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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

Structure of PGGA-PTX, a random ester conjugate of poly(l-γ-glutamylglutamine) and paclitaxel. There are approximately 5 non-conjugated monomer glutamylglutamine units per paclitaxel-conjugated monomer glutamylglutamine unit
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Fig1: Structure of PGGA-PTX, a random ester conjugate of poly(l-γ-glutamylglutamine) and paclitaxel. There are approximately 5 non-conjugated monomer glutamylglutamine units per paclitaxel-conjugated monomer glutamylglutamine unit

Mentions: We have developed a novel formulation of PTX that utilizes both the ability of a polymer to enhance solubility and to form nanoparticles with the goal of even further enhancing the therapeutic efficacy of PTX. The polymer backbone of this formulation consists of poly(l-glutamic acid) to which a glutamate side chain has been added to each monomer in the polymer to create poly(l-glutamylglutamate) (PGG). As shown in Fig. 1, these both increases the number of –COOH groups available to interact with water molecules so that solubility is enhanced and approximately doubles the molecular weight of the polymer. When PTX is conjugated to this polymer to an extent of 35% (w/w) to create poly-(γ-l-glutamylglutamine)–paclitaxel (PGG–PTX), the tendency of the hydrophobic PTX molecules to interact with each other causes the polymer to collapse to form a nanoparticle of ~20 nm in aqueous solutions as determined by dynamic light scattering. This particle is considerably smaller than the nanoparticles that make up Abraxane (80–120 nm) which may favor both the exit of this particle from the vascular compartment once it reaches a tumor, and movement through the tumor extracellular fluid.Fig. 1


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)

Structure of PGGA-PTX, a random ester conjugate of poly(l-γ-glutamylglutamine) and paclitaxel. There are approximately 5 non-conjugated monomer glutamylglutamine units per paclitaxel-conjugated monomer glutamylglutamine unit
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Structure of PGGA-PTX, a random ester conjugate of poly(l-γ-glutamylglutamine) and paclitaxel. There are approximately 5 non-conjugated monomer glutamylglutamine units per paclitaxel-conjugated monomer glutamylglutamine unit
Mentions: We have developed a novel formulation of PTX that utilizes both the ability of a polymer to enhance solubility and to form nanoparticles with the goal of even further enhancing the therapeutic efficacy of PTX. The polymer backbone of this formulation consists of poly(l-glutamic acid) to which a glutamate side chain has been added to each monomer in the polymer to create poly(l-glutamylglutamate) (PGG). As shown in Fig. 1, these both increases the number of –COOH groups available to interact with water molecules so that solubility is enhanced and approximately doubles the molecular weight of the polymer. When PTX is conjugated to this polymer to an extent of 35% (w/w) to create poly-(γ-l-glutamylglutamine)–paclitaxel (PGG–PTX), the tendency of the hydrophobic PTX molecules to interact with each other causes the polymer to collapse to form a nanoparticle of ~20 nm in aqueous solutions as determined by dynamic light scattering. This particle is considerably smaller than the nanoparticles that make up Abraxane (80–120 nm) which may favor both the exit of this particle from the vascular compartment once it reaches a tumor, and movement through the tumor extracellular fluid.Fig. 1

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