title: Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment.
abstract: Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard, we have synthesized Pem-PEG-Gem, wherein pemetrexed (Pem) and gemcitabine (Gem) are conjugated to a heterobifunctional polyethylene glycol (PEG) polymer for the effective treatment of Non-Small Cell Lung Cancer (NSCLC). Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.
authors.affiliation: Laboratory of Nanomedicine, Institute of Life Sciences, Chandrasekharpur, Bhubaneswar 751023, Odisha, India.
authors.forename: Mallaredy
authors.initials: M
authors.lastname: Vandana
authors.affiliation: Laboratory of Nanomedicine, Institute of Life Sciences, Chandrasekharpur, Bhubaneswar 751023, Odisha, India. Electronic address: sanjeebsahoo2005@gmail.com.
authors.forename: Sanjeeb K
authors.initials: SK
authors.lastname: Sahoo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D000068437:Pemetrexed / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010873:Pinocytosis; D011092:Polyethylene Glycols / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D000093542:Gemcitabine
chemical_list: D004337:Drug Carriers; D004338:Drug Combinations; D000068437:Pemetrexed; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D000093542:Gemcitabine
keywords: Bioavailability; Combination therapy; Cytotoxicity; Gemcitabine; PEGylation; Pemetrexed