Drug delivery system prevents transplant rejection

Following a tissue graft transplant — such as that of the face, hand, arm, or leg — it is standard for doctors to give transplant recipients immunosuppressant drugs immediately to prevent their immune systems from rejecting and attacking the new body part. However, that incurs the risk of toxicities and side effects, because suppressing the immune system can make a patient vulnerable to infection.

In a global collaboration, researchers from Harvard-affiliated Brigham and Women’s Hospital (BWH), the Institute for Stem Cell Biology and Regenerative Medicine in Bangalore, India, and University Hospital of Bern, Switzerland, have developed a way to deliver immunosuppressant drugs locally and when prompted, through the use of a biomaterial that self-assembles into a hydrogel, a gelatinlike material. The novel system is able to targeted and controlled release of the medication, so that it is delivered where and when it is needed.

The study was published online today in Science Translational Medicine.

The hydrogel-drug combo, which contains the immunosuppressant drug tacrolimus, is injected under the skin after transplant surgery. The hydrogel remains inactive until it detects an inflammation/immune response from the transplant site, at which point it delivers the immunosuppressant drug within the transplanted graft for months.

In pre-clinical studies conducted by the researchers, a one-time, local injection of the hydrogel-drug combo prevented graft rejection for more than 100 days. This compared with 35.5 days for recipients receiving only tacrolimus, and 11 days for recipients without treatment or only receiving hydrogel.

The innovation may also be applied in medical situations outside of transplant surgery.

“This new approach to delivering immunosuppressant therapy suggests that local delivery of the drug to the grafted tissue has benefits in reducing toxicity, as well as markedly improving therapeutic outcomes, and may lead to a paradigm shift in clinical immunosuppressive therapy in transplant surgery,” said Harvard Medical School associate professor of medicine Jeff Karp, Division of Biomedical Engineering, BWH Department of Medicine, co-corresponding study author.

Inflammation-directed drug release offers judicious use of a locally injected drug that extends the release for months while eliminating systemic toxicity, added Robert Rieben, associate professor of transplantation immunology, Department of Clinical Research, University of Bern, co-corresponding study author. “Continuous release of the drugs irrespective of disease severity is a hallmark of existing drug delivery vehicles and could be a thing of the past.”

“This safe, controlled release platform approach functions for over three months from a single injection, and that has broad implications,” said Karp. “Nearly every disease has an inflammatory component. Thus we believe the materials we have developed could be used for localized treatment of multiple inflammatory diseases.”

Added Praveen Kumar Vemula, co-corresponding study author: “This approach should also improve patient compliance, as it obviates the need for daily medications. Also, we plan to expand this prototype for the treatment of numerous diseases such as psoriasis, arthritis, and cancer.” Vemula, now affiliated with the Institute for Stem Cell Biology and Regenerative Medicine in Bangalore, India, developed the hydrogel with Karp while a postdoc in the Karp laboratory.

This research was supported by the National Institutes of Health, American Society for Surgery of the Hand, Olga Mayenfisch Foundation, Julia Bangerter-Rhyner Foundation, and a Harvard Institute of Translational Immunology/Helmsley Trust Pilot Grant.

Karp is a founder of, and has a financial interest in, Skintifique, a company that is developing self-assembled hydrogels for skin applications. The Karp lab developed the hydrogel technology and it was licensed by BWH to Skintifique.