Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio. / Das, Manasmita; Jain, Roopal; Agrawal, Ashish Kumar; Thanki, Kaushik; Jain, Sanyog.

In: Bioconjugate Chemistry, Vol. 25, No. 3, 19.03.2014, p. 501-9.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Das, M, Jain, R, Agrawal, AK, Thanki, K & Jain, S 2014, 'Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio', Bioconjugate Chemistry, vol. 25, no. 3, pp. 501-9. https://doi.org/10.1021/bc400477q

APA

Das, M., Jain, R., Agrawal, A. K., Thanki, K., & Jain, S. (2014). Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio. Bioconjugate Chemistry, 25(3), 501-9. https://doi.org/10.1021/bc400477q

Vancouver

Das M, Jain R, Agrawal AK, Thanki K, Jain S. Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio. Bioconjugate Chemistry. 2014 Mar 19;25(3):501-9. https://doi.org/10.1021/bc400477q

Author

Das, Manasmita ; Jain, Roopal ; Agrawal, Ashish Kumar ; Thanki, Kaushik ; Jain, Sanyog. / Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio. In: Bioconjugate Chemistry. 2014 ; Vol. 25, No. 3. pp. 501-9.

Bibtex

@article{26915e39a3f34d6d944998bf33342519,
title = "Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio",
abstract = "The present study reports the synthesis, characterization, and biological evaluation of a novel macromolecular bipill, synthesized by appending two different anticancer agents, viz., gemcitabine (GEM) and methotrexate (MTX), to the distal ends of a long-circulating poly(ethylene glycol) (PEG) spacer. Covalent conjugation of GEM and MTX via PEG linker not only transformed the solubility profiles of constituent drug molecules, but significantly improved their stability in the presence of plasma. In vitro cytotoxicity studies confirmed that GEM-PEG-MTX exerts higher cytotoxicity (IC50 0.181 μM at 24 h) in human breast adenocarcinoma MCF-7 cell lines, when compared to free drug congeners, i.e., free GEM (IC50 0.294 μM at 24 h) and free MTX (IC50 0.591 μM at 24 h). Tumor growth inhibition studies in chemically induced breast cancer bearing rats established the superiority of GEM-PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential drug candidates while alleviating drug-associated side effects.",
keywords = "Animals, Antimetabolites, Antineoplastic, Cell Proliferation, Cell Survival, Deoxycytidine, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Kidney, Liver, MCF-7 Cells, Macromolecular Substances, Mammary Neoplasms, Experimental, Methotrexate, Mice, Molecular Structure, Polyethylene Glycols, Rats, Rats, Sprague-Dawley, Risk Factors, Structure-Activity Relationship, Journal Article, Research Support, Non-U.S. Gov't",
author = "Manasmita Das and Roopal Jain and Agrawal, {Ashish Kumar} and Kaushik Thanki and Sanyog Jain",
year = "2014",
month = mar,
day = "19",
doi = "10.1021/bc400477q",
language = "English",
volume = "25",
pages = "501--9",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "3",

}

RIS

TY - JOUR

T1 - Macromolecular bipill of gemcitabine and methotrexate facilitates tumor-specific dual drug therapy with higher benefit-to-risk ratio

AU - Das, Manasmita

AU - Jain, Roopal

AU - Agrawal, Ashish Kumar

AU - Thanki, Kaushik

AU - Jain, Sanyog

PY - 2014/3/19

Y1 - 2014/3/19

N2 - The present study reports the synthesis, characterization, and biological evaluation of a novel macromolecular bipill, synthesized by appending two different anticancer agents, viz., gemcitabine (GEM) and methotrexate (MTX), to the distal ends of a long-circulating poly(ethylene glycol) (PEG) spacer. Covalent conjugation of GEM and MTX via PEG linker not only transformed the solubility profiles of constituent drug molecules, but significantly improved their stability in the presence of plasma. In vitro cytotoxicity studies confirmed that GEM-PEG-MTX exerts higher cytotoxicity (IC50 0.181 μM at 24 h) in human breast adenocarcinoma MCF-7 cell lines, when compared to free drug congeners, i.e., free GEM (IC50 0.294 μM at 24 h) and free MTX (IC50 0.591 μM at 24 h). Tumor growth inhibition studies in chemically induced breast cancer bearing rats established the superiority of GEM-PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential drug candidates while alleviating drug-associated side effects.

AB - The present study reports the synthesis, characterization, and biological evaluation of a novel macromolecular bipill, synthesized by appending two different anticancer agents, viz., gemcitabine (GEM) and methotrexate (MTX), to the distal ends of a long-circulating poly(ethylene glycol) (PEG) spacer. Covalent conjugation of GEM and MTX via PEG linker not only transformed the solubility profiles of constituent drug molecules, but significantly improved their stability in the presence of plasma. In vitro cytotoxicity studies confirmed that GEM-PEG-MTX exerts higher cytotoxicity (IC50 0.181 μM at 24 h) in human breast adenocarcinoma MCF-7 cell lines, when compared to free drug congeners, i.e., free GEM (IC50 0.294 μM at 24 h) and free MTX (IC50 0.591 μM at 24 h). Tumor growth inhibition studies in chemically induced breast cancer bearing rats established the superiority of GEM-PEG-MTX conjugate over all other pharmaceutical preparations including free drugs, physical mixture of GEM and MTX, and PEGylated GEM/MTX. Toxicity studies in tumor bearing rats as well as healthy mice corroborated that dual drug conjugation is an effective means to synergize the therapeutic indices of potential drug candidates while alleviating drug-associated side effects.

KW - Animals

KW - Antimetabolites, Antineoplastic

KW - Cell Proliferation

KW - Cell Survival

KW - Deoxycytidine

KW - Dose-Response Relationship, Drug

KW - Drug Screening Assays, Antitumor

KW - Female

KW - Humans

KW - Kidney

KW - Liver

KW - MCF-7 Cells

KW - Macromolecular Substances

KW - Mammary Neoplasms, Experimental

KW - Methotrexate

KW - Mice

KW - Molecular Structure

KW - Polyethylene Glycols

KW - Rats

KW - Rats, Sprague-Dawley

KW - Risk Factors

KW - Structure-Activity Relationship

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1021/bc400477q

DO - 10.1021/bc400477q

M3 - Journal article

C2 - 24506698

VL - 25

SP - 501

EP - 509

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 3

ER -

ID: 168217424