feng Z, Zhao G, Yu L, Gough D, Howell SB - Cancer Chemother. Pharmacol. (2009)

Bottom Line: PGG-PTX was approximately 1.5-fold less potent than Abraxane.PGG-PTX has activity that is superior to that of Abraxane in multiple tumor models.PGG-PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens.

View Article: PubMed Central - PubMed

Affiliation: Biogroup, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92058, USA.

ABSTRACT

Purpose: Poly-(gamma-L-glutamylglutamine)-paclitaxel (PGG-PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked to the polymer via ester bonds. PGG-PTX is of interest because it spontaneously forms very small nanoparticles in plasma. In mouse models, PGG-PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor. In this study, the efficacy of PGG-PTX was compared to that of Abraxane, an established nanoparticular formulation of PTX, in three different tumor models.

Methods: Efficacy was quantified by delay in tumor growth of NCI H460 human lung cancer, 2008 human ovarian cancer and B16 melanoma xenografts growing in athymic mice following administration of equitoxic doses of PGG-PTX and Abraxane administered on either a single dose or every 7 day schedule. Toxicity was assessed by change in total body weight.

Results: The efficacy and toxicity of PGG-PTX was shown to increase with dose in the H460 model. PGG-PTX was approximately 1.5-fold less potent than Abraxane. PGG-PTX produced statistically significantly greater inhibition of tumor growth than Abraxane in all three tumor models when mice were given single equitoxic doses of drug. When given every 7 days for 3 doses, PGG-PTX produced greater inhibition of tumor growth while generating much less weight loss in mice bearing H460 tumors.

Conclusion: PGG-PTX has activity that is superior to that of Abraxane in multiple tumor models. PGG-PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens.

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Related in: MedlinePlus

Tumor growth delay as a function of PGG–PTX dose in mice bearing NCI-H460 tumors. Saline controls (filled circle), PGG–PTX 100 (filled diamond), PGG–PTX 150 (filled square), PGG–PTX 200 (filled triangle), PGG–PTX 250 (filled square), PGG–PTX 300 mg PTX/kg (thick line). Vertical bars ±SEM
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Fig2: Tumor growth delay as a function of PGG–PTX dose in mice bearing NCI-H460 tumors. Saline controls (filled circle), PGG–PTX 100 (filled diamond), PGG–PTX 150 (filled square), PGG–PTX 200 (filled triangle), PGG–PTX 250 (filled square), PGG–PTX 300 mg PTX/kg (thick line). Vertical bars ±SEM

Mentions: The dose–effect relationship for PGG–PTX was explored in mice bearing NCI-H460 lung cancer xenografts. Mice were inoculated with NCI-H460 cells SC at 4 sites and randomly assigned to control or experimental groups. A single dose of PGG–PTX was administered IP when average tumor volume was 30–40 mm3. Figure 2 shows that there was a well-defined progressive increase in tumor growth inhibition as the dose of PGG–PTX was increased from 100 to 300 mg PTX/kg. To assess the statistical significance of this difference, a plot was made for each individual tumor of the log of the tumor volume as a function of time. The slope of this curve was then determined and the mean and standard error of the slopes of each group was calculated. The mean values for each group were compared to each other using the Student’s t test. This analysis demonstrated that a significant delay in tumor growth was first detected at a dose of 150 mg PTX/kg (P = 0.042), and that the significance of the difference relative to the untreated mice increased progressively with dose with P values being 0.006 at 200 mg PTX/kg, 0.0004 at 250 mg PTX/kg and 3.6 × 10−7 at 300 mg PTX/kg. The acute weight loss over the first week after dosing also increased progressively with dose ranging from 1% at a dose of 150 mg PTX/kg to 8% at a dose of 250 mg PTX/kg. Thus, PGG–PTX exhibited significant antitumor activity in this model even at a dose that caused minimal weight loss, and both its antitumor activity and toxicity increased in a well-defined dose-dependent manner.Fig. 2


Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane.

Feng Z, Zhao G, Yu L, Gough D, Howell SB - Cancer Chemother. Pharmacol. (2009)

Tumor growth delay as a function of PGG–PTX dose in mice bearing NCI-H460 tumors. Saline controls (filled circle), PGG–PTX 100 (filled diamond), PGG–PTX 150 (filled square), PGG–PTX 200 (filled triangle), PGG–PTX 250 (filled square), PGG–PTX 300 mg PTX/kg (thick line). Vertical bars ±SEM
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2824123&req=5

Fig2: Tumor growth delay as a function of PGG–PTX dose in mice bearing NCI-H460 tumors. Saline controls (filled circle), PGG–PTX 100 (filled diamond), PGG–PTX 150 (filled square), PGG–PTX 200 (filled triangle), PGG–PTX 250 (filled square), PGG–PTX 300 mg PTX/kg (thick line). Vertical bars ±SEM
Mentions: The dose–effect relationship for PGG–PTX was explored in mice bearing NCI-H460 lung cancer xenografts. Mice were inoculated with NCI-H460 cells SC at 4 sites and randomly assigned to control or experimental groups. A single dose of PGG–PTX was administered IP when average tumor volume was 30–40 mm3. Figure 2 shows that there was a well-defined progressive increase in tumor growth inhibition as the dose of PGG–PTX was increased from 100 to 300 mg PTX/kg. To assess the statistical significance of this difference, a plot was made for each individual tumor of the log of the tumor volume as a function of time. The slope of this curve was then determined and the mean and standard error of the slopes of each group was calculated. The mean values for each group were compared to each other using the Student’s t test. This analysis demonstrated that a significant delay in tumor growth was first detected at a dose of 150 mg PTX/kg (P = 0.042), and that the significance of the difference relative to the untreated mice increased progressively with dose with P values being 0.006 at 200 mg PTX/kg, 0.0004 at 250 mg PTX/kg and 3.6 × 10−7 at 300 mg PTX/kg. The acute weight loss over the first week after dosing also increased progressively with dose ranging from 1% at a dose of 150 mg PTX/kg to 8% at a dose of 250 mg PTX/kg. Thus, PGG–PTX exhibited significant antitumor activity in this model even at a dose that caused minimal weight loss, and both its antitumor activity and toxicity increased in a well-defined dose-dependent manner.Fig. 2

Bottom Line: PGG-PTX was approximately 1.5-fold less potent than Abraxane.PGG-PTX has activity that is superior to that of Abraxane in multiple tumor models.PGG-PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens.

View Article: PubMed Central - PubMed

Affiliation: Biogroup, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92058, USA.

ABSTRACT

Purpose: Poly-(gamma-L-glutamylglutamine)-paclitaxel (PGG-PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked to the polymer via ester bonds. PGG-PTX is of interest because it spontaneously forms very small nanoparticles in plasma. In mouse models, PGG-PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor. In this study, the efficacy of PGG-PTX was compared to that of Abraxane, an established nanoparticular formulation of PTX, in three different tumor models.

Methods: Efficacy was quantified by delay in tumor growth of NCI H460 human lung cancer, 2008 human ovarian cancer and B16 melanoma xenografts growing in athymic mice following administration of equitoxic doses of PGG-PTX and Abraxane administered on either a single dose or every 7 day schedule. Toxicity was assessed by change in total body weight.

Results: The efficacy and toxicity of PGG-PTX was shown to increase with dose in the H460 model. PGG-PTX was approximately 1.5-fold less potent than Abraxane. PGG-PTX produced statistically significantly greater inhibition of tumor growth than Abraxane in all three tumor models when mice were given single equitoxic doses of drug. When given every 7 days for 3 doses, PGG-PTX produced greater inhibition of tumor growth while generating much less weight loss in mice bearing H460 tumors.

Conclusion: PGG-PTX has activity that is superior to that of Abraxane in multiple tumor models. PGG-PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens.

Show MeSH
Related in: MedlinePlus