Researchers develop new method to increase effectiveness of
nanomedicines
New technique uses complement inhibitor Factor I to prevent proteins from attacking treatment-carrying nanoparticles

Date:
January 11, 2022
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers have discovered a new, more effective method of
preventing the body's own proteins from treating nanomedicines
like foreign invaders, by covering the nanoparticles with a
coating to suppress the immune response that dampens the therapy's
effectiveness.



FULL STORY ========================================================================== Researchers at Penn Medicine have discovered a new, more effective method
of preventing the body's own proteins from treating nanomedicines like
foreign invaders, by covering the nanoparticles with a coating to suppress
the immune response that dampens the therapy's effectiveness.


==========================================================================
When injected into the bloodstream, unmodified nanoparticles are
swarmed by elements of the immune system called complement proteins,
triggering an inflammatory response and preventing the nanoparticles
from reaching their therapeutic targets in the body. Researchers have
devised some methods to reduce this problem, but the Penn Medicine team,
whose findings are published in Advanced Materials, has invented what may
be the best method yet: coating nanoparticles with natural suppressors
of complement activation.

Nanoparticles are tiny capsules, typically engineered from proteins
or fat- related molecules, that serve as delivery vehicles for certain
types of treatment or vaccine -- usually those containing RNA or DNA. The best-known examples of nanoparticle-delivered medicines are mRNA vaccines against COVID- 19.

"It turned out to be one of those technologies that just works right away
and better than anticipated," said study co-senior author Jacob Brenner,
MD, PhD, an associate professor of Pulmonary Medicine in the Division
of Pulmonary, Allergy, and Critical Care.

The Complement Problem Therapies based on RNA or DNA generally need
delivery systems to get them through the bloodstream into target
organs. Harmless viruses often have been used as carriers or "vectors"
of these therapies, but nanoparticles are increasingly considered safer alternatives. Nanoparticles also can be tagged with antibodies or other molecules that make them hone in precisely on targeted tissues.



========================================================================== Despite its promise, nanoparticle-based medicine has been greatly limited
by the complement attack problem. Circulating complement proteins
treat nanoparticles as if they were bacteria, immediately coating
nanoparticle surfaces and summoning large white blood cells to gobble
up the "invaders." Researchers have attempted to reduce the problem by pre-coating nanoparticles with camouflaging molecules -- for example, the organic compound polyethylene glycol (PEG) attracts water molecules to
form a watery, protective shell around nanoparticles. But nanoparticles camouflaged with PEG or other protective substances still draw at least
some complement attack. In general, nanoparticle-based medicines that must
move through the bloodstream to do their work (mRNA COVID-19 vaccines are injected into muscle, not the bloodstream) have had a very low efficiency
in getting to their target organs, usually less than one percent.

Borrowing a Strategy In the study, Brenner and Myerson and their team
came up with an alternative or add-on approach to protect nanoparticles
-- an approach based on natural complement-inhibitor proteins that
circulate in the blood, attaching to human cells to help protect them
from complement attack.

The researchers found that, in lab-dish experiments, coating standard
PEG- protected nanoparticles with one of these complement inhibitors,
called Factor I, provided dramatically better protection from complement attack. In mice, the same strategy prolonged the half-life of standard nanoparticles in the bloodstream, allowing a much larger fraction of
them to reach their targets.

"Many bacteria also coat themselves with these factors to protect
against complement attack, so we decided to borrow that strategy for nanoparticles," said co-senior author Jacob Myerson, PhD, a senior
research scientist in the Department of Systems Pharmacology and
Translational Therapeutics at Penn.



==========================================================================
In a set of experiments in mouse models of severe inflammatory illness,
the researchers also showed that attaching Factor I to nanoparticles
prevents the hyper-allergic reaction that otherwise could be fatal.

Further testing will be needed before nanomedicines incorporating Factor I
can be used in people, but in principle, the researchers said, attaching
the complement-suppressing protein could make nanoparticles safer and
more efficient as therapeutic delivery vehicles so that they could be
used even in severely ill patients.

The researchers now plan to develop strategies for protecting not only nanomedicines but also medical devices, such as catheters, stents
and dialysis tubing, which are similarly susceptible to complement
attack. They also plan to investigate other protective proteins beside
Factor I.

"We're recognizing now that there's a whole world of proteins that we can
put on the surface of nanoparticles to defend them from immune attack,"
Brenner said.

Funding was provided by the National Institutes of Health (K08-HL-138269,
R01- HL-153510, K99-HL-153696, and R01 HL-157189).

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


========================================================================== Journal Reference:
1. Zhicheng Wang, Elizabeth D. Hood, Jia Nong, Jing Ding, Oscar A.

Marcos‐Contreras, Patrick M. Glassman, Kathryn M. Rubey,
Michael Zaleski, Carolann L. Espy, Damodara Gullipali, Takashi Miwa,
Vladimir R.

Muzykantov, Wen‐Chao Song, Jacob W. Myerson, Jacob S. Brenner.

Combating Complement's Deleterious Effects on Nanomedicine
by Conjugating Complement Regulatory Proteins to
Nanoparticles. Advanced Materials, 2022; 2107070 DOI:
10.1002/adma.202107070 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220111112007.htm

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