Summary:
UCLA researchers in the department of Bioengineering have developed a biodegradable material that is capable of releasing insulin in the presence of excess glucose mimicking the insulin secretion properties of pancreatic B-cells as a treatment for Diabetes Mellitus.
Background:
Diabetes mellitus currently affects more than 463 million people worldwide, and it is estimated to affect more than 700 million in 2045. Insulin replacement therapy remains the current standard of care (SOC) for treating type 1 and advanced type 2 diabetes. In healthy individuals, β-cells of the pancreas secret insulin that is responsible for regulating blood glucose levels (BGL). Daily administration of exogenous insulin via injection or infusion is tedious; multiple factors such as age, lifestyle, stress levels, physical activity and dietary intake affect the bioavailability and activity levels of the exogenous insulin. Therefore, a synthetic system that can mimic β-cells by releasing insulin in a glucose-dependent manner is attractive for facilitating insulin administration by maximizing effectiveness and increasing safety
To date, various glucose-responsive insulin delivery systems, such as microneedles, hydrogels, nanoparticles or microparticles, complexes, liposomes, cells, and insulin analogs, have been extensively investigated. Of these, a glucose-responsive, charge-switchable complex has been validated with robust glucose-responsive performance in animal models. However, the non-degradable polymer backbone caused biocompatibility issues due to its low molecular weight thereby, increasing the basal insulin release rate.
Therefore, a high molecular weight biodegradable cationic macromolecule would potentially resolve this problem by enhancing the stability of insulin complex thus, reducing the basal insulin release rate. In addition, a systemic investigation of the factors affecting glucose-responsive performance is essential in guiding the design and preparation of an insulin formulation with prolonged, efficacious treatment characteristics.
Innovation:
UCLA researchers have developed a cationic polymer by modifying biodegradable poly(L-lysine) (PLL) with 4-carboxy-3-fluoro-phenylboronic acid (FPBA), a widely used glucose-sensing component. Subsequently, these polymers are complexed with insulin that is negatively charged at an isoelectric pH between 5.3 to 5.35; this substantially increases the polymer complex stability.
This novel PLL-FPBA polymer – insulin complex has a loading efficiency higher than 90%. In different in vivo studies, this novel polymer mimicked after the pancreatic B-cells i.e., released insulin in the presence of high blood glucose levels. Researchers also found that PLL-FPBA polymer – insulin complex induced sustained release of insulin thereby, prolonging the anti-hyperglycemic effect of native insulin, extending normoglycemia for more than 20 hours and remaining effective even at 72 hours post-treatment. Thus, this proposed technology has the capacity to improve quality of life and quality of treatment of Diabetes Mellitus for hundreds of millions of people.
Potential Applications:
- Diabetes Mellitus Treatment
- Blood Glucose Stabilization
- Glucose Induced Anionic Drug Delivery
Advantages:
- Enhanced Stability of the polymer complex
- Sustained basal insulin release rates
- Responsive to Blood Glucose Levels
- Biodegradable
- Safe
- No toxicity observed
- Robust response to physiological stressors
Development-to-date:
The novel material proposed has been developed and demonstrated in vitro as well as in vivo mouse models.
Related Papers (From the inventors only):
Injectable Biodegradable Polymeric Complex for Glucose-Responsive Insulin Delivery. Jinqiang Wang, Zejun Wang, Guojun Chen, Yanfang Wang, Tianyuan Ci, Hongjun Li, Xiangsheng Liu, Daojia Zhou, Anna R. Kahkoska, Zhuxian Zhou, Huan Meng, John B. Buse, and Zhen Gu; ACS Nano 2021 15 (3), 4294-4304; DOI: 10.1021/acsnano.0c07291
Related Patents:
WO2019104006A1, “Charge-switchable polymeric depot for glucose-triggered insulin delivery with ultrafast response”, 2017.