title: Self-Delivery Nanoparticles of Amphiphilic Methotrexate-Gemcitabine Prodrug for Synergistic Combination Chemotherapy via Effect of Deoxyribonucleotide Pools.
abstract: The distinct and complementary biochemical mechanisms of folic acid analog methotrexate (MTX) and cytidine analog gemcitabine (GEM) make their synergistic combination effective. Unfortunately, such a combination faces severe pharmacokinetic problems and several transportation barriers. To overcome these problems, a new strategy of amphiphilic small molecule prodrug (ASMP) is developed to improve their synergistic combination effect. The ASMP was prepared by the amidation of the hydrophilic GEM with the hydrophobic MTX at a fixed ratio. Owing to its inherent amphiphilicity, the MTX-GEM ASMP self-assembled into stable nanoparticles (ASMP-NPs) with high drug loading capacity (100%), in which the MTX and GEM could self-deliver without any carriers and release synchronously in cancer cells. In vitro studies showed that the MTX-GEM ASMP-NPs could greatly improve the synergistic combination effects by the reason of arresting more S phase of the cell cycle and reducing levels of deoxythymidine triphosphate (dTTP), deoxyadenosine triphosphate (dATP), and deoxycytidine triphosphate (dCTP). The stronger synergistic effects caused the higher cell cytotoxicity and apoptotic ratio, and circumvented the multidrug resistance (MDR) of tumor cells. Additionally, MTX-GEM ASMP-NPs could achieve the same anticancer effect with the greatly reduced dosage compared with the free drugs according to the dose-reduction index (DRI) values of MTX and GEM in MTX-GEM ASMP-NPs, which may be beneficial for reducing the side effects.
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, P. R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, P. R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, P. R. China.
authors.forename: Minxi
authors.initials: M
authors.lastname: Hu
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, P. R. China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University , 800 Dongchuan Road, Shanghai 200240, P. R. China.
authors.forename: Deyue
authors.initials: D
authors.lastname: Yan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008727:Methotrexate / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D011355:Prodrugs / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011355:Prodrugs; D003841:Deoxycytidine; D053148:Caspase 3; D008727:Methotrexate; D000093542:Gemcitabine