Advances in Subcutaneous Delivery Systems of Biomacromolecular Agents for Diabetes Treatment

Abstract

Diabetes mellitus is a major threat to human health. Both its incidence and prevalence have been rising steadily over the past few decades. Biomacromolecular agents such as insulin and glucagon-like peptide 1 receptor agonists are commonly used hypoglycemic drugs that play important roles in the treatment of diabetes. However, their traditional frequent administration may cause numerous side effects, such as pain, infection or local tissue necrosis. To address these issues, many novel subcutaneous delivery systems have been developed in recent years. In this review, we survey recent developments in subcutaneous delivery systems of biomacromolecular hypoglycemic drugs, including sustained-release delivery systems and stimuli-responsive delivery systems, and summarize the advantages and limitations of these systems. Future opportunities and challenges are discussed as well.

Keywords: diabetes mellitus; glucagon-like peptide 1 receptor agonists; insulin; stimuli-responsive; subcutaneous injection; sustained-release.

Figure 1

Computer-generated images of insulin (A), exenatide (B) and liraglutide (C).

Figure 2

Schematic illustration of various subcutaneous delivery systems used for antidiabetic biomacromolecular drugs.

Figure 3

SEM pictures of microcapsules by monoaxial ultrasonic atomizer method. (A) Picture of freeze-dried microcapsules, (B) picture of one microcapsule, (C) the cross-sectioned picture. (D) Light microimage of microcapsules loading insulin, (E) picture of a cross-sectioned microcapsule loading insulin, and (F) confocal laser microimage of FITC microcapsules loading insulin with nile red PLGA. Reprinted with permission from Kim BS, Oh JM, Hyun H et al Insulin-loaded microcapsules for in vivo delivery. Mol Pharm. 2009;6(2):353–365. Copyright © 2009 American Chemical Society.

Figure 4

Synthetic processes and structure diagrams of MIC-MS. Reprinted by permission from Springer Nature. Wang J, Li S, Chen T et al Nanoscale cationic micelles of amphiphilic copolymers based on star-shaped PLGA and PEI cross-linked PEG for protein delivery application. J Mater Sci Mater Med. 2019;30(8):93. Copyright 2019.

Figure 5

(A) Schematic diagram of the complexes between PAE and amino acid of insulin. Reprinted from Huynh DP, Nguyen MK, Pi BS et al Functionalized injectable hydrogels for controlled insulin delivery. Biomaterials. 2008;29(16):2527–2534. Copyright 2008, with permission from Elsevier. (B) The plasma release profile of insulin in SD rats. Reproduced from Huynh DP, Im GJ, Chae SY et al Controlled release of insulin from pH/temperature-sensitive injectable pentablock copolymer hydrogel. J Control Release. 2009;137(1):20–24. Copyright 2009, with permission from Elsevier.

Figure 6

Different insulin release situations under the physiological glucose-responsive system. Reprinted with permission from Xu C, Lei C, Huang L et al Glucose-responsive nanosystem mimicking the physiological insulin secretion via an enzyme-polymer layer-by-layer coating strategy. Chemistry of Materials. 2017;29(18):7725–7732. Copyright © 2017 American Chemical Society.

Figure 7

Schematic diagram of the preparation and reaction of nanoparticles. Reprinted with permission from Wang Y, Fan Y, Zhang M et al Glycopolypeptide nanocarriers based on dynamic covalent bonds for glucose dual-responsiveness and self-regulated release of insulin in diabetic rats. Biomacromolecules. 2020;21(4):1507–1515. Copyright © 2020 American Chemical Society.

Figure 8

(A) A schematic diagram of the integration of a chitosan microgel with insulin-loaded PLGA nanocapsules. (B) The blood glucose levels in STZ-induced diabetic mice following different conditions: 1) a subcutaneous injection of microgel with FUS treatment (950 kHz; 20 μs; 30 s) (red line); 2) a subcutaneous injection of microgel without FUS treatment (black line); 3) an injection of PBS solution with FUS treatment (green line) (n = 5). Reproduced by permission from Springer Nature. Di J, Yu J, Wang Q et al Ultrasound-triggered noninvasive regulation of blood glucose levels using microgels integrated with insulin nanocapsules. Nano Research. 2017;10(4): 1393–1402. Copyright 2017.

Figure 9

(A) Schematic diagram of developed device and the cross-section of membrane. (B) Blood glucose levels following repeated administration under the same irradiance (gray box; 570 mW/cm²; 30 min) in four stages within 14d (n = 3). Reproduced from Timko BP, Arruebo M, Shankarappa SA et al Near-infrared-actuated devices for remotely controlled drug delivery. Proc Natl Acad Sci USA. 2014;111(4):1349–1354. Copyright (2014) National Academy of Sciences.