Exactly into a new heart
In a new study, experts from the Johns Hopkins University School of Medicine and the National Cancer Institute demonstrated in mice that they can easily deliver an effective drug against transplant rejection directly to the area surrounding the transplanted heart by packing it into a small three-dimensional hydrogel cocoon. In addition, the release of the drug inside the body is distributed over time, which eliminates the need for daily intake.
Preventing rejection of a transplanted heart often puts the patient in a difficult position, as if between a hammer and an anvil. If the recipient receives a large amount of drugs to suppress immunity, it can cause serious side effects, including kidney damage, hypertension, blood sugar imbalance and even lymphoma. A lower dose of immunosuppressants is safer for general health, but it increases the risk of rejection of the transplanted organ.
Therefore, a method of targeted drug delivery is needed, which would allow you to get the effect only where it is necessary. It is also important to protect the drug from premature decay and maintain a high concentration during the entire time needed to retrain the immune system.
Two earlier studies have already used hydrogel to successfully deliver immunosuppressants to different organs. The group set out to adapt the method to deliver the drug to the transplanted heart.
The drug that the researchers wanted to introduce is tofacitinib, it inhibits the mechanism used by cells to communicate their susceptibility to cytokines. In a healthy body, cytokines play a crucial role in activating T-lymphocytes to attack and remove threatening bacteria or viruses. However, in the presence of a transplanted heart, they can direct the immune system to destroy the transplant.
To find out if a hydrogel courier could be used to deliver tofacitinib, the researchers first transplanted mouse hearts into the necks of recipient mice to create an animal model of a human transplant. Then they incubated tofacitinib for 24 hours with protein fragments that gathered around the drug, like a child's toy "Grow your Crystal".
The authors found that the transformation of tofacitinib into crystal best controls the release of the drug from the hydrogel. The resulting microcrystalline tofacitinib hydrogel (MTH) was extremely stable, kept the encapsulated drug in its original state and could be injected into the transplant site using a syringe.
The researchers tested the MTH delivery system on their model in tandem with another immunosuppressant, CTLA4-Ig, which was administered separately. This was the first experience of using such a specific combination therapy.
To determine whether the MTH injection site is relevant for targeted delivery, the researchers injected the hydrogel-packed drug locally, directly into the transplant area, and remotely, into the tail vein As expected, only mice with local injection showed a significant increase in graft retention time.
The average survival of transplanted hearts in the locally injected group was approximately 125 days, compared to 35 days for mice injected with MTH remotely. The researchers also tested the plasma of mice of the first group and found minimal traces of tofacitinib – this means that the hydrogel shell of MTH keeps the drug in the transplant zone and allows it to act in conjunction with CTLA4-Ig, providing powerful and long-lasting protection of the organ.
According to the authors, without treatment with tofacitinib and CTLA4, the transplanted mouse hearts would have stopped beating within 10 days.
The advantage of using MTH as a drug delivery system is that the hydrogel releases its contents slowly, from 5 to 20 days, and does not cause other complications, since it is biocompatible, biodegradable and does not cause inflammation. Scientists plan to improve control over the rate of drug release so that human trials can be carried out, for example, to create a customized capsule to release the drug only when the transplanted heart is attacked by the immune system.
The researchers also believe that the MTH delivery system can also be used to combat rejection of other transplanted organs and to treat autoimmune diseases.
Article by P. Majumder et al. Multiphase Assembly of Small Molecule Microcrystalline Peptide Hydrogel Allows Immunomodulatory Combination Therapy for Long Term Heart Transplant Survival published in the Small magazine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Johns Hopkins Medicine: Tiny biological package gets drug right to the 'heart' of transplant rejection.