Jump to main content
Jump to site search


Targeted co-delivery of aldose reductase inhibitor epalrestat and chemotherapeutic doxorubicin via redox-sensitive prodrug approach promotes synergistic tumor suppression

Abstract

Rapidly growing evidence suggests a strong dependence of polyol pathway enzyme Aldose Reductase (AR) in cancer progression and invasion. Thus, inhibiting the AR through therapeutic inhibitors have a potential application in cancer treatment. Epalrestat (EPR) is the only marketed AR inhibitor with proven safety and efficacy in the management of complications like diabetic neuropathy. However, its short half-life and highly hydrophobic nature restrict its use as an anticancer agent. In the present study, we first developed a redox-sensitive prodrug of EPR by conjugating Tocopherol Polyethylene Glycol Succinate (TPGS) which can form a self-assembled micellar prodrug (EPR-SS-TPPGS). Subsequently, to achieve synergistic chemotherapeutic efficacy Doxorubicin (Dox) was co-loaded into the EPR-SS-TPGS micelles where the system disrupts under tumor redox environment and co-deliver Dox and EPR in a ratiometric manner. We then employed TPGS conjugated Vitamin-B6 as targeting moiety and prepared the mixed micelles to facilitate VTC receptor-mediated uptake. The encapsulation of Dox and EPR with the developed prodrug approach showed significant synergies with increased intracellular accumulation and redox triggered release in MDA-MB-231 and 4T1 cell lines leading to superior cell cycle arrest, mitochondrial membrane potential, and apoptosis. Prolonged circulation half-life and tumor site bioavailability was achieved for both the drugs with the developed approach. Surprisingly, EPR and Dox combination significantly down-regulated the CD44 receptor expression which is the main contributing factor of tumor metastasis. Further, in-vivo evaluation demonstrated a significant reduction in Dox-induced cardiotoxicity. In summary, this nanoencapsulation paradigm of AR inhibitors with chemotherapeutic agents lays the foundation of new opportunities in combination chemotherapy.

Back to tab navigation

Supplementary files

Publication details

The article was received on 11 Feb 2019, accepted on 10 Apr 2019 and first published on 15 Apr 2019


Article type: Paper
DOI: 10.1039/C9BM00221A
Citation: Biomater. Sci., 2019, Accepted Manuscript

  •   Request permissions

    Targeted co-delivery of aldose reductase inhibitor epalrestat and chemotherapeutic doxorubicin via redox-sensitive prodrug approach promotes synergistic tumor suppression

    V. T. Banala, S. Urandur, S. Sharma, M. Sharma, R. P. Shukla, D. Marwaha, S. Gautham, M. Sharma and P. R. Mishra, Biomater. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C9BM00221A

Search articles by author

Spotlight

Advertisements