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Improving Therapeutic Potential of Farnesylthiosalicylic Acid: Tumor Specific Delivery via Conjugation with Heptamethine Cyanine Dye.
- Source :
-
Molecular pharmaceutics [Mol Pharm] 2017 Jan 03; Vol. 14 (1), pp. 1-13. Date of Electronic Publication: 2016 Dec 16. - Publication Year :
- 2017
-
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 (IC <subscript>50</subscript> = 16.8 ± 0.5 μM) than parent FTS (IC <subscript>50</subscript> = ∼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.
- Subjects :
- Animals
Biological Availability
Breast Neoplasms metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Drug Delivery Systems methods
Farnesol pharmacology
Female
Humans
MCF-7 Cells
Mice
Mice, Nude
TOR Serine-Threonine Kinases antagonists & inhibitors
Tissue Distribution
ras Proteins metabolism
Antineoplastic Agents pharmacology
Breast Neoplasms drug therapy
Carbocyanines administration & dosage
Farnesol analogs & derivatives
Salicylates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1543-8392
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 26992462
- Full Text :
- https://doi.org/10.1021/acs.molpharmaceut.5b00906