(100b) Glucose-Responsive Nanoparticles Based on Enzymatic Sensors for Self-Regulated Insulin Delivery

115%">Glucose-responsive nanoparticles
based on enzymatic sensors

115%">for self-regulated insulin delivery

115%">Lisa R Volpatti, Morgan A. Matranga,
Abel B. Cortinas, Robert Langer, Daniel G. Anderson

115%">Koch Institute &
Department of Chemical Engineering, MIT, Cambridge, MA 02139

Motivation: Diabetes mellitus is a disease characterized by poor glycemic control
which often leads to severe complications including cardiovascular disease and
kidney failure. Many diabetic patients continually monitor their blood sugar
and self-administer multiple daily doses of insulin to combat hyperglycemia. Most
commercial glucometers rely on the enzymatic sensor, glucose oxidase (GOx), to detect glucose levels. To better mimic native
insulin activity, the GOx sensor can also be incorporated
into an insulin delivery system. By coupling the sensing with a responsive
polymeric material, insulin can be released in a self-regulated manner. Here,
we report a glucose-responsive insulin delivery system based on the enzymatic
sensing of glucose oxidase that achieves superior glycemic control compared to systems
lacking the glucose sensor.

Methods: GOx
acts as a glucose sensor by catalyzing the reaction of glucose to gluconic acid, consuming oxygen and producing hydrogen
peroxide as a byproduct. Therefore, polymers that respond to changes in pH,
oxidation, or hypoxia may be used in conjunction with this enzyme for self-regulated
insulin delivery. Here, acetalated-dextran (Ac-dex) nanoparticles (NPs) were formulated containing
insulin, GOx, and catalase. Ac-dex
rapidly degrades as a result of the reduced pH from the GOx
reaction when glucose levels are high, thus releasing insulin on demand.
Catalase provides added biocompatibility by disproportionating
the hydrogen peroxide byproduct.

  font-family:" arial>

" arial>Results: font-family:" arial>To distinguish between glucose-responsive and
non-responsive insulin release, diabetic mice were administered nanoparticles
containing enzymes and insulin (NPs), nanoparticles without enzymes (NPs (–
Enzymes)), or nanoparticles without insulin (NPs (– Insulin)). Following a glucose
injection, only the NP group was able to regain glycemic control within 3 h
(Figure 1a). Therefore, the glucose sensor and the
insulin are necessary to produce consistent glycemic control with significantly
reduced areas under the curve (AUCs, Figure 1b). Diabetic mice were found to
have the best glycemic control when administered NPs, compared to an equivalent
dose of a long-acting acylated analog of insulin
(commercially known as insulin detemir) and naked
insulin (Figure 1c). Specifically, for the time interval between 6 – 9 h, the
long-acting insulin and naked insulin groups both have significantly higher
AUCs than the NP group (Figure 1d). Therefore, for the same dose of insulin,
glucose-responsive NPs provide better extended glycemic control compared to
long-acting or naked insulin treatments.

  mso-bidi-font-size:11.0pt;font-family:" arial>

Conclusions: The enzymatic sensor
glucose oxidase can provide a trigger for applications in self-regulated
insulin delivery. The resulting glucose-responsive nanoparticles provide better
glycemic control than a system without such sensing capabilities, which may
improve diabetes therapies in the future.