[GRG] Rx: Proteins Administered PO

To Members and Friends of the Los Angeles Gerontology
Research Group:Getting
proteins past the stomach for absorption… — Steve Coles

“Polymers Key to Oral Protein-Based
Drugs”
Friday, June 28, 2013; (R&D) — For protein-based drugs such
as insulin to be taken orally rather than injected, bioengineers need to
find a way to shuttle them safely through the stomach to the small
intestine where they can be absorbed and distributed by the bloodstream.
Progress has been slow, but in a new study, researchers report an
important technological advance: They show that a ?bioadhesive? coating
significantly increased the intestinal uptake of polymer nanoparticles in
rats and that the nanoparticles were delivered to tissues around the body
in a way that could potentially be controlled.?The
results of these studies provide strong support for the use of
bioadhesive polymers to enhance nano- and micro-particle uptake from the
small intestine for oral drug delivery,? wrote the researchers in the
Journal of Controlled Release, led by corresponding author Edith
Mathiowitz, Professor of Medical Science at Brown University.
Mathiowitz, who teaches in Brown?s Dept. of Molecular Pharmacology,
Physiology, and Biotechnology, has been working for more than a decade to
develop bioadhesive coatings that can get nanoparticles to stick to the
mucosal lining of the intestine so that they will be taken up into its
epithelial cells and transferred into the bloodstream. The idea is that
protein-based medicines would be carried in the nanoparticles.In the new
study, Mathiowitz put one of her most promising coatings, a chemical
called PBMAD, to the test both on the lab bench and in animal
models. Mathiowitz and her colleagues have applied for a patent related
to the work, which would be assigned to Brown University. In prior
experiments, Mathiowitz and her group have shown not only that PBMAD has
bioadhesive properties, but also that it withstands the acidic
environment of the stomach and then dissolves in the higher pH of the
small intestine.Adhere, Absorb,
ArriveThe newly published results focused on the question of how
many particles, whether coated with PBMAD or not, would be taken up by
the intestine and distributed to tissues. For easier tracking throughout
the body, Mathiowitz?s team purposely used experimental and control
particles made of materials that the body would not break down. Because
they were ?non-erodible? the particles did not carry any medicine.The
researchers used particles about 500 nm in diameter made of two different
materials: polystyrene, which adheres pretty well to the
intestine?s mucosal lining, and another plastic called PMMA, that
does not. They coated some of the PMMA particles in PBMAD, to see if the
bioadhesive coating could get PMMA particles to stick more reliably to
the intestine and then get absorbed.First the
team, including authors Joshua Reineke of Wayne State University and
Daniel Cho of Brown, performed basic benchtop tests to see how well each
kind of particles adhered. The PBMAD-coated particles proved to have the
strongest stickiness to intestinal tissue, binding more than twice as
strongly as the uncoated PMMA particles and about 1.5 times as strongly
as the polystyrene particles.The main
experiment, however, involved injecting doses of the different particles
into the intestines of rats to see whether they would be absorbed and
where those that were taken up could be found five hours later. Some rats
got a dose of the polystyrene particles, some got the uncoated PMMA and
some got the PBMAD-coated PMMA particles.
Measurements showed that the rats absorbed 66.9 percent of the
PBMAD-coated particles, 45.8 percent of the polystyrene particles, and
only 1.9 percent of the uncoated PMMA particles.  Meanwhile, the
different particles had very different distribution profiles around the
body. More than 80 percent of the polystyrene particles that were
absorbed went to the liver and another 10 percent went to the kidneys.
The PMMA particles, coated or not, found their way to a much wider
variety of tissues, although in different distributions. For example,
the  PBMAD-coated particles were much more likely to reach the
heart, while the uncoated ones were much more likely to reach the
brain.Pharmaceutical
Potential
“The apparent fact that the differing surface
properties of the similarly-sized particles had such distinct
distributions in the rats? tissues after the same five-hour period
suggests that scientists could learn to tune particles to reach specific
parts of the body, essentially targeting doses of medicines taken
orally,” Mathiowitz said.  ?The distribution in the body can be
somehow controlled with the type of polymer that you use,? she
said.For now,
she and her Group have been working hard to determine the biophysics of
how the PBMAD-coated particles are taken up by the intestines. More work
also needs to be done, for instance to demonstrate actual delivery of
protein-based medicines in sufficient quantity to tissues where they are
needed.  But Mathiowitz said the new results give her considerable
confidence.?What this
means now is that if I coat bioerodible nanoparticles correctly, I can
enhance their uptake,? she said. ?Bioerodible nanoparticles are what we
would ultimately like to use to deliver proteins. The question we address
in this paper is how much can we deliver. The numbers we saw make the
goal more feasible.?Another
frontier for the delivery of nanoparticles is devising a safe method to
make nanoparticles, Mathiowitz said, but, ?we have already developed safe
and reproducible methods to encapsulate proteins in tiny nanoparticles
without compromising their biological activity.?Source:
Brown
Univ.
Topics:

R &
D Daily

Biology

Material Science

Nanomedicine

Nanotechnology

Polymers

L. Stephen Coles, M.D., Ph.D., Co-Founder
Los Angeles Gerontology Research GroupURL:
http://www.grg.org
E-mail: scoles@grg.orgE-mail:
scoles@ucla.edu

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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