Novel Graft-Implanted Macrophage-Targeted Nanoemulgels for In Situ Immunosuppression in Vascularized Composite Allotransplantation
Abstract
Despite evolving clinical experience and progress in the understanding of the biology of vascularized composite allografts (VCA), one of the main factors preventing wider acceptance or routine clinical application is the associated adverse effects of long-term immunosuppression. Antirejection therapy can lead to diabetes mellitus, nephrotoxicity, osteonecrosis, leukopenia, hypertension, hyperlipidemia, and opportunistic bacterial and viral infections. Since VCAs are non-lifesaving procedures, the risks and toxicity of immunosuppression must be carefully balanced against their potential life-enhancing benefits in recipients. Unlike most solid organ transplantations, VCAs offer unique opportunities for local delivery of immunosuppressive medications directly to the graft. The rationale for such site-specific, transplant-delivered immunosuppression is to reduce systemic exposure and global adverse effects. Hypothetically, localized graft immunosuppression such as proposed with novel drug-loaded gels could facilitate minimization of overall dosing, frequency, and duration of systemic immunosuppression and also help reduce the number of systemic drugs required for desired efficacy and improved graft survival. Our team has identified that specific immune cells called macrophages are major players during inflammatory responses after VCA transplantation. In prior studies, we delivered single immunosuppressive drugs packaged in gels directly by injection to the VCA transplant and effectively controlled acute but not chronic rejection. Specifically, in this proposal we are proposing newer “nanoemulgels,” which are unique as they contain extremely low concentrations of combinations of drugs like tacrolimus, rapamycin, or mycophenolic acid that are released only in the presence of inflammation and macrophages. This reduces the levels of the drugs in the blood to negligible or undetectable amounts while increasing their levels in the transplanted tissues to suppress not just acute but also chronic rejection. This gel, called the Macrophage Enabled Nanoemulgel Delivery System (MENDS), combines two drugs, sirolimus and mycophenolic acid (that are not toxic to the kidney and effective in chronic rejection) with very low doses of tacrolimus (that is effective in acute rejection). Chronic rejection can cause loss of grafts due to narrowing of blood vessels. Hypothetically, site-specific graft immunosuppression such as proposed with novel MENDS delivery platform could facilitate minimization of overall dosing, frequency, and duration of systemic immunosuppression and also help reduce the number of systemic drugs required for desired efficacy and improved graft survival. Immunosuppressive drugs can be encapsulated in such gels to create “inflammation-responsive depot” that can be customized for controlled, continuous, or on-demand local release in VCA tissues in response to biological stimuli (such as beginning of rejection). These systems can be embedded in transplanted tissue to provide programmed release of drugs over extended periods of time and enhance the therapeutic effect. Gels as proposed are a novel class of biomaterials with promising wide-ranging applications outside of VCA in dermatology, cardiology, and cancer. Graft embedded drug delivery can have a huge impact in VCA. VCA could benefit from the forefront of nanotherapeutics and biomaterial based drug delivery, which offers the most immediate payoff for target (disabled) Service members, with lower risk and morbidity. VCA could allow shorter rehabilitation and earlier return of combat Soldiers to prior professional responsibilities. We are confident that the proposed work will establish the utility of this platform as a graft-embedded drug delivery technology for chronic rejection (as well as acute rejection) mitigation, achieving major impact specifically in VCA transplantation, and more generally across many clinical applications in transplantation medici
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010771
Entities
People
- Praveen K Vemula
Organizations
- Institute for Stem Cell Biology and Regenerative Medicine
- United States Army