title: Improving Therapeutic Potential of Farnesylthiosalicylic Acid: Tumor Specific Delivery via Conjugation with Heptamethine Cyanine Dye.
abstract: The RAS and mTOR inhibitor S-trans-trans-farnesylthiosalicylic acid (FTS) is a promising anticancer agent with moderate potency, currently undergoing clinical trials as a chemotherapeutic agent. FTS has displayed its potential against a variety of cancers including endocrine resistant breast cancer. However, the poor pharmacokinetics profile attributed to its high hydrophobicity is a major hindrance for its continued advancement in clinic. One of the ways to improve its therapeutic potential would be to enhance its bioavailability to cancer tissue by developing a method for targeted delivery. In the current study, FTS was conjugated with the cancer-targeting heptamethine cyanine dye 5 to form the FTS-dye conjugate 11. The efficiency of tumor targeting properties of conjugate 11 against cancer cell growth and mTOR inhibition was evaluated in vitro in comparison with parent FTS. Cancer targeting of 11 in a live mouse model of MCF7 xenografts was demonstrated with noninvasive, near-infrared fluorescence (NIRF) imaging. The results from our studies clearly suggest that the bioavailability of FTS is indeed improved as indicated by log P values and cancer cell uptake. The FTS-dye conjugate 11 displayed higher potency (IC50= 16.8 ± 0.5 μM) than parent FTS (IC50= ∼51.3 ± 1.8 μM) and inhibited mTOR activity in the cancer cells at a lower concentration (12.5 μM). The conjugate 11 was shown to be specifically accumulated in tumors as observed by in vivo NIRF imaging, organ distribution, and ex vivo tumor histology along with cellular level confocal microscopy. In conclusion, the conjugation of FTS with cancer-targeting heptamethine cyanine dye improved its pharmacological profile.
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou 51006, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California 90048, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: School of Materials Science & Engineering, Beijing Institute of Technology , Beijing 100081, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Wang
authors.forename: Mahendra D
authors.initials: MD
authors.lastname: Chordia
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou 51006, China.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California 90048, United States.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002232:Carbocyanines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D012459:Salicylates / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014018:Tissue Distribution; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002232:Carbocyanines; D012459:Salicylates; C085321:cyanine dye 5; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins
keywords: NIRF imaging; Ras inhibitor; breast cancer; cancer targeting; drug delivery; farnesylthiosalicylic acid; heptamethine cyanine dye; mTOR inhibitor