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Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

ABSTRACT: Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin via a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as "stored insulin", is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.

SUBMITTER: Chen Q

PROVIDER: S-EPMC10738036 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

Chen Qian Q Xiao Zhisheng Z Wang Chao C Chen Guojun G Zhang Yuqi Y Zhang Xudong X Han Xiao X Wang Jinqiang J Ye Xiao X Prausnitz Mark R MR Li Song S Gu Zhen Z

ACS nano 20221102 11

Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high ...[more]

PMID: 36322923

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Project description:Background: Precise and dynamic blood glucose regulation is paramount for both diagnosing and managing diabetes. Continuous glucose monitoring (CGM) coupled with insulin pumps forms an artificial pancreas, enabling closed-loop control of blood glucose levels. Indeed, this integration necessitates advanced micro-nano fabrication techniques to miniaturize and combine sensing and delivery modules on a single electrode. While microneedle technology can mitigate discomfort, concerns remain regarding infection risk and potential sensitivity limitations due to their short needle length. Methods: This study presents the development of an integrated electronic/fluidic microneedle patch (IEFMN) designed for both glucose sensing and insulin delivery. The use of minimally invasive microneedles mitigates nerve contact and reduces infection risks. The incorporation of wired enzymes addresses the issue of "oxygen deprivation" during glucose detection by decreasing the reliance on oxygen. The glucose-sensing electrodes employ wired enzyme functionalization to achieve lower operating voltages and enhanced resilience to sensor interference. The hollow microneedles' inner channel facilitates precise drug delivery for blood glucose regulation. Results: Our IEFMN-based system demonstrated high sensitivity, selectivity, and a wide response range in glucose detection at relatively low voltages. This effectively reduced interference from both external and internal active substances. The microneedle array ensured painless and minimally invasive skin penetration, while wired enzyme functionalization not only lowered sensing potential but also improved glucose detection accuracy. In vivo, experiments conducted in rats showed that the device could track subcutaneous glucose fluctuations in real-time and deliver insulin to regulate blood glucose levels. Conclusions: Our work suggests that the IEFMN-based system, developed for glucose sensing and insulin delivery, exhibits good performance during in vivo glucose detection and drug delivery. It holds the potential to contribute to real-time, intelligent, and controllable diabetes management.

Project description:Transdermal insulin delivery is a promising method for diabetes management, providing the potential for controlled, sustained release and prolonged insulin effectiveness. However, the large molecular weight of insulin hinders its passive absorption through the stratum corneum (SC) of the skin, and high doses of insulin are required, which limits the commercial viability. We developed ethosome (ET) and trans-ethosome (TET) nanovesicle formulations containing a biocompatible lipid-based ionic liquid, [EDMPC][Lin], dissolved in 35% ethanol. TET formulations were obtained by adding isopropyl myristate (IPM), Tween-80, or Span-20 as surfactants to ET formulations. Dynamic light scattering, ζ-potential, transmission electron microscopy, and confocal laser scanning microscopy studies revealed that the nanovesicles had a stable particle size. The formulations remained stable at 4 °C for more than 3 months. ET and TET formulations containing IPM (TET1) significantly (p < 0.0001) enhanced the transdermal penetration of FITC-tagged insulin (FITC-Ins) in both mouse and pig skin, compared with that of the control FITC-Ins solution and other TET formulations, by altering the molecular structure of the SC layer. These nanovesicles were found to be biocompatible and nonirritants (cell viability >80%) in the in vitro and in vivo studies on three-dimensional (3D) artificial human skin and a diabetic mouse model, respectively. The ET and TET1 formulations were applied to the skin of diabetic mice at an insulin dosage of 30 IU/kg. The nanovesicle formulations significantly reduced blood glucose levels (BGLs) compared with the initial high BGL value (>150 mg/dL). The nanovesicle-treated mice maintained low BGLs for over 15 h, as opposed to only 2 h in the injection group. The ET and TET1 formulations reduced the BGLs by 62 and 34%, respectively, of the initial value. These ET and TET1 formulations have a high potential for use in commercial transdermal insulin patches, enhancing comfort and adherence in diabetes treatment.

Project description:Levothyroxine (LT-4) sodium has shown variable bioavailability following oral administration. This can be assigned to the significant influence of gastrointestinal conditions, food and drugs administered concomitantly on the rate and extent of absorption from the gastrointestinal tract. Thus, the aim of this research study was to establish an efficient transdermal delivery system of LT-4 sodium via the application of hyaluronic acid dissolving microneedles. Microneedles-based drug delivery system consists of sharp-tip needles that puncture the top layers of the skin in a minimally invasive manner to create physical channels through which therapeutic molecules can easily diffuse into/across the skin. Hyaluronic acid polymer at different ratios (5-60 %) was used to prepare microneedle arrays (100 needles per array) using a micromoulding technique. Characterisation tests were carried out to select the optimum formulation. F11 formula containing 50% w/v hyaluronic acid and 1% v/v Tween 80 formula showed an appropriate needle shape with dimensions of 432 ± 6.4 μm in height and a tip diameter of 9.8 ± 1.3 μm. The microneedle arrays demonstrated a suitable mechanical strength after applying a force of 32 N per array and an excellent insertion ability both in Parafilm M® and human skin. The in vivo dissolution of microneedles was started rapidly within 5 minutes following the insertion in the skin and completed at 1 hour. Ex vivo permeation study using human skin has shown a significant improvement in LT-4 sodium delivery across the skin compared to control preparations (drug solution and microneedle free film). The microneedle array F11 has significantly (P ≤ 0.05) increased LT-4 sodium permeation through the skin (cumulative permeated amount of 32 ± 2 μg/cm2) in comparison to the control solution (cumulative permeated amount of 0.7 ± 0.07 μg/cm2) and the microneedle free film (cumulative permeated amount of 0.1 ± 0.02 μg/cm2) over 7 hours. The findings from the irritation test revealed that mild erythema was produced from the application of microneedle arrays which disappeared within 24 hours. Accordingly, dissolving hyaluronic acid microneedles could be a feasible and effective approach to delivering LT-4 sodium transdermally without causing significant skin damage.

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Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

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Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

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