Two-stage peptide hydrogels as sprayable miRNA depot for malignant pleural mesothelioma

Authors

• P Majumder
• A Singh
• C Hoang
• JP Schneider

Abstract

Malignant Pleural Mesothelioma (MPM) is a rare but highly aggressive asbestos-related tumor that develops within the chest cavity. Due to long period of latency and extremely challenging surgical procedures, finding treatments for MPM has been challenging. Surgical resection of MPM leaves a large surface area of tissue that can possibly be directly treated with therapy to prevent recurrence. However, this necessitates the use of a drug delivery vehicle that can cover large areas of tissue having complex surface topology. We are developing a biodegradable hydrogel that can encapsulate therapeutics and be delivered as a misty spray directly to the pleural cavity to allow uniform coverage of the tissue surface with drug. The gel is prepared from self-assembling peptides that allow the direct encapsulation of nanoparticles containing miR-215, a microRNA shown to induce a p53 positive feedback loop causing apoptosis in MPM cells. Fabrication of the delivery platform begins by first condensing miR-215 with the positively charged amphiphilic peptide MAX1 affording nanoparticles capable of trafficking the RNA into cells after being delivered by the spray gel to the tissue. We show that these nanoparticles ferry miR-215 into human MPM cells via endocytosis, resulting in coordinated downregulation of multiple cell cycle transcripts. We also show that miRNA-nanoparticles can be stably encapsulated into sprayable gels to achieve sustained miRNA release for about a month. Appropriate control of release rate is possible by varying the net charge of the sprayable peptide matrix. Based on these results, the efficacy of the sprayable miRNA-215 depot will now be evaluated under pre-clinical settings. Together, our work describes a simple and effective delivery platform that could be extended for a diverse array of locoregional therapies.

Scientific Focus Area: Chemical Biology

This page was last updated on Friday, March 26, 2021