title: Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model.
abstract: Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase, is a chemotherapeutic agent for treating a variety of neoplasms. Impairment of drug import into cells and increase in drug export from cells may render cells resistant to MTX. MTX, when locally administered in a soluble form, is rapidly absorbed through capillaries into the circulatory system, which may also account for therapeutic failure in patients. To retain MTX within tumor cells for longer duration and alter its pharmacokinetic behavior, we proposed a new formulation of MTX bound to the gold nanoparticle (AuNP) that serves as drug carriers. In this study, we developed the MTX-AuNP conjugate and examined its cytotoxic effect in vitro and antitumor effect in vivo. Spectroscopic examinations revealed that MTX can be directly bound onto AuNP via the carboxyl group (-COOH) to form the MTX-AuNP complex and kinetically released from the nanoparticles. The accumulation of MTX is faster and higher in tumor cells treated with MTX-AuNP than that treated with free MTX. Notably, MTX-AuNP shows higher cytotoxic effects on several tumor cell lines compared with an equal dose of free MTX. This can be attributed to the "concentrated effect" of MTX-AuNP. Administration of MTX-AuNP suppresses tumor growth in a mouse ascites model of Lewis lung carcinoma (LL2), whereas an equal dose of free MTX had no antitumor effect. In conclusion, these results suggest that by combining nanomaterials with anticancer drugs MTX-AuNP may be more effective than free MTX for cancer treatment.
authors: Department of Biochemistry and Molecular Biology, Institute of Clinical Pharmacy, National Cheng Kung University, Tainan, Taiwan.
authors: Yu-Hung
authors: YH
authors: Chen
authors: Chiau-Yuang
authors: CY
authors: Tsai
authors: Pon-Yu
authors: PY
authors: Huang
authors: Meng-Ya
authors: MY
authors: Chang
authors: Pai-Chiao
authors: PC
authors: Cheng
authors: Chen-Hsi
authors: CH
authors: Chou
authors: Dong-Hwang
authors: DH
authors: Chen
authors: Chrong-Reen
authors: CR
authors: Wang
authors: Ai-Li
authors: AL
authors: Shiau
authors: Chao-Liang
authors: CL
authors: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D008727:Methotrexate / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009368:Neoplasm Transplantation
chemical_list: D000970:Antineoplastic Agents; D006046:Gold; D008727:Methotrexate