Stimulus-responsive nanoparticles for glucose-controlled insulin release

Abstract

A glucose-sensitive nanoparticle composition comprising a biodegradable polymer matrix encapsulating insulin and functionalized with glucose-sensitive molecular groups, wherein the nanoparticles are configured to release insulin in response to an increased glucose concentration.

Description

FIELD OF INVENTION

[0001] The present invention lies in the field of biomedical nanotechnology and pharmaceutical sciences, more specifically in the development of stimuli-responsive nanomaterials for therapeutic drug delivery. The invention relates in particular to a glucose-sensitive nanoparticle system for the intelligent and controlled release of insulin in diabetic patients. It combines advances in polymer chemistry, nanomedicine, and endocrinology to create an autonomous insulin delivery mechanism that mimics the physiological function of the pancreas. The invention also relates to pharmaceutical formulations containing the aforementioned nanoparticles and their applications in the treatment of diabetes mellitus through non-invasive or minimally invasive procedures. BACKGROUND OF THE INVENTION

[0002] Diabetes mellitus is a chronic metabolic disorder characterized by impaired insulin secretion or action, leading to hyperglycemia and associated complications. Conventional treatment relies heavily on exogenous insulin administration via injections or insulin pumps. However, these methods are limited by their inability to accurately mimic physiological insulin secretion, often resulting in unpredictable blood glucose fluctuations, patient discomfort, and the risk of hypoglycemia due to overdose or inappropriately timed administration. Furthermore, frequent injections reduce patient compliance and complicate long-term management of the disease.

[0003] Recent advances in biomedical research have explored the concept of closed-loop insulin delivery systems, often referred to as an "artificial pancreas." While electronic insulin pumps with glucose sensors have demonstrated their potential, their high cost, complex maintenance, and invasive nature limit their widespread use. Therefore, researchers have turned to developing biochemically intelligent systems capable of automatically regulating insulin release based on endogenous glucose concentration.

[0004] Stimulus-responsive nanomaterials have emerged as a promising approach for such intelligent delivery systems. These materials can alter their physical or chemical properties in response to specific environmental influences such as pH, temperature, or biomolecular triggers. Among these, glucose-responsive systems are particularly relevant for diabetes therapy. Existing strategies include the use of glucose oxidase, phenylboronic acid, or concanavalin A-based materials to detect glucose fluctuations. However, challenges such as enzyme instability, immunogenicity, and poor reversibility of glucose binding have limited their clinical application.

[0005] Therefore, there is a great need for a biocompatible, stable, and responsive nanotransporter capable of delivering insulin proportionally to glucose concentration without external devices. The present invention addresses this need by introducing stimulation-sensitive nanoparticles that integrate glucose-sensitive functions into a polymeric nanostructure. These nanoparticles not only provide sustained protection of insulin against degradation but also ensure release only under hyperglycemic conditions, closely resembling the body's natural feedback mechanism. This advancement could revolutionize diabetes management by eliminating the need for frequent dosing and maintaining a stable glucose level. SUMMARY OF THE INVENTION

[0006] The present invention relates to a new class of stimulation-sensitive nanoparticles designed for glucose-triggered insulin release. The system consists of a nanoscale polymer matrix encapsulating insulin and functionalized with glucose-sensitive groups that dynamically respond to fluctuating blood glucose concentrations. The nanoparticles are designed to maintain insulin stability under normoglycemic conditions and to trigger controlled release in hyperglycemia through chemical or structural transformation mechanisms.

[0007] The nanoparticle formulation comprises a biodegradable polymer such as poly(lactic acid-co-glycolic acid) (PLGA), chitosan, or polycaprolactone as the structural matrix. The surface of these nanoparticles is modified with phenylboronic acid (PBA) or glucose oxidase (GOx) derivatives to confer glucose sensitivity. These molecular components react with glucose molecules in the physiological medium, altering the hydrophilic-hydrophobic equilibrium or generating local pH changes, which causes the matrix to disintegrate or swell and release insulin.

[0008] In one embodiment, the nanoparticles consist of a core-shell architecture, with the inner core containing encapsulated insulin stabilized by albumin or polyethylene glycol (PEG), while the outer shell consists of a glucose-sensitive polymer layer. As the glucose concentration rises, the reactive shell swells or cleaves due to interaction with glucose, resulting in controlled diffusion of insulin. This design ensures feedback-controlled insulin release, mimicking the function of pancreatic β-cells.

[0009] These nanoparticles can be synthesized via emulsion solvent evaporation, nanoprecipitation, or self-assembly techniques. Insulin is encapsulated under mild conditions to preserve its bioactivity. Following synthesis, the glucose-sensitive polymer is either grafted or deposited onto the nanoparticle surface. The nanoparticles have a mean diameter of 100–200 nm and offer high stability, excellent bioavailability, and a minimal immunogenic response.

[0010] Following administration, these nanoparticles circulate in the bloodstream and remain inert at normal glucose levels. When the glucose concentration exceeds the threshold (e.g., 120 mg / dL), the glucose-sensitive layer interacts with glucose molecules. In PBA-based systems, a reversible covalent bond forms between glucose and PBA, leading to increased hydrophilicity and matrix swelling, which facilitates insulin diffusion. In enzyme-based systems, GOx catalyzes glucose oxidation, generating gluconic acid and hydrogen peroxide, which locally lower the pH and cause polymer degradation, thereby triggering insulin release.

[0011] The rate of insulin release is directly proportional to the glucose level, thus achieving self-regulation. Once the glucose level has normalized, the polymer's structural equilibrium is restored, thereby halting further insulin release. This reversible and repeatable reaction mechanism creates a truly autonomous insulin delivery platform.

[0012] The nanoparticles can be formulated as injectable suspensions, implantable hydrogels, or integrated into transdermal patches. The biocompatibility and non-toxicity of the components ensure safety during long-term use. In vitro and in vivo experiments confirm a rapid response to glucose fluctuations, stable insulin loading, and improved pharmacodynamic performance compared to conventional delivery methods.

[0013] The present invention thus provides an advanced nanoplatform that integrates glucose monitoring, insulin protection, and controlled release in a single self-regulating system. It offers significant clinical advantages in diabetes treatment, including reduced injection frequency, minimized hypoglycemic episodes, and improved patient compliance. DETAILED DESCRIPTION OF THE INVENTION

[0014] The following description details the invention and how it is to be implemented. The present invention relates to a novel class of stimulation-sensitive nanoparticles specifically designed for glucose-triggered insulin release. The innovative concept consists of developing a biocompatible nanotransport system capable of autonomously and self-regulating insulin delivery based on physiological glucose levels, thereby eliminating the need for frequent manual insulin injections and minimizing the risk of hypoglycemia. The system utilizes polymeric nanoparticles equipped with glucose-sensitive functional groups that can detect and respond to elevated glucose concentrations by altering their physicochemical structure to release the encapsulated insulin in a controlled and reversible manner.

[0015] The invention relates to a nanoscale insulin delivery platform made from biodegradable and biocompatible polymers such as poly(lactic acid-coglycolic acid) (PLGA), chitosan, or polycaprolactone (PCL), which serve as the structural matrix of the nanoparticles. The polymers are selected based on their degradation rate, hydrophilicity, and compatibility with insulin. The nanoparticle architecture follows a core-shell configuration, with the inner core containing stabilized insulin and the outer shell consisting of a glucose-sensitive polymer layer functionalized with glucose-binding units such as phenylboronic acid (PBA) derivatives or enzyme conjugates such as glucose oxidase (GOx). The combination of these materials results in a hybrid polymer system capable of dynamically responding to changes in blood glucose concentration.

[0016] The nanoparticles are synthesized using emulsion solvent evaporation or nanoprecipitation techniques, which ensure a uniform particle size distribution and high encapsulation efficiency. In a typical process, an organic phase containing PLGA or a related polymer dissolved in an organic solvent such as dichloromethane or ethyl acetate is emulsified with an aqueous phase containing insulin and stabilizers such as bovine serum albumin or polyethylene glycol (PEG). The emulsion undergoes high-speed homogenization or ultrasonic treatment to generate nanoemulsion droplets. Subsequent evaporation of the solvent under reduced pressure or gentle stirring leads to the formation of solid nanoparticles that encapsulate insulin within the polymer matrix.To impart glucose sensitivity, the surface of the nanoparticles is functionalized with phenylboronic acid groups via carbodiimide coupling or other covalent conjugation reactions, thereby ensuring stable surface modification.

[0017] In another embodiment, glucose oxidase is immobilized on the nanoparticle surface by covalent bonding or adsorption. The enzyme acts as a biological sensor and catalyzes the oxidation of glucose to gluconic acid and hydrogen peroxide. The local formation of gluconic acid leads to a decrease in pH around the nanoparticle surface, which in turn causes the polymer shell to swell, decompose, or become permeable, thus enabling controlled diffusion of insulin. This mechanism closely mimics the natural glucose sensing and insulin secretion function of the pancreatic β-cells in the body, enabling an intelligent and automatic feedback system for insulin regulation.

[0018] The glucose-dependent behavior of the nanoparticles can be attributed to reversible chemical reactions between glucose molecules and the functionalized surface groups. In PBA-based nanoparticles, glucose forms cyclic esters with the boronic acid groups, leading to increased hydrophilicity of the polymer shell. This hydrophilic transition improves water uptake, causes the nanoparticle to expand, and facilitates insulin release by diffusion. The extent and rate of insulin release are directly proportional to the glucose concentration, enabling a finely tuned feedback mechanism. Once the glucose level returns to normal, the reversible bond breaks, the nanoparticle contracts back to its original configuration, and further insulin release ceases, thus preventing hypoglycemia.

[0019] To ensure the biological integrity and bioactivity of the insulin during encapsulation and release, the manufacturing process is carried out under mild temperature and pH conditions. Lyoprotectants and surfactants such as trehalose, mannitol, or Tween 80 are included in the formulation to stabilize the insulin against denaturation. The nanoparticles typically have a diameter between 100 and 200 nanometers, which ensures efficient cellular uptake and a long circulation time in the bloodstream. The surface charge is optimized to slightly negative or near-neutral values ​​to prevent aggregation and facilitate biocompatibility with physiological membranes.

[0020] The nanoparticle formulation can be dispersed in isotonic or phosphate-buffered saline for injectable administration. It can also be embedded in hydrogel matrices for transdermal patches or microneedle delivery systems. Following injection or application, the nanoparticles disperse in the subcutaneous tissue or systemic circulation and remain dormant at normal glucose levels. In hyperglycemia, the nanoparticles react almost immediately, releasing insulin in response to the rise in glucose concentration. The release rate is modulated by the density of the glucose-dependent groups, the polymer degradation rate, and the insulin loading capacity, all of which can be fine-tuned during synthesis to achieve patient-specific therapeutic profiles.

[0021] The system's performance can be evaluated through in vitro release assays and in vivo pharmacokinetic studies. In vitro tests show that at physiological glucose concentrations (~5 mM), the nanoparticles exhibit minimal insulin leakage and maintain a capsule stability of over 90% for several hours. In hyperglycemia (-10-20 mM glucose), the insulin release rate increases significantly, with near-complete release occurring within a few hours, confirming effective glucose sensitivity.

[0022] In vivo experiments in diabetic animal models demonstrate a significant reduction in blood glucose levels after a single administration of the nanoparticles, maintaining sustained normoglycemia over a longer period compared to conventional insulin injections. Histopathological examinations show only minimal inflammatory or cytotoxic reactions, confirming the biocompatibility and safety of the system.

[0023] The selection of materials and functionalization strategies ensures that the nanoparticles are fully biodegradable and do not accumulate in tissues. PLGA is degraded to lactic acid and glycolic acid, both of which are naturally metabolized via the Krebs cycle. Chitosan, when used, provides mucoadhesive and permeation-enhancing properties, thus improving insulin uptake across biological barriers. Modification with polyethylene glycol prolongs the systemic circulation time by preventing rapid clearance through the reticuloendothelial system. The addition of antioxidant stabilizers and enzyme inhibitors to the formulation further enhances the longevity of the glucose-sensitive components.

[0024] The invention can be extended to several design variants to achieve the desired performance characteristics. In one variant, a dual-action nanoparticle system is developed in which both pH and glucose act as stimuli. Here, the nanoparticle shell contains pH-sensitive polymers such as poly(N-isopropylacrylamide) or Eudragit derivatives together with glucose-reactive units. Under hyperglycemic conditions, the enzymatic production of gluconic acid lowers the local pH, thereby synergistically enhancing polymer swelling and insulin release. In another variant, nanoparticles are incorporated into a hydrogel network to form a smart insulin patch that releases insulin transdermally upon detection of elevated glucose levels in the interstitial fluid. This approach eliminates the need for injections and improves patient comfort and adherence.

[0025] The characterization of the nanoparticles includes the evaluation of their size distribution, zeta potential, morphology, and encapsulation efficiency using techniques such as dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and high-performance liquid chromatography (HPLC). Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR) confirm the successful surface functionalization with glucose-sensitive molecular groups. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) assess thermal stability, while X-ray diffraction (XRD) evaluates crystallinity. The reactivity of the nanoparticles to glucose is quantified by measuring insulin release profiles at different glucose concentrations in buffered media, thus determining precise reaction kinetics.

[0026] The system's pharmacokinetic and pharmacodynamic profiles exhibit a superior therapeutic index compared to conventional insulin formulations. Following administration, plasma insulin levels rise proportionally to glucose levels, ensuring a dynamic equilibrium without exceeding the hypoglycemic range. The nanoparticles provide sustained insulin release over 24 to 72 hours, significantly reducing the dosing frequency. The closed-loop feedback mechanism ensures near-physiological control of glucose homeostasis and effectively mimics pancreatic function without external monitoring or intervention.

[0027] In clinical applications, the invention can serve as an injectable insulin depot, a subcutaneous implant, or a component of wearable transdermal systems. The design's flexibility allows for adaptation to both type 1 and type 2 diabetics. For example, patients requiring basal insulin support can benefit from slow-release formulations, while patients needing a rapid post-meal response can use faster-acting versions of the nanoparticles. The adjustability of the polymer composition, functional group density, and particle size enables precise customization of the release kinetics for individualized treatment regimens.

[0028] From a manufacturing perspective, the process is scalable and compatible with pharmaceutical-grade production environments. Solvent evaporation, nanoprecipitation, and self-assembly processes can be easily adapted for large-scale batch production with consistent quality. Lyophilization with cryoprotectants enables long-term storage stability without significant loss of reactivity or bioactivity. The nanoparticles can be sterilized by filtration or gamma irradiation, maintaining their integrity for clinical use.

[0029] The stimulation-sensitive nanoparticles described in this invention represent a significant advance in insulin delivery technology. Unlike mechanical insulin pumps or sensor-controlled electronic systems, this approach is based solely on biochemical self-regulation and requires no batteries, programming, or manual adjustment. The nanotransporters effectively function as artificial β-cells, detecting glucose fluctuations and releasing insulin accordingly. This autonomous behavior, combined with biodegradability and biocompatibility, makes the system ideal for chronic use.

[0030] Furthermore, the system's modularity allows for the future integration of additional functions. For example, the co-encapsulation of antioxidants or anti-inflammatory drugs can provide additional protection for pancreatic cells and improve treatment outcomes. Alternatively, fluorescent or magnetic nanoparticles can be integrated for real-time imaging and monitoring of the delivery process, enabling theranostic applications. The invention thus offers a versatile platform for next-generation diabetes management, combining intelligent responsiveness, safety, and therapeutic efficacy.

[0031] In summary, the present invention offers a sophisticated, glucose-dependent nanotransport system capable of self-regulating insulin release. The nanoparticles exhibit excellent stability, precise responsiveness, and high biocompatibility, enabling an autonomous therapeutic mechanism closely resembling physiological insulin regulation. The innovative combination of polymer chemistry, nanotechnology, and biomedical engineering embodied in this invention establishes a new paradigm in intelligent drug delivery systems for diabetes treatment, offering a long-term, efficient, and patient-friendly solution to a global health challenge.

Claims

[1] A glucose-sensitive nanoparticle composition comprising a biodegradable polymer matrix encapsulating insulin and functionalized with glucose-sensitive molecular groups, wherein the nanoparticles are configured to release insulin in response to an increased glucose concentration. [2] The nanoparticle composition according to claim 1, wherein the polymer matrix comprises one or more polymers selected from poly(lactic acid-co-glycolic acid) (PLGA), chitosan, polycaprolactone or polyethylene glycol-based copolymers. [3] The nanoparticle composition according to claim 1 comprises phenylboronic acid derivatives or glucose oxidase enzymes that can react with glucose to induce a structural change or pH change that leads to insulin release. [4] The nanoparticle composition according to claim 1, wherein the particles have a core-shell configuration, the inner core containing stabilized insulin and the outer shell comprising the glucose-sensitive polymer layer.