Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma

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 methoxybenzoylary-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.

Genome editing of PD-L1 mediated by nucleobase-modified polyamidoamine for cancer immunotherapy

“…Melanoma is a highly metastatic tumor, with the lungs being one of the most common sites of distant metastasis. 41 Thus, a model of mouse melanoma pulmonary metastasis was established through the intravenous injection of B16F10 cells, and different nanoparticles were intravenously administered to evaluate their anti-tumor efficacy (Fig. 5A).…”

Nanomedicines for combating multidrug resistance of cancer

“…Apart from the inhibitors that directly act on the MDR‐related drug efflux transporters, there are some other chemical substances shown to potentially reverse the MDR of cancer cells in an indirect manner. Evidence from previous studies suggests that the inhibition of microtubules (Bacher et al, 2001; Z. Wang, Chen, et al, 2012b; Yang et al, 2017) or NF‐κB (Nakanishi & Toi, 2005) can sensitize the drug‐resistant cancer cells to anticancer treatments. Therefore, utilizing nanocarriers to achieve the co‐delivery of chemodrugs and inhibitors, for example, pyrrolidinedithiocarbamate (Fan et al, 2010) and curcumin (Misra & Sahoo, 2011), both of which can inhibit NF‐κB activation, represents a feasible strategy to combat MDR.…”

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…used SMART‐100 conjugated PEG‐PCC‐g‐DC‐g‐SMART lipopolymer to overcome poor water solubility of SMART‐100 and demonstrated PEG‐PCC‐g‐DC‐g‐SMART inhibited tubulin polymerization, enhanced cytotoxicity in melanoma cells, reduced colony formation, and cell invasion. Moreover, systemic administration of PEG‐PCC‐g‐DC‐g‐SMART significantly inhibited metastatic lung nodules and prolonged mice survival rate . Table summarizes the important lipopolymer nanocarrier formulations developed to treat various cancers.…”