1. Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma.
- Author
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Yang R, Mondal G, Ness RA, Arnst K, Mundra V, Miller DD, Li W, and Mahato RI
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Cell Cycle drug effects, Cell Line, Tumor, Female, Humans, Lung drug effects, Lung pathology, Lung Neoplasms pathology, Melanoma pathology, Mice, Mice, Inbred C57BL, Microtubules pathology, Models, Molecular, Neoplasm Invasiveness pathology, Polymers administration & dosage, Polymers chemistry, Thiazoles administration & dosage, Thiazoles chemistry, Tubulin Modulators administration & dosage, Tubulin Modulators chemistry, Lung Neoplasms drug therapy, Lung Neoplasms secondary, Melanoma drug therapy, Microtubules drug effects, Neoplasm Invasiveness prevention & control, Polymers therapeutic use, Thiazoles therapeutic use, Tubulin Modulators therapeutic use
- Abstract
Melanoma is the most aggressive type of skin cancer. It is highly metastatic, migrating through lymph nodes to distant sites of the body, especially to lungs, liver and brain. Systemic chemotherapy remains the mainstay of treatment; however, the development of multidrug resistance (MDR) restricts the efficacy of current chemotherapeutic drugs. We synthesized a series of microtubule destabilizers, substituted methoxybenzoyl-ary-thiazole (SMART) compounds, which inhibited tubulin polymerization and effectively circumvented MDR. Due to poor water solubility of SMART compounds, co-solvent delivery is required for their systemic administration, which is usually associated with hepatotoxicity, nephrotoxicity and hemolysis. To solve this problem and also to increase circulation time, we synthesized a new SMART analogue, SMART-OH, and its polymer-drug conjugate, methoxy-poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-SMART-graft-dodecanol) (abbreviated as P-SMART), with 14.3±2.8% drug payload of SMART-OH. Similar to its parent drug, P-SMART showed significant anticancer activity against melanoma cells in cytotoxicity, colony formation, and cell invasion studies. In addition, P-SMART treatment led to cell cycle arrest at G2/M phase and cell accumulation in sub-G1 phase. We established a model of metastatic melanoma to the lung in C57/BL6 albino mice to determine in vivo efficacy of P-SMART and SMART-OH at the dose of 20mg/kg. P-SMART treatment resulted in significant inhibition of tumor growth and prolonged mouse median survival. In conclusion, P-SMART, a novel polymer-microtubule destabilizer conjugate, has the potential to treat metastatic melanoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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