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Synthesis, characterization, and in vivo efficacy evaluation of PGG-docetaxel conjugate for potential cancer chemotherapy.

Yang D, Van S, Shu Y, Liu X, Ge Y, Jiang X, Jin Y, Yu L - Int J Nanomedicine (2012)

Bottom Line: Conjugated DTX was found to have 2000 times improved water solubility compared with free DTX.However, PGG-DTX showed better antitumor activity in NCI-H460 lung cancer-bearing mice with minimal weight loss compared to that of free DTX.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Engineering and Technology Institute, Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China.

ABSTRACT

Aim: This work is intended to develop and evaluate a biopolymeric poly(L-γ-glutamylglutamine) (PGG)-docetaxel (DTX) conjugate that can spontaneously self-assemble in aqueous solutions to become nanoparticles.

Methods: DTX was covalently attached to hydrophilic PGG by direct esterification, and the conjugate was characterized by proton nuclear magnetic resonance spectroscopy, molecular weight gel permeation chromatography, solubility, size distribution and morphology, and hemolysis. Conjugated DTX was found to have 2000 times improved water solubility compared with free DTX. Dynamic light scattering, transmission electron microscopy, and atomic force microscopy revealed the particle size, distribution and morphology of the PGG-DTX conjugate. In addition, the conjugate was further tested for in vitro cytotoxicity and in vivo antitumor efficacy on the human non-small cell lung cancer cell line NCI-H460.

Results: Conjugated DTX was found to have 2000 times improved water solubility compared with free DTX. The conjugate formed nanoparticles with an average diameter of 30 nm in spherical shape and unimodal particle size distribution. The conjugate exhibited about 2% hemolysis at 10 mg/mL, compared with 56% for Tween 80(®) at 0.4 mg/mL, and 33% for Cremophor EL(®) at 10 mg/mL. In addition, the conjugate was further tested for in vitro cytotoxicity and in vivo antitumor efficacy on the human non-small cell lung cancer cell line NCI-H460. As expected, conjugated DTX exhibited lower cytotoxicity compared to that of free DTX, in concentration-dependent manner. However, PGG-DTX showed better antitumor activity in NCI-H460 lung cancer-bearing mice with minimal weight loss compared to that of free DTX.

Conclusion: The PGG-DTX conjugate may be considered as an attractive and promising polymeric DTX conjugate for non-small cell lung cancer treatment.

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Antitumor efficacy in nude mice bearing NCI-H460 human non-small cell lung carcinoma tumors. (A) Mean tumor growth curves. (B) Body weight change.Note: Data presented as means ± standard error.Abbreviations: PBS, phosphate-buffered saline; PGG, poly(L-γ-glutamyl-glutamine); DTX, docetaxel.
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f6-ijn-7-581: Antitumor efficacy in nude mice bearing NCI-H460 human non-small cell lung carcinoma tumors. (A) Mean tumor growth curves. (B) Body weight change.Note: Data presented as means ± standard error.Abbreviations: PBS, phosphate-buffered saline; PGG, poly(L-γ-glutamyl-glutamine); DTX, docetaxel.

Mentions: Figure 6 shows a plot of tumor volume and weight loss as a function of time in mice bearing NCI-H460 lung cancer. These mice were treated for 3 days with three doses of either PBS (negative control), PGG–DTX (20 mg/kg, 40 mg/kg, 60 mg/kg, 80 mg/kg), or DTX (5 mg/kg, positive control). The PBS-treated group of mice showed a progressive increase in tumor growth for mean tumor volume up to day 37. The mice treated with DTX (5 mg/kg) showed significant tumor-growth inhibition (P < 0.05), relative to the PBS group (Figure 6A). However, DTX treatment caused an obvious decrease in body weight on day 15, which slowly recovered to its normal value (Figure 6B). In contrast, PGG–DTX treatments of 20 mg/kg, 40 mg/kg, 60 mg/kg, and 80 mg/kg DTX equivalent caused minimal weight loss, within an acceptable range of 10%. Tumor-growth inhibition of PGG–PTX treatment (60 mg/kg DTX equivalent) was comparable to that of the treatment of free DTX (5 mg/kg), and inhibition of tumor growth of PGG–DTX treatment (80 mg/kg DTX equivalent) outperformed the treatment of free DTX 5 mg/kg, in a statistically significant manner. Table 2 shows – after treatment with PGG–DTX and DTX – the tumor-growth inhibition rate and tumor volume on day 37, drug-related deaths up to day 37, and mean body weight on day 37 versus day 1, as a mean ± standard error of six mice/group. No drug-related deaths were observed. The tumor volume and tumor-inhibition rate of mice treated with 20 mg/kg and 40 mg/kg DTX equivalent of PGG–DTX on day 37 were the same. However, as the dose of PGG–DTX increased from 40 mg/kg to 60 mg/kg, and to 80 mg/kg of DTX equivalent, the mean tumor volume decreased linearly, while tumor-inhibition rate increased linearly. These results clearly indicate the superiority of PGG–DTX over DTX, demonstrating that the proper use of macromolecular carriers can increase the potency and the therapeutic indices of DTX.


Synthesis, characterization, and in vivo efficacy evaluation of PGG-docetaxel conjugate for potential cancer chemotherapy.

Yang D, Van S, Shu Y, Liu X, Ge Y, Jiang X, Jin Y, Yu L - Int J Nanomedicine (2012)

Antitumor efficacy in nude mice bearing NCI-H460 human non-small cell lung carcinoma tumors. (A) Mean tumor growth curves. (B) Body weight change.Note: Data presented as means ± standard error.Abbreviations: PBS, phosphate-buffered saline; PGG, poly(L-γ-glutamyl-glutamine); DTX, docetaxel.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3278226&req=5

f6-ijn-7-581: Antitumor efficacy in nude mice bearing NCI-H460 human non-small cell lung carcinoma tumors. (A) Mean tumor growth curves. (B) Body weight change.Note: Data presented as means ± standard error.Abbreviations: PBS, phosphate-buffered saline; PGG, poly(L-γ-glutamyl-glutamine); DTX, docetaxel.
Mentions: Figure 6 shows a plot of tumor volume and weight loss as a function of time in mice bearing NCI-H460 lung cancer. These mice were treated for 3 days with three doses of either PBS (negative control), PGG–DTX (20 mg/kg, 40 mg/kg, 60 mg/kg, 80 mg/kg), or DTX (5 mg/kg, positive control). The PBS-treated group of mice showed a progressive increase in tumor growth for mean tumor volume up to day 37. The mice treated with DTX (5 mg/kg) showed significant tumor-growth inhibition (P < 0.05), relative to the PBS group (Figure 6A). However, DTX treatment caused an obvious decrease in body weight on day 15, which slowly recovered to its normal value (Figure 6B). In contrast, PGG–DTX treatments of 20 mg/kg, 40 mg/kg, 60 mg/kg, and 80 mg/kg DTX equivalent caused minimal weight loss, within an acceptable range of 10%. Tumor-growth inhibition of PGG–PTX treatment (60 mg/kg DTX equivalent) was comparable to that of the treatment of free DTX (5 mg/kg), and inhibition of tumor growth of PGG–DTX treatment (80 mg/kg DTX equivalent) outperformed the treatment of free DTX 5 mg/kg, in a statistically significant manner. Table 2 shows – after treatment with PGG–DTX and DTX – the tumor-growth inhibition rate and tumor volume on day 37, drug-related deaths up to day 37, and mean body weight on day 37 versus day 1, as a mean ± standard error of six mice/group. No drug-related deaths were observed. The tumor volume and tumor-inhibition rate of mice treated with 20 mg/kg and 40 mg/kg DTX equivalent of PGG–DTX on day 37 were the same. However, as the dose of PGG–DTX increased from 40 mg/kg to 60 mg/kg, and to 80 mg/kg of DTX equivalent, the mean tumor volume decreased linearly, while tumor-inhibition rate increased linearly. These results clearly indicate the superiority of PGG–DTX over DTX, demonstrating that the proper use of macromolecular carriers can increase the potency and the therapeutic indices of DTX.

Bottom Line: Conjugated DTX was found to have 2000 times improved water solubility compared with free DTX.However, PGG-DTX showed better antitumor activity in NCI-H460 lung cancer-bearing mice with minimal weight loss compared to that of free DTX.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Engineering and Technology Institute, Institutes for Advanced Interdisciplinary Research, East China Normal University, Shanghai, People's Republic of China.

ABSTRACT

Aim: This work is intended to develop and evaluate a biopolymeric poly(L-γ-glutamylglutamine) (PGG)-docetaxel (DTX) conjugate that can spontaneously self-assemble in aqueous solutions to become nanoparticles.

Methods: DTX was covalently attached to hydrophilic PGG by direct esterification, and the conjugate was characterized by proton nuclear magnetic resonance spectroscopy, molecular weight gel permeation chromatography, solubility, size distribution and morphology, and hemolysis. Conjugated DTX was found to have 2000 times improved water solubility compared with free DTX. Dynamic light scattering, transmission electron microscopy, and atomic force microscopy revealed the particle size, distribution and morphology of the PGG-DTX conjugate. In addition, the conjugate was further tested for in vitro cytotoxicity and in vivo antitumor efficacy on the human non-small cell lung cancer cell line NCI-H460.

Results: Conjugated DTX was found to have 2000 times improved water solubility compared with free DTX. The conjugate formed nanoparticles with an average diameter of 30 nm in spherical shape and unimodal particle size distribution. The conjugate exhibited about 2% hemolysis at 10 mg/mL, compared with 56% for Tween 80(®) at 0.4 mg/mL, and 33% for Cremophor EL(®) at 10 mg/mL. In addition, the conjugate was further tested for in vitro cytotoxicity and in vivo antitumor efficacy on the human non-small cell lung cancer cell line NCI-H460. As expected, conjugated DTX exhibited lower cytotoxicity compared to that of free DTX, in concentration-dependent manner. However, PGG-DTX showed better antitumor activity in NCI-H460 lung cancer-bearing mice with minimal weight loss compared to that of free DTX.

Conclusion: The PGG-DTX conjugate may be considered as an attractive and promising polymeric DTX conjugate for non-small cell lung cancer treatment.

Show MeSH
Related in: MedlinePlus