by Lindy Keane Carter
Transplant medicine has made significant strides over the last 30 years in developing immunosuppressive drugs that decrease organ rejection within the first three months, but the Holy Grail–drugs that will improve long-term graft outcome without systemic effects–remains elusive. Graft rejection occurs in 15% to 20% of kidney transplants and up to 50% of heart and lung transplants. Although drugs such as rapamycin can improve these odds, they are seldom used during transplant because of their negative effects throughout the body.
Three MUSC scientists have successfully demonstrated in mouse models a way to deliver rapamycin via a nanocarrier to a transplanted kidney and its local environment only, leaving the rest of the body’s immune system unaffected. Their initial findings were presented at the State of the Art Winter Symposium of the American Society of Transplant Surgeons in January 2014.1
Ann-Marie Broome, Ph.D., MBA, is a biomedical engineer and nanotechnologist who developed the nanocarrier, a trackable, drug-carrying micelle that targets the kidney and its region. Satish N. Nadig, M.D., PhD, is a transplant surgeon who ensured that the basic science would readily translate to human transplant clinics. Carl Atkinson, PhD, an expert in the innate immune system and the development of adaptive anti-graft immune responses, ensured that the nanocarrier itself was immunologically inert to allow for organ tolerance.
The novelty in their approach is that they have combined therapeutic tools that are already in use in medicine–nanocarriers, targeted therapy, and rapamycin–and introduced them to transplant surgery. “This has never been done before in transplant medicine,” says Nadig. “It’s the opposite of the approach used currently in cancer. While many oncologists are trying to enhance the immune system surrounding a tumor to fight it, we are facilitating the proliferation of the T-cells that induce tolerance to the organ while suppressing the effector cells that attack the new graft.”
Nadig’s experience as a transplant surgeon led him to choose laboratory models that would translate to the clinic. For example, the team added the rapamycin nanocarrier, referred to as TRaM, to the perfusion solution in which the organ was stored. “So before it experienced the insult of transplant, the organ was immunologically protected,” says Nadig.
Broome’s TRaMs are “decorated” with tracking fluorophores and various other molecules that target the endothelial cells lining the kidney’s blood vessels and the transplanted kidney itself. The nanoparticles are taken up into the cells, where a change in pH triggers their rupture and the release of the drug. In this way, the immunosuppressant is delivered only to cells in the region involved in the surgery. The nanoparticles not internalized by the target cells remain intact, their payload of immunosuppressant safe inside, and circulate harmlessly until excreted.
Broome anticipates that she will be able to tailor these nanoparticles to other organs and applications. “We can personalize the nanoparticle to any transplanted organ,” says Broome. “This is a novel platform technology with endless possibilities, not just a one-trick pony.”
The collaborators are planning to develop these approaches through their new company, ToleRam Nanotech, LLC.
1 Broome, AM, Dixit S, Levey N, Atkinson C, Nadig S. “Towards targeted drug delivery in transplantation: Use of immunosuppressant nanoparticle therapy.” Paper presented at: American Society of Transplant Surgeons 14th Annual State of the Art Winter Symposium; January, 2014; Miami, FL.
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