Nanotechnology and Nanomedicine in Diabetes

In this case, the hydrogen peroxide produced by the GOx enzymatic action caused the Ag coating to dissolve and expose increasingly large areas of Au on the surface of the nanoshells, thereby causing a red shift in surface plasmon resonance peaks 6. This shift, sampled at a standard time interval, could detect glucose concentrations from 0. Additionally, Bahshi and co-workers developed two optical techniques for detecting glucose 8. This causes an increase in fluorescence in the visible spectral region peaks near nm as the AuNPs grow. Sampling time for both systems was on the order of 20—50 min, and glucose concentrations tested were on the order of 0—2.

Nanomaterials can also be used as a catalyst to cause fluorescence of materials in the presence of hydrogen peroxide. This has been exploited by Song and co-workers who demonstrated that carboxyl modified planar graphene can catalyse the oxidation of 3,3,5,5-tetramethylbenzidine TMB to produce a blue color when reacted with the hydrogen peroxide produced by GOx activity Additionally, the glucose concentration of blood could be accurately measured. Yetisen and co-workers Figure 5 developed an optical glucose sensor by fabricating a poly acrylamide pAAm hydrogel functionalized with 3- acrylamido phenylboronic acid 3-PBA and Ag NPs As glucose entered the hydrogel and bound to the PBA, the hydrophobicity of the hydrogel increased, causing it to swell in proportion to glucose concentration The swelling modulated the distance between the embedded AgNPs, and caused a glucose-dependent shift in the frequency of refracted laser light.

Additionally, achieving a steady state response with this hydrogel took 50 min—1.

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The sensor was reported to be more accurate than commercially available test strips, and could detect an exceptionally wide range of glucose concentrations 0. This sensor was designed to detect the glucose concentration of urine, which correlates with BGL In this study, a boronic acid functionalized hydrogel was formed and included suspended silver nanoparticles. The functionalized hydrogel swelled and contracted in proportion to glucose concentration, as a result of the binding interaction between glucose and the boronic acid.

As the hydrogel swells, the distance between the Au NPs modulates in response to glucose concentration, and thereby causes a shift in the wavelength of the refracted light. A wavelength shift of nm across the visible spectrum was reported for glucose concentrations ranging from 0mM—10mM. When the FRET pairs are separated, the intensity of nm light is significant, but decreases sharply upon glucose binding 9. The mutant GBP protein was synthesized within the cells, and could be used to analyse the glucose concentration within the cells The resulting ability to see real time glucose metabolism within the cell is important for understanding diabetes pathology and may be useful in understanding possible intracellular therapies Furthermore, this approach may be especially useful for studying the pathology of type 2 diabetes Within the cell, elevated glucose concentrations were found close to the cell membrane, and low glucose concentrations were found close to the nucleus A novel method for glucose detection developed by Stuart, et al.

This facilitates the localization of glucose to the NP surface and leads to a detectable FRET signal based on glucose concentration There are several benefits of such a system over the traditional open loop system, including tighter control of BGLs, which can reduce the complications characteristic of diabtes 39 , Closed-loop systems may also lead to a decrease in the dosage of insulin, and reduce the number of hypoglycemic and hyperglycemic events.

These advantages have led to considerable interest in developing closed-loop systems. The reported systems have demonstrated favourable results in terms of responsiveness and biocompatibility 7 , Designing such a membrane is a complex challenge and is being approached from several perspectives. Typically, the cells are rapidly engulfed by fibrotic overgrowths as a result of an immune response Another technique for encapsulating islet cells is the Layer by Layer LbL deposition of a semi-permeable membrane onto the cells 7 , A persistent challenge of using LbL deposition for islet cell encapsulation is avoiding the use of polyionic polymers, which are cytotoxic 44 , Alternative binding strategies are needed to create LbL coatings on the cells that have increased stability and reduced cytotoxicity.

Recently, Gattas-Asfura and co-workers reported a new LbL technique utilizing interpolymeric covalent linking to enhance the stability of the LbL coatings Covalent linkages and electrostatic forces between the films increased the stability and thickness of the resultant bilayer. This bioorthoganal functionalization technique for interpolymeric linking also serves as a method for functionalizing the surface of the islet and can be modified to include secondary therapeutic agents such as immunosuppressant drugs or bioactive groups that enhance the nutrient supply However, the coatings still face the issue of cytotoxicity due to the inclusion of polyionic polymers.

A solution to the polyionic induced cytotoxicity was recently reported by Kozlovskaya and coworkers The group reported an LbL coating strategy that used hydrogen bonding between tannic acid TA , a natural polyphenol with poly N -vynilpyrrolidone PVNOP which holds the polymeric films together.

The interactions between TA and the cell membrane proteins resulted in a highly stable coating. The hydrogen bonded films maintained good stability for up to 7 days after the initial coating. Furthermore, the cells coated with the bilayers displayed no significant increase in cytotoxicity compared to un-coated cells. Significant challenges in terms of immunoisolation of the islet cells remain before islet cell transplantation can become a clinically viable option.

Synthetic closed-loop systems are often characterized by their method of glucose detection. Glucose can be detected through enzymatic methods using enzymes such as glucose oxidase GOx , Binding of glucose to synthetic groups such as those in Phenylboronic acid PBA , or binding to glucose binding proteins such as Concavalin A Con A 13 as seen in Figure 6. Schematic of typical strategies for glucose responsive insulin release. Reprinted with permission from Ref 5. Copyright Chemical Society Reviews. Glucose oxidase is capable of enzymatically catalysing the oxidation of glucose to gluconic acid with high specificity.

The rate of enzymatic production of gluconic acid is directly related to the local glucose concentration. A typical closed-loop system utilizing glucose oxidase is comprised of a pH sensitive polymer matrix containing both insulin and GOx. The matrix undergoes a physical change such as hydrolysis or volume phase transition as the pH of the system is altered by gluconic acid production, thereby releasing the insulin entrapped within the matrix in a glucose dependent fashion 6 , Gu and co-workers recently developed a glucose-responsive nano-network for insulin delivery using GOx as the glucose sensing element Figure 7 A double emulsion method was used to prepare acetal modified dextran m-dextran nanoparticles which included insulin, GOx and catalase CAT.

The nanoparticles were coated with either positively charged chitosan or negatively charged alginate. The opposing surface charges caused the nanoparticles to assemble into a porous 3D nano-network. The conversion of glucose to gluconic acid triggered the hydrolysis of the acetal groups to ethanol and acetone which results in the phase transition of hydrophobic m-dextran to dextran, which is hydrophilic. This phase transition results in the release of the entrapped insulin in a glucose-responsive fashion. The nano-network architecture endowed the system with sufficient mechanical strength to overcome a burst release at the injection site.

Furthermore, the porous structure led to the presence of microchannels which facilitated higher rates of glucose diffusion through the nano-network leading to near zero order enzyme kinetics. Schematic of the glucose-responsive nano-network. A Acetal modified dextran nanoparticles containing insulin and GOx. The nanoparticles are coated with positively charged chitosan or negatively charged alginate. B Acetal modified dextran molecule. C Assembly of oppositely charged nanoparticles to form a nano-network and insulin release upon the enzymatic generation of gluconic acid under hyperglycaemic conditions.

D Injection of the nano-network into a STZ-induced diabetic mouse model. More recently, Tai and co-workers developed an enzyme based biomimetic polymersome for glucose-responsive insulin delivery Under neutral conditions the polymersome forms a bilayer structure which contains the insulin and allows glucose and oxygen to diffuse through the membrane. The enzymatic production of gluconic acid in response to hyperglycaemic glucose concentrations results in the degradation of the polymer membrane by degrading the ser-ketal linkage into PEG-Poly Serine , ethanol, and acetone.

The degradation of the membrane causes a subsequent release of insulin.

Nanotechnology and Nanomedicine in Diabetes : Lan-anh Le :

The polymersome bilayer structure led to excellent mechanical stability of the system. No insulin release was observed from the vesicles without a glucose stimulus over a course of 1 month. In vivo studies revealed that insulin released from the polymersomes retained bioactivity and were effective for regulating the glucose levels of diabetic mice for up to 5 days.

Gordijo and co-workers developed a glucose-responsive nanocomposite membrane for insulin delivery 10 , The shrinking of the membrane leads to insulin release across the membrane by increasing the porosity of the hydrogel network. However, degradation of the enzyme is a significant challenge for glucose-responsive systems utilizing GOx. As H 2 O 2 accumulates as a product of the enzymatic reaction, the activity of GOx is degraded. To address this, the CAT enzyme is often included to scavenge the H 2 O 2 and catalyse its conversion to O 2 10 , 48 , The rigid MnO 2 NPs increased the mechanical strength of the system as well the longevity of the enclosed enzyme.

Most glucose-responsive insulin delivery systems utilize the degradation of a polymer matrix or a phase transition to mediate the release of insulin. However, attention has recently been directed to mesoporous silica nanoparticles MSNs as a result of their rigid structure and high surface area.

Recent Advances in Nanotechnology for Diabetes Treatment

Recently, Chen and co-workers developed a glucose dependent drug release system The system is comprised of MSNs loaded with rhodamine as a model drug. As the glucose concentration increases, it competes with glucosamine to bind to the GOx. Glucose binding to GOx results in uncapping of the MSNs and leads to the release of the encapsulated drug.

In vitro studies indicated that rhodamine release from the NP was glucose dependent, and that no release was observed in the absence of glucose. Furthermore, drug release was correlated with glucose concentration. In addition to Rhodamine, other drugs such as Insulin could be stored within MSNs and capped with a glucose responsive element 52 — Glucose binding proteins can bind to glucose or glucosyl moieties in glycopolymers 5.

The most common class of glucose binding proteins are lectins. Lectins are a family of proteins that can bind to carbohydrates, and have a significant role in cell signaling The most common lectin used for insulin delivery systems is Concanavalin A Con A. It is the preferred GBP because of its high affinity for glucose. Con A can bind to gluconic acid modified insulin G-insulin and be included in hydrogels. Under hyperglycaemic conditions, competition between G-insulin and glucose leads to the release of G-insulin in a glucose dependent manner. The system is comprised of Con A bound to a mannose moiety, which is used to cap the pores of the MSN which contain rhodamine as a model drug.

The resulting system was both pH and glucose-responsive.

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Triggering of the system by pH occurs because Con A exists as a dimer or monomer at low pH, and assumes a tetrameric state at neutral pH. Competitive binding of glucose with the capped Con A led to a release of the drug loaded within the MSN. In the absence of a glucose or a pH trigger, no drug release occurred. A disadvantage of protein based glucose sensing is that environmental factors such as pH and temperature must be tightly controlled to prevent protein denaturation. The possibility of denaturation limits the glucose sensing applications and sensor lifetimes of protein based systems.

This poses challenges for the long term measurement of blood glucose by such sensors. An attractive alternative is the use of Phenylboronic acid and its derivatives as the glucose sensing moiety in both BGL measurement and insulin delivery applications.

The ability of Phenylboronic acid to reversibly bind to polyols has been well established This has allowed Boronic acid derivatives to serve as the detection element in glucose-responsive insulin delivery and BGL measurement applications.

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The equilibrium between the two states is pushed towards the tetrahedral state in the presence of diols and polyols such as those found in glucose This equilibrium can be utilized to trigger the dissolution of amphiphilic nanocarriers and thus release insulin 59 — The equilibrium shift from the neutral to the charged form can also trigger the swelling of crosslinked hydrogel matrices. Upon glucose complexation with the PBA, the hydrophilicity of the matrix increased, causing the matrix to swell and release insulin in a glucose-responsive fashion Since this initial work several other insulin delivery systems have been devised which utilize the PBA moiety for its glucose sensing properties 48 , 60 , 65 , One approach for glucose-responsive insulin delivery is the use of crosslinked polymer matrices with incorporated PBA.

These matrices can reversibly swell when PBA forms a boronate ester with glucose. The ester formation leads to an accumulation of negative charge on the matrix, which results in repulsive forces that cause the cross-linked matrix to swell and release insulin. The micelle was capable of swelling in response to glucose concentration.

The core of the micelle shifted from being hydrophobic to hydrophilic as the glucose formed a complex with the PBA moiety in the core of the micelle. The insulin stored within the micelle was then released in glucose dependent manner.

Nanotechnology and Nanomedicine in Diabetes

In the absence of glucose the micelle was stable and no insulin release was detected. One of the primary issues with using PBA in clinical systems is that the tetrahedral form requires a pH higher than those observed in most physiological systems. Yao and co-workers developed a polymeric glucose-responsive insulin delivery system that operates under neutral pH conditions Electron donating groups were included within the polymer to increase its Lewis acidity and thereby reduce the pKa required to form the boronate ester.

The system was stable at normal blood sugar levels, and this stability reduced the risk of a burst release of insulin, which is highly desirable in a self-regulating insulin delivery device. Polymer based insulin delivery systems have great versatility. Modifying the structure of the polymer can be used to tune the insulin release behaviour and sensitivity.

Kim and co-workers synthesized a PEG-polyboroxole block co-polymer polymersome which was capable of self-assembly into micelles or cylindrical polymersomes based on the polyboroxole block length The group reported that at neutral pH, binding of the boroxole group to monosaccharides such as glucose 0. The polymersomes did not dissolve in the absence of monosaccharaides, and instead maintained their morphology for up to 3 months. The boroxole group showed a stronger binding affinity for fructose over glucose, but the versatility this system shows promise for self-regulated insulin delivery platforms.

Several groups have attempted to create platforms which exhibit a step wise response to glucose concentration and can deliver multiple drugs. Zhao and co-workers used Mesoporous Silica Nanoparticles MSNs as a platform for glucose-responsive release of Insulin and cyclic adenosine monophosphate cAMP — a trigger for the production of insulin from pancreatic beta cells Furthermore, MSNs have been shown to be internalized by cells through endocytosis; this facilitates the uptake of cAMP, which normally encounters difficulty in crossing the cell membrane. The system was well realized and showed almost no leaching of cAMP without a glucose or fructose trigger.

An ideal payload of insulin to lower blood glucose is about — pM The prospect of a dual delivery system is an exciting one, and has led to an increase in interest in MSNs for insulin delivery 37 , 52 , 66 , However, the modification of insulin with gluconic acid raises questions about the bioavailability of the drug once released from the MSN. Wu and coworkers designed a multifunctional hybrid nanogel system to serve as an insulin delivery device and glucose sensor Figure 8 10 , The polymer is capable of crosslinking to form a nanogel which undergoes a phase transition in response to glucose concentration.

The group included silver nanoparticles in the core of the nanogel that endows it with strong fluorescence. The wavelength of this flourescence changes as the nanogel swells and shrinks in proportion to glucose concentration. In addition to the sensing mechanism, the system is also capable of dispensing insulin in a glucose-responsive fashion by swelling in response to hyperglycaemic conditions. The system was capable of phase transitions at a physiologically relevant pH 7.

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Insulin release at basal levels could be sustained for over 2 days. Glucose-responsive insulin delivery systems utilizing phenylboronic acid.

A Insulin release via pH responsive micelles. B Multifunctional hydrogel for glucose-responsive insulin release and glucose concentration measurement. As the smart hydrogel swells in response to hyperglycemic conditions, the insulin is released and the fluorescence of the silver nanoparticles AgNPs is modulated. This fluorescence change can be detected and used to quantify the glucose concentration and the release of insulin.

Significant advances in both glucose sensors and self-regulated insulin delivery systems have been facilitated by nanotechnology. Amperometric sensors utilizing nanotechnology now facilitate rapid, accurate, and highly sensitive glucose measurements in blood and other clinically relevant fluids, such as tears and urine. Additionally, recent advances in fluorescent glucose detection holds the potential to lead to continuous in vivo glucose measurement. The realization of sensors which do not require repeated finger pricks to draw blood for glucose testing is highly desirable, as alternatives which avoid the pain, tissue damage, and patient noncompliance associated with the legacy clinical standard are highly desirable 5.

Furthermore, the clinical realization of a continuous glucose sensor could lead to closed-loop systems which could utilize existing insulin pumps 6. This could relieve the patient of the significant burden of continuously managing their diabetes, and may tremendously improve their long term health outcomes and well-being. Based on current developments in nanoscale glucose sensing, we can expect great clinical applications of this technology in the near future Progress in closed-loop insulin delivery systems has been encouraging and shows tremendous promise for the treatment of diabetes.

Current closed-loop systems are capable of releasing large amounts of insulin; however, clinical realization requires tight control of insulin release to reduce the risk of insulin overdose. Glucagon, a hormone which works antagonistically with insulin, could be co-delivered to reduce the risk of hypoglycaemia 3. Additionally, because insulin is a growth factor, long term exposure to excess insulin can cause changes to the cell division process Systems that offer remote control for the release of insulin are a promising development in dynamic insulin delivery.

Stanley and co-workers developed nanoparticles coated with antibodies capable of binding to TRPV1 calcium channels on genetically engineered cells. The application of a kHz RF signal causes localized heating of the channel via heating of the nanoparticles, and this heating causes subsequent passage of calcium into the cell, triggering the production of insulin within the cell The cells then release this insulin into the bloodstream Additionally, Di, et al.

A nano-network 48 comprised of PLGA nanoparticles containing insulin was used to form an insulin reservoir, which could be selectively degraded by the application of focused ultrasound and lead to insulin release in response to ultrasound application These remotely triggered strategies may lead to novel insulin delivery modalities which can reduce the pain associated with repeatedly injecting insulin and increase patient compliance, 5 and may serve as an element of closed-loop glucose therapies.

The best way of tackling the challenges ahead is by taking a multidisciplinary approach and incorporating knowledge of material science, physical chemistry, and pharmacology to develop more nuanced systems that are dynamic and stable. In this study, Yum, et al used fluorescent carbon nanotubes with boronic acid to fabricate an optical glucose sensor. As the boronic acid binds to the nanotubes, the fluorescence is quenched. Sajeesh , Chandra P. Bonn, and Christian W.

Patel, and Victor R. We provide complimentary e-inspection copies of primary textbooks to instructors considering our books for course adoption. Learn More about VitalSource Bookshelf. CPD consists of any educational activity which helps to maintain and develop knowledge, problem-solving, and technical skills with the aim to provide better health care through higher standards. It could be through conference attendance, group discussion or directed reading to name just a few examples.

We provide a free online form to document your learning and a certificate for your records. Already read this title? Please accept our apologies for any inconvenience this may cause. Exclusive web offer for individuals. Add to Wish List. Toggle navigation Additional Book Information. Description Table of Contents. Summary Understanding the importance of nanosciences in diabetes is problematic as some texts can be too technical for the novice. Request an e-inspection copy. Nanomedicine and the Cardiovascular System. Nanotechnology in Health Care.