Decitabine nanoparticles and docetaxel combination shrinks mammary carcinoma induced by DMBA in female sprague-dawley rats

P. Jain, N. Kumar, M. Tiwari, J. V. Rao, C. Shilpee, N. Udupa

Research output: Contribution to journalArticle

Abstract

Docetaxel (DTX) is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Unfortunately, there is altered response to DTX due to resistance. DNA methylation, an epigenetic event, plays a vital role in cancer and chemotherapy drug resistance. Exploiting the gene reactivation by using epigenetically acting agents in combination with cytotoxic therapies, is a strategy of huge clinical relevance. Decitabine (DEC) is one such epigenetic drug. It has low oral bioavailability (4-5%) due to rapid degradation in acidic conditions and metabolism by cytidine deaminase in the liver and is therefore administered in clinical settings as i.v. infusion. In spite of the numerous advantages of oral chemotherapy, there is no conveniently administrable oral dosage form available for DEC. Since PLGA has an advantage of overcoming acidic and enzymatic degradation, the present investigation was aimed at fabricating PLGA 50:50 nanoparticles of decitabine (DEC-NPs); and thereafter, examine a combination treatment in vitro and in vivo with docetaxel (DTX). DEC-NPs were formulated by spontaneous emulsification solvent diffusion technique. The optimized formulation had PS of 124.3 ± 4.2 nm, ZP of -23.2 ± 1.2 mV, and EE of 41.8 ± 4.3%. A comparative study indicated that the cytotoxicity of DTX and DEC combination on MCF-7 cells was significantly higher (p <0.05) than DTX and DEC alone. Furthermore, cell uptake studies in Caco-2 cells, evidenced enhanced uptake of DEC-NPs in comparison to DEC. For in vivo studies, 8week old female SD rats were used and induced mammary tumour with 2 oral doses of DMBA in olive oil; 40 and 20 mg/kg. The results demonstrated that the combination of DEC and DEC-NPs with DTX significantly improved (p <0.05) the tumour response rate, significantly reduced (p <0.05) the tumour weight and volume when compared to single agents DTX or DEC. Treatment groups with DEC-NPs also displayed better response, as compared to DEC. The study proves that DEC and DEC-NPs enhance the anticancer potential of DTX.

Original languageEnglish
Pages (from-to)397-405
Number of pages9
JournalInternational Journal of Toxicological and Pharmacological Research
Volume8
Issue number5
Publication statusPublished - 01-10-2016

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decitabine
docetaxel
9,10-Dimethyl-1,2-benzanthracene
Nanoparticles
Sprague Dawley Rats
Breast Neoplasms
Tumor Burden
Epigenomics

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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title = "Decitabine nanoparticles and docetaxel combination shrinks mammary carcinoma induced by DMBA in female sprague-dawley rats",
abstract = "Docetaxel (DTX) is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Unfortunately, there is altered response to DTX due to resistance. DNA methylation, an epigenetic event, plays a vital role in cancer and chemotherapy drug resistance. Exploiting the gene reactivation by using epigenetically acting agents in combination with cytotoxic therapies, is a strategy of huge clinical relevance. Decitabine (DEC) is one such epigenetic drug. It has low oral bioavailability (4-5{\%}) due to rapid degradation in acidic conditions and metabolism by cytidine deaminase in the liver and is therefore administered in clinical settings as i.v. infusion. In spite of the numerous advantages of oral chemotherapy, there is no conveniently administrable oral dosage form available for DEC. Since PLGA has an advantage of overcoming acidic and enzymatic degradation, the present investigation was aimed at fabricating PLGA 50:50 nanoparticles of decitabine (DEC-NPs); and thereafter, examine a combination treatment in vitro and in vivo with docetaxel (DTX). DEC-NPs were formulated by spontaneous emulsification solvent diffusion technique. The optimized formulation had PS of 124.3 ± 4.2 nm, ZP of -23.2 ± 1.2 mV, and EE of 41.8 ± 4.3{\%}. A comparative study indicated that the cytotoxicity of DTX and DEC combination on MCF-7 cells was significantly higher (p <0.05) than DTX and DEC alone. Furthermore, cell uptake studies in Caco-2 cells, evidenced enhanced uptake of DEC-NPs in comparison to DEC. For in vivo studies, 8week old female SD rats were used and induced mammary tumour with 2 oral doses of DMBA in olive oil; 40 and 20 mg/kg. The results demonstrated that the combination of DEC and DEC-NPs with DTX significantly improved (p <0.05) the tumour response rate, significantly reduced (p <0.05) the tumour weight and volume when compared to single agents DTX or DEC. Treatment groups with DEC-NPs also displayed better response, as compared to DEC. The study proves that DEC and DEC-NPs enhance the anticancer potential of DTX.",
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Decitabine nanoparticles and docetaxel combination shrinks mammary carcinoma induced by DMBA in female sprague-dawley rats. / Jain, P.; Kumar, N.; Tiwari, M.; Rao, J. V.; Shilpee, C.; Udupa, N.

In: International Journal of Toxicological and Pharmacological Research, Vol. 8, No. 5, 01.10.2016, p. 397-405.

Research output: Contribution to journalArticle

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N2 - Docetaxel (DTX) is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Unfortunately, there is altered response to DTX due to resistance. DNA methylation, an epigenetic event, plays a vital role in cancer and chemotherapy drug resistance. Exploiting the gene reactivation by using epigenetically acting agents in combination with cytotoxic therapies, is a strategy of huge clinical relevance. Decitabine (DEC) is one such epigenetic drug. It has low oral bioavailability (4-5%) due to rapid degradation in acidic conditions and metabolism by cytidine deaminase in the liver and is therefore administered in clinical settings as i.v. infusion. In spite of the numerous advantages of oral chemotherapy, there is no conveniently administrable oral dosage form available for DEC. Since PLGA has an advantage of overcoming acidic and enzymatic degradation, the present investigation was aimed at fabricating PLGA 50:50 nanoparticles of decitabine (DEC-NPs); and thereafter, examine a combination treatment in vitro and in vivo with docetaxel (DTX). DEC-NPs were formulated by spontaneous emulsification solvent diffusion technique. The optimized formulation had PS of 124.3 ± 4.2 nm, ZP of -23.2 ± 1.2 mV, and EE of 41.8 ± 4.3%. A comparative study indicated that the cytotoxicity of DTX and DEC combination on MCF-7 cells was significantly higher (p <0.05) than DTX and DEC alone. Furthermore, cell uptake studies in Caco-2 cells, evidenced enhanced uptake of DEC-NPs in comparison to DEC. For in vivo studies, 8week old female SD rats were used and induced mammary tumour with 2 oral doses of DMBA in olive oil; 40 and 20 mg/kg. The results demonstrated that the combination of DEC and DEC-NPs with DTX significantly improved (p <0.05) the tumour response rate, significantly reduced (p <0.05) the tumour weight and volume when compared to single agents DTX or DEC. Treatment groups with DEC-NPs also displayed better response, as compared to DEC. The study proves that DEC and DEC-NPs enhance the anticancer potential of DTX.

AB - Docetaxel (DTX) is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Unfortunately, there is altered response to DTX due to resistance. DNA methylation, an epigenetic event, plays a vital role in cancer and chemotherapy drug resistance. Exploiting the gene reactivation by using epigenetically acting agents in combination with cytotoxic therapies, is a strategy of huge clinical relevance. Decitabine (DEC) is one such epigenetic drug. It has low oral bioavailability (4-5%) due to rapid degradation in acidic conditions and metabolism by cytidine deaminase in the liver and is therefore administered in clinical settings as i.v. infusion. In spite of the numerous advantages of oral chemotherapy, there is no conveniently administrable oral dosage form available for DEC. Since PLGA has an advantage of overcoming acidic and enzymatic degradation, the present investigation was aimed at fabricating PLGA 50:50 nanoparticles of decitabine (DEC-NPs); and thereafter, examine a combination treatment in vitro and in vivo with docetaxel (DTX). DEC-NPs were formulated by spontaneous emulsification solvent diffusion technique. The optimized formulation had PS of 124.3 ± 4.2 nm, ZP of -23.2 ± 1.2 mV, and EE of 41.8 ± 4.3%. A comparative study indicated that the cytotoxicity of DTX and DEC combination on MCF-7 cells was significantly higher (p <0.05) than DTX and DEC alone. Furthermore, cell uptake studies in Caco-2 cells, evidenced enhanced uptake of DEC-NPs in comparison to DEC. For in vivo studies, 8week old female SD rats were used and induced mammary tumour with 2 oral doses of DMBA in olive oil; 40 and 20 mg/kg. The results demonstrated that the combination of DEC and DEC-NPs with DTX significantly improved (p <0.05) the tumour response rate, significantly reduced (p <0.05) the tumour weight and volume when compared to single agents DTX or DEC. Treatment groups with DEC-NPs also displayed better response, as compared to DEC. The study proves that DEC and DEC-NPs enhance the anticancer potential of DTX.

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