Tiny biological package gets drug right to the 'heart' of transplant
rejection

Date:
September 3, 2020
Source:
Johns Hopkins Medicine
Summary:
For patients who receive a heart transplant in the near future,
the old adage, 'Good things come in small packages,' may become
words to live by.

Researchers have demonstrated in mice that they can easily deliver
a promising anti-rejection drug directly to the area surrounding
a grafted heart by packaging it within a tiny three-dimensional,
protein gel cocoon known as a hydrogel.



FULL STORY ==========================================================================
For patients who receive a heart transplant in the near future, the old
adage, "Good things come in small packages," may become words to live
by. In a recent study, researchers at Johns Hopkins Medicine and the
National Cancer Institute (NCI) demonstrated in mice that they can easily deliver a promising anti- rejection drug directly to the area surrounding
a grafted heart by packaging it within a tiny three-dimensional, protein
gel cocoon known as a hydrogel. Best of all, the researchers say that the release of the drug is spread out over time, making it highly regulatable
and eliminating the need for daily medication to keep rejection in check.


==========================================================================
The findings are presented in the Aug. 18, 2020, issue of the journal
Small.

Preventing the rejection of a transplanted heart has often been a
Catch-22 situation. If you give an organ recipient large amounts of immune suppression drugs, there may be serious side effects, including kidney
damage, hypertension, blood sugar imbalances and even lymphomas. Lowering
the dose may be safer for general health but increases the risk that
rejection will not be properly controlled and the grafted heart will
be lost.

"What was needed was a drug delivery method that would get the
anti-rejection medication only where needed; protect the drug from
premature degradation; and maintain a high concentration for the period
of time needed to retrain the immune system," says study co-author Giorgio Raimondi, M.Sc., Ph.D., assistant professor of plastic and reconstructive surgery at the Johns Hopkins University School of Medicine.

"Two earlier studies used the hydrogel method to successfully deliver conventional immunosuppressive drugs to other sites, and this prompted us
to try it out for transplanted hearts," Raimondi explains. "Additionally,
work by a team at the NCI Frederick National Laboratory for Cancer
Research under Joel Schneider [Ph.D., a study co-author] showed that hydrogel-drug packages can be administered by syringe." The drug these researchers wanted to supply to transplanted hearts is tofacitinib,
an inhibitor of the process by which cells alert their receptiveness to
binding with inflammation-inducing proteins called cytokines.

In normal immune responses to foreign invaders within the body, cytokines
play a critical role in alerting specialized white blood cells --
T lymphocytes - - to attack and remove the threatening bacteria or
viruses. However, cytokines in the presence of a transplanted heart can
direct the immune system to destroy the graft.



==========================================================================
To see if a hydrogel courier could be used to deliver tofacitinib,
the researchers first grafted mouse hearts into the necks of recipient
mice to create an animal model of a human transplant. Next, they mixed tofacitinib with a solution of small protein fragments that assembled themselves around the drug during a 24-hour incubation process that
Raimondi likens to the "make your own crystal" kits popular with children.

"We found that making tofacitinib into a crystal best controlled how
the drug spreads out from the hydrogel," says study lead author Poulami Majumder, Ph.D., former NCI at Frederick postdoctoral fellow. "The
resulting 'microcrystalline tofacitinib hydrogel,' or MTH, was extremely stable, preserved the encapsulated drug in pristine condition and could
be injected at the transplantation site simply by using a syringe."
The researchers tested the MTH delivery system in their mouse model
in tandem with a second immunosuppressant drug, CTLA4-Ig, which was
injected separately.

This was the first time that this specific combination therapy had
been tried.

To determine if the location of MTH delivery was important, the
researchers injected the packaged medicine locally, at the transplant
site, and distantly, near the mouse's tail. As expected, only the group
of mice with local injections showed a significant increase of graft
survival time.

"The average survival of the grafted hearts in the locally injected group
was approximately 125 days compared with just 35 days for mice injected
with MTH far from the transplant," Raimondi says. "We also tested the
plasma of the former group and found only minimally detectable traces
of tofacitinib - - meaning that MTH delivery keeps the drug close to
the transplant site and enables it act synergistically with CTLA4-Ig
to provide enhanced and lasting protection of the organ." Without the tofactinib/CTLA4 treatment, Raimondi says, the transplanted mouse hearts stopped beating within 10 days.

Raimondi says that among the advantages to using MTH as a drug-delivery
system are that the hydrogel releases its content slowly, over a period
of 5 to 20 days, and does not cause other complications because it is biocompatible, noninflammatory and biodegradable. He and his colleagues
believe that using crystal engineering to further improve the hydrogel
capsule, more control over the release rate can be obtained -- a critical
goal to meet before human trials can be attempted -- or, the capsule
can be made "tunable" to deliver drug only when the grafted heart is
attacked by the immune system.

The researchers also feel that with additional research and testing, the
MTH delivery system could be applied to fighting rejection of transplanted organs other than the heart and in the treatment of autoimmune diseases.


========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Poulami Majumder, Yichuan Zhang, Marcos Iglesias, Lixin Fan,
James A.

Kelley, Caroline Andrews, Nimit Patel, Jason R. Stagno,
Byoung Chol Oh, Georg J. Furtmu"ller, Christopher C. Lai,
Yun‐Xing Wang, Gerald Brandacher, Giorgio Raimondi, Joel
P. Schneider. Multiphase Assembly of Small Molecule Microcrystalline
Peptide Hydrogel Allows Immunomodulatory Combination Therapy for
Long‐Term Heart Transplant Survival. Small, 2020; 2002791
DOI: 10.1002/smll.202002791 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200903095611.htm

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