Reduced folate carrier independent internalization of PEGylated pemetrexed: a potential nanomedicinal approach for breast cancer therapy.
Pemetrexed has been widely used as an effective chemotherapeutic agent for the treatment of a variety of cancers including breast cancer. It is a multitargeted antifolate that gets transported to cells primarily by reduced folate carrier (RFC) and exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. The loss of RFC leads to impaired transport of pemetrexed, which in turn decreases its intracellular concentration and reduces its cytotoxic effect on cancer cells. Furthermore, the multidrug resistance (MDR) related proteins (MRPs) contribute to pemetrexed efflux from the cancer cells. These observations prompted us to develop PEGylated pemetrexed that follows an efficient cellular internalization route independent of RFC and simultaneously bypasses the MRP efflux mechanism for acting as an efficient chemotherapeutic agent. Thus, the present study focuses on PEGylation of pemetrexed for its superior therapeutic efficiency by evaluating its cellular uptake and retention by flow cytometry, confocal microscopy, and reversed-phase high-performance liquid chromatography (RP-HPLC) in breast cancer cell lines having RFC expression and lacking RFC expression, that is, MCF7 and MDA MB231, respectively. In addition, the treatment of PEGylated pemetrexed lead to enhanced cytotoxicity due to S-phase arrest and apoptosis in the above mentioned cell lines. Interestingly, the longer circulation time of PEGylated pemetrexed in animal model concomitant with the RFC independent uptake and enhanced cytotoxicity suggests it to be a potential candidate for cancer therapy in a clinical setting.
Laboratory of Nanomedicine, Institute of Life Sciences , Chandrasekarpur, Bhubaneswar, Odisha, India.
Mallaredy
M
Vandana
Sanjeeb K
SK
Sahoo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D050997:Nanomedicine / Q000379:methods; D000068437:Pemetrexed; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D058978:Reduced Folate Carrier Protein / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005971:Glutamates; D058978:Reduced Folate Carrier Protein; D000068437:Pemetrexed; D011092:Polyethylene Glycols; D006147:Guanine; D005492:Folic Acid