Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma

Ruinan Yang, Goutam Mondal, Rachel A. Ness, Kinsie Arnst, Vaibhav Mundra, Duane D. Miller, Wei Li, Ram I. Mahato

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 20 mg/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.

Original languageEnglish (US)
Pages (from-to)32-41
Number of pages10
JournalJournal of Controlled Release
Volume249
DOIs
StatePublished - Mar 10 2017

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Thiazoles
Microtubules
Melanoma
Polymers
Lung
Multiple Drug Resistance
Pharmaceutical Preparations
Dodecanol
Transplants
Ethylene Glycol
G2 Phase
G1 Phase
Skin Neoplasms
Tubulin
Hemolysis
Cell Cycle Checkpoints
Polymerization
Cell Division
Solubility

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma. / Yang, Ruinan; Mondal, Goutam; Ness, Rachel A.; Arnst, Kinsie; Mundra, Vaibhav; Miller, Duane D.; Li, Wei; Mahato, Ram I.

In: Journal of Controlled Release, Vol. 249, 10.03.2017, p. 32-41.

Research output: Contribution to journalArticle

Yang, Ruinan ; Mondal, Goutam ; Ness, Rachel A. ; Arnst, Kinsie ; Mundra, Vaibhav ; Miller, Duane D. ; Li, Wei ; Mahato, Ram I. / Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma. In: Journal of Controlled Release. 2017 ; Vol. 249. pp. 32-41.
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AU - Yang, Ruinan

AU - Mondal, Goutam

AU - Ness, Rachel A.

AU - Arnst, Kinsie

AU - Mundra, Vaibhav

AU - Miller, Duane D.

AU - Li, Wei

AU - Mahato, Ram I.

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AB - 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 20 mg/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.

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