Biocompatible Therapeutic Platform for Precise Regulation of Vascularized Composite Allotransplant Rejection via Enhanced Costimulation Blockage
Abstract
Vascularized composite allotransplantation is now a valid therapeutic option. However, the debilitating side effects of current immunosuppressive therapy counterbalance its benefits. We have discovered that pharmacological inhibition of inflammatory cytokines, through the Jak3/1 inhibitor Tofacitinib (Tofa), is effective in synergizing with the biologic CTLA4-Ig to promote long-term transplant survival. To translate this combination strategy into a clinical application, we propose a novel two-component delivery platform that combines two technologies: injectable peptide hydrogels, and lipid nanoparticles (LNp). The goal of this proposal is to optimize such a platform to tune the localized delivery of Tofa-loaded LNp to the activity of rejection-associated proteases and demonstrate the confined effect on the rejection response. Major finding from this first year of investigation are: 1) injectable peptide hydrogels can be designed to be protease sensitive; 2) certain LNp formulations are compatible with encapsulation within hydrogels. These composites represent a new class of immune-modulating implantable material.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1089995
Entities
People
- Joel P. Schneider
Organizations
- National Cancer Institute