Topical Administration of an Apoptosis Inducer Mitigates Bleomycin-Induced Skin Fibrosis

Authors

Md Nurul Huda
Edgar A Borrego
Cristina D Guerena
Armando Varela-Ramirez
Renato J Aguilera
Christine M Hamadani
Eden E L Tanner
Abu Zayed Md Badruddoza
Sandeep K Agarwal
Md Nurunnabi

Publication Date

5-12-2023

Journal

ACS Pharmacology & Translational Science Journal

DOI

10.1021/acsptsci.3c00039

PMID

37200808

PMCID

PMC10186622

PubMedCentral® Posted Date

4-28-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

ionic liquid, navitoclax, apoptosis, skin fibrosis, topical, scleroderma

Abstract

Pathological fibrosis is distinguished from physiological wound healing by persistent myofibroblast activation, suggesting that therapies that induce myofibroblast apoptosis selectively could prevent progression and potentially reverse the established fibrosis, such as for scleroderma (a heterogeneous autoimmune disease characterized by multiorgan fibrosis). Navitoclax (NAVI) is a BCL-2/BCL-xL inhibitor with antifibrotic properties and has been investigated as a potential therapeutic for fibrosis. NAVI makes myofibroblasts particularly vulnerable to apoptosis. However, despite NAVI's significant potency, clinical translation of BCL-2 inhibitors, NAVI in this case, is hindered due to the risk of thrombocytopenia. Therefore, in this work, we utilized a newly developed ionic liquid formulation of NAVI for direct topical application to the skin, thereby avoiding systemic circulation and off-target-mediated side effects. The ionic liquid composed of choline and octanoic acid (COA) at a 1:2 molar ionic ratio increases skin diffusion and transportation of NAVI and maintains their retention within the dermis for a prolonged duration. Topical administration of NAVI-mediated BCL-xL and BCL-2 inhibition results in the transition of myofibroblast to fibroblast and ameliorates pre-existing fibrosis, as demonstrated in a scleroderma mouse model. We have observed a significant reduction of α-SMA and collagen, which are known as fibrosis marker proteins, as a result of the inhibition of anti-apoptotic proteins BCL-2/BCL-xL. Overall, our findings show that COA-assisted topical delivery of NAVI upregulates apoptosis specific to myofibroblasts, with minimal presence of the drug in the systemic circulation, resulting in an accelerated therapeutic effect with no discernible drug-associated toxicity.