(65b) Approaches for Creating Smart Insulin Delivery Systems

Approaches for Creating Smart Insulin Delivery Systems
Lisa R Volpatti, Morgan A. Matranga, Abel C.
Cortinas, Robert S. Langer, Daniel G. Anderson

Koch
Institute of Integrative Cancer Research & Dept. of Chemical Engineering,
MIT, Cambridge, MA 02139

Motivation: Diabetes mellitus is a class of diseases in which
the body either does not produce (Type 1) or is insensitive to (Type 2)
insulin, resulting in poorly controlled blood glucose levels. To combat chronic
hyperglycemia and prevent severe complications such as blindness, cardiovascular
disease, and kidney failure, Type 1 and many Type 2 diabetic patients are
dependent on multiple daily doses of exogenous insulin. Patient compliance is a
major challenge, however, due to the need to measure blood glucose levels up to
six times a day, inject the appropriate amount of insulin, and carefully
monitor diet. To reduce this large patient burden, an attractive diabetes
therapy is a glucose-responsive insulin delivery system that would
self-regulate a patient’s blood glucose levels.

Results: Here we will discuss three types of chemically
glucose-responsive insulin delivery systems that employ the
enzyme glucose oxidase as a glucose sensor. Glucose oxidase converts glucose to
gluconic acid thus reducing the pH of the
microenvironment when glucose levels are high. This change in pH acts as a
trigger to release insulin on demand. The first system (Fig 1a) uses a pH
responsive polymer, acetalated-dextran, to form
nanoparticles that physically encapsulate both insulin and glucose oxidase. The
particles rapidly degrade in the presence of acid affording this system the advantage
of being a fast acting therapeutic. The second system (Fig 1b) is comprised of
alginate microgels that encapsulate these nanoparticles to create a depot of
insulin for sustained glucose-responsive release in vivo for up to two weeks. The third system (Fig. 1c) is based on
the electrostatic complexation of insulin to positively charged polymers, such
as polyethylenimine and poly(beta-amino
esters). When the pH is reduced below insulin’s isoelectric point, the complex
will dissociate, releasing insulin only in response to elevated levels of
glucose. The synthesis, formulation, in
vitro characterization, and in vivo
results in both a healthy and diabetic mouse model will briefly be discussed
for each of these systems, highlighting their pros and cons.

Conclusions: Here we show various approaches to creating a self-regulated insulin delivery system that
achieves tight glycemic control in vivo.
We conclude with perspectives on the future of glucose-responsive insulin
delivery and discuss ideas for further work.