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Background
Justin Shofner is originally from Pikeville,
Kentucky. He graduated with a B.S. in Chemical
Engineering from the University of Kentucky while
doing research for Dr. Barbara L. Knutson. He has
since enrolled in the graduate program in Chemical
Engineering at the University of Texas at Austin and
is seeking a Ph.D.
Research Summary
One of the effective strategies for enhancing
bioavailability of proteins exploits the
receptor-mediated endocytotic pathway used by the
cells for the selective and efficient uptake of
specific macromolecules required for various cell
processes. By coupling proteins and peptides to
ligands that can recognize specific receptors on the
epithelial cells, transcellular delivery of these
macromolecular biopharmaceuticals may be achieved.
Since only those molecules that are conjugated to
the ligands are transcytosed, this process
eliminates the potential side effects associated
with the unspecific transport via the paracellular
pathway. Transferrin is one of the most widely
investigated proteins for enhancing the cellular
uptake of therapeutic agents. It is a naturally
occurring protein involved in iron transport.
Absorptive uptake of the iron-bound transferrin is
often used to enhance the transcytosis of
therapeutic agents and drug carriers across
polarized cells such as the epithelial cells and the
endothelial cells. Transferrin-receptor (TfR)
mediated delivery systems have been exploited in our
labs for delivery of drugs.
TfR-mediated cellular uptake has also been
exploited for targeted delivery of anticancer drugs,
proteins, and therapeutic genes into primary
proliferating malignant cells that over express the
transferrin receptors. Covalent coupling of
transferrin with therapeutic drugs, proteins, or
genetic infusion of therapeutic peptides into the
structure of transferrin results in complexes with
improved specificity and cytotoxicity toward
malignant cells and enhanced uptake characteristics.
We have recently demonstrated improved efficacy
of orally administered insulin by conjugating
insulin with transferrin through disulfide linkages.
Transferrin receptors are present in high density in
human GI epithelium, and transferrin can resist
tryptic and chymotryptic degradation. We developed a
delivery system consisting of the complexation
hydrogels acting as delivery vehicles for insulin-transferrin
conjugates. The use of P(MAA-g-EG)-based
microparticles as delivery vehicles for the insulin-transferrin
conjugates constitutes a superior transmucosal
delivery system for insulin. The system may improve
the efficacy of oral insulin administration since: (i)
insulin in the conjugated form may be further
protected from enzymatic degradation due to steric
hindrance created by the conjugated transferrin;
(ii) owing to the mucoadhesive nature of the
delivery system, most of the conjugate will be
released within the localized microenvironment of
the small intestine’s filamentous brush border
creating a high local concentration of the
conjugate; (iii) the conjugate will have larger
residence time in the small intestine; and (iv) the
insulin-transferrin conjugate can cross the
intestinal barrier by TfR-mediated transcellular
pathway, which may further increase the efficiency
of insulin absorption.
The main vision of my PhD thesis will be to study
a truly new system (transporter/biological molecule)
that will improve the transport of proteins across
the intestinal wall. In your case, the polymer
carrier will be the one well studied already, i.e.,
poly(ethylene glycol) (PEG) chains grafted on
poly(methacrylic acid) (PMAA) backbone chain,
henceforth designated as P(MAA-g-EG). However, the
long term goal will be to come up with an improved
transporter.
Publications
Bothun, G.D., Kho, Y.W.,
Berberich, J.A., Shofner, J.,
Robertson, T., Tatum, K.J., Knutson, B.L. Surface
activity of lysozyme and dipalmitoyl
phosphatidylcholine vesicles at compressed and
supercritical fluid interfaces, tent. accepted,
J. Phys. Chem. B. |
