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.
authors: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, S.A.S. Nagar (Mohali), Punjab 160062, India.
authors: Manasmita
authors: M
authors: Das
authors: Roopal
authors: R
authors: Jain
authors: Ashish Kumar
authors: AK
authors: Agrawal
authors: Kaushik
authors: K
authors: Thanki
authors: Sanyog
authors: S
authors: Jain
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D061986:MCF-7 Cells; D046911:Macromolecular Substances / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008727:Methotrexate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D046911:Macromolecular Substances; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D008727:Methotrexate; D000093542:Gemcitabine