Zhejiang University Seeks Technology Transfer of a Glucose-Responsive Insulin Derivative at RMB 600,000

Feb 04, 2026 08:00 CST Updated 08:00

Recently, Zhejiang University addressed the ““A Phenylboronic Acid-Based Insulin Derivative, Its Preparation Method, and Applications”Pending public notice for the transfer of two technological achievements, which are proposed to be transferred through listed trading, with the listing price beingRMB 600,000. The inventor of this achievement is the Dean of the College of Pharmaceutical Sciences, Zhejiang UniversityProfessor Zhen Gu and his team members, Yang Zhang and Jinqiang Wang.

Gu Zhen:Qiushi Chair Professor of Zhejiang University, Assistant to the President, Dean of the International Joint Institute, Dean of Jinhua Research Institute, Chang Jiang Scholar of the Ministry of Education, Director of the State Key Laboratory of Advanced Drug Delivery and Release Systems, Member of the Academic Advisory Committee of the Chinese Academy of Medical Sciences, Member of the National Steering Committee for Graduate Education in Pharmacy, Council Member of the Chinese Pharmaceutical Association and Vice Chair of its Pharmaceutics Professional Committee, Standing Council Member of the Chinese Society for Biomaterials and Vice Chair of its Youth Working Committee. The research directions of the “iMedication-Intelligent Medicine Laboratory,” supervised by Professor Gu Zhen, include delivery systems for biological macromolecules (proteins/nucleic acids), drug-device combination products, physiologically responsive materials, vaccine formulations, and cell therapy strategies. He has published or had accepted more than 200 academic papers as corresponding or co-corresponding author in journals such as Cell and Nature, holds over 100 authorized enterprise patents, and five original drug/technology products related to his work are currently undergoing clinical trials.

This technology belongs toInsulin Derivative Technologydomain, by introducing at specific sites of the insulin moleculePhenylboronic acid group, constructing insulin derivatives with intelligent glucose-responsive functionality—whose phenylboronic acid groups can form phenylboronate ester bonds in situ with endogenous proteins, generatingInsulin-Protein Complex; When blood glucose levels rise, glucose specifically cleaves this ester bond to rapidly release insulin for lowering blood sugar, whereas at normal glucose concentrations, it is released continuously and slowly. This breakthrough overcomes the bottleneck of existing insulin therapies in matching the dynamic fluctuations of human blood glucose, achieving stable and precise glycemic control. It not only maintains blood glucose levels within the normal range in diabetic subjects in a steady and sustained manner but also effectively avoids the risk of hypoglycemia.

Clinical Dilemmas in Diabetes Management: Navigating the Delicate Balance Between Glycemic Variability and Fear of Hypoglycemia

Diabetes is a chronic metabolic disorder characterized by hyperglycemia, resulting from insufficient insulin secretion or impaired insulin utilization. As the core hormone regulating blood glucose in the human body, insulin secretion is a tightly regulated process in healthy individuals: during fasting states, insulin is secreted at low levels to maintain baseline blood glucose; whereas after meals, insulin secretion rapidly increases to counteract postprandial glucose spikes. For patients with type 1 diabetes and those with advanced type 2 diabetes,Exogenous Insulin Replacement TherapyIt is a key measure for sustaining life, controlling metabolic disorders, and delaying the progression of complications.

Currently, the mainstream insulin therapy regimens in clinical practice primarily rely onMultiple daily injections (basal insulin + prandial insulin) or subcutaneous infusion via insulin pump. To reduce injection frequency, long-acting insulin analogs represented by insulin glargine and insulin degludec have been developed. These agents typically undergo fatty acid side-chain modifications to slow absorption rates and prolong drug half-life, enabling once-daily dosing, either through non-specific hydrophobic binding to albumin in the blood or by forming precipitate microcrystals in the subcutaneous tissue.

However, this “long-acting” strategy is essentially a passive release mechanism. Once the drug is administered into the body, the release rate remains relatively constant, unable to sense and match real-time blood glucose fluctuations caused by factors such as dietary intake, physical activity, and emotional stress. This has led to two irreconcilable contradictions in diabetes treatment:

An Extremely Narrow Therapeutic Window and Supply-Demand Imbalance:Insulin administration is a delicate balance between “too much” and “too little.” Due to its lack of responsiveness to blood glucose concentrations, exogenous insulin struggles to mimic physiological, on-demand secretion. Patients often face the risk of inadequate postprandial glycemic control (hyperglycemia) or excessive drug release between meals and during the night (hypoglycemia).

The Life-Threatening Risks of Hypoglycemia:Hypoglycemia is common during insulin therapy. Severe hypoglycemia can lead to loss of consciousness, brain damage, and even death. Due to fear of nocturnal hypoglycemia, patients and physicians are often reluctant to adopt more aggressive dosing regimens to achieve glycemic targets, resulting in many patients remaining in a state of chronic hyperglycemia, which increases the incidence of complications such as cardiovascular, cerebrovascular, and renal diseases.

Therefore, there is an urgent clinical need for a novel insulin formulation that not only reduces injection frequency like long-acting insulins but also overcomes the limitation of “blind release” associated with existing long-acting agents, thereby achieving rapid and sensitive responsiveness to blood glucose concentrations.

Technological Breakthrough: A “Smart Switch” Based on Fluorophenylboronic Acid Modification

To address the challenge that existing long-acting insulins cannot sense blood glucose fluctuations and are prone to causing hypoglycemia, this invention proposesAn Innovative Strategy for Insulin Derivatives Based on Fluorophenylboronic Acid Modification. It employs precise chemical modification strategies to introduce specific fluorinated phenylboronic acid groups at designated amino acid sites of the insulin molecule (such as the N-terminus of the A-chain, the N-terminus of the B-chain, or the ε-amino group of lysine at position B29), thereby reconstructing the in vivo behavior profile of insulin at its molecular origin.

The core of this innovative design lies inDevelopment of a Reversible, Glucose Concentration-Dependent “In Situ Reservoir in Vivo”. After the drug is injected into the bloodstream, the phenylboronic acid groups modified on the surface of insulin can specifically bind to the abundant albumin in the blood, forming a stable in situPhenylboronic Acid Ester BondThe formation of this “insulin-protein complex” effectively shields against enzymatic degradation and rapid renal clearance, significantly prolonging the drug’s half-life, similar to traditional long-acting formulations. Furthermore, unlike the “dead-lock” mechanism associated with conventional fatty acid modifications, the phenylboronate ester bond serves as a sensitive “chemical sensor.”

When blood glucose levels in the patient rise due to food intake or other factors, glucose exhibits a stronger binding affinity for phenylboronic acid groups. This enables it to rapidly cleave the chemical bonds between phenylboronic acid and albumin through competitive binding. This specific competitive displacement mechanism allows insulin to achieve“On-demand release”: It rapidly dissociates and releases insulin during hyperglycemia to mimic physiological insulin secretion and blunt blood glucose peaks; whereas when blood glucose returns to normal or remains at low levels, the vast majority of insulin molecules remain “dormant” on albumin in an inactive state.

The experimental data in the package insert strongly corroborate the superiority of this mechanism. In a mouse model of type 1 diabetes, the derivative demonstrated remarkable long-acting glycemic control capabilities. After a single dose, it maintained blood glucose levels within the normal range (<200 mg/dL) for over 200 hours (approximately 8 days), with virtually no hypoglycemic events observed during this period. In contrast, under the same experimental conditions, commercially available long-acting insulin, at a dosage intended to control blood glucose for one week, resulted in the death of 40% of the mice due to severe hypoglycemia. This indicates that, while achieving ultra-long-acting therapeutic effects, this technology establishes a robust “safety barrier” against hypoglycemia, providing diabetic patients with an intelligent treatment modality that is truly both highly effective and safe.

Vying for the High Ground in “Smart Drug Delivery”: Cracking the “Impossible Triangle” of Insulin Therapy

In the diabetes drug market, although the iteration of insulin has never ceased, in"Long-Acting," "Safe," and "Intelligent"Among these three, there has always been an "impossible trinity" that is difficult to balance.

Currently, first-line clinical treatment regimens mainly consist ofLong-acting analogs such as insulin glargine and insulin degludecas the primary approach. As demonstrated by relevant patents held by domestic pharmaceutical giants such as Hengrui Medicine, these drugs primarily rely on fatty acid side-chain modifications or genetic engineering to passively extend their half-life through “hydrophobic interactions.” Although they have successfully reduced the dosing frequency to once daily, they essentially remain a form of “blind administration”—the drug is released at a constant rate regardless of whether the patient’s blood glucose levels are at a peak or a trough. This mechanism, which prioritizes prolonged action over glycemic responsiveness, leaves the risk of hypoglycemia like a sword hanging over patients’ heads and limits physicians’ ability to achieve optimal glycemic control targets.

In the frontier exploration of “smart insulin,” the scientific community has attempted various approaches. This includes early research published by Professor Zhen Gu’s team in *Nature Biomedical Engineering*, which utilized phenylboronic acid-modified polymeric materials to encapsulate insulin, forming micro- and nano-structured complexes to achieve glucose responsiveness. However, such encapsulation technologies often face challenges including delayed response times and biosafety concerns arising from the long-term accumulation of polymeric materials in the body, thereby posing significant obstacles to clinical translation. Furthermore, early attempts at chemical modification (such as simple monoboronic acid functionalization) were limited by insufficient affinity for glucose under physiological pH conditions, making it difficult to achieve a true on–off switching effect within the physiological blood glucose concentration range.

The achievements proposed for transfer by Zhejiang University provide important technical insights and molecular design paradigms for the development of the smart insulin field. In the future, with the further integration of chemical biology, drug design, and formulation technologies,“On-Demand Release” Precision Therapy ModelIt may become an important direction for industry development, bringing breakthrough progress to chronic disease management.