Glucose-Responsive Insulin Delivery via Surface-Functionalized Titanium Dioxide Nanoparticles: A Promising Theragnostic against Diabetes Mellitus

Bhaben Sharmah; Nazim Uddin Afzal; Rikraj Loying; Arup Roy; Jatin Kalita; Joydeep Das; Prasenjit Manna

doi:10.1021/acsabm.4c01426

Glucose-Responsive Insulin Delivery via Surface-Functionalized Titanium Dioxide Nanoparticles: A Promising Theragnostic against Diabetes Mellitus

ACS Appl Bio Mater. 2024 Dec 24. doi: 10.1021/acsabm.4c01426. Online ahead of print.

Authors

Bhaben Sharmah^{1

2}, Nazim Uddin Afzal^{1

2}, Rikraj Loying^{1

2}, Arup Roy^{3

2}, Jatin Kalita^{1

2}, Joydeep Das⁴, Prasenjit Manna^{1

2}

Affiliations

¹ Center for Infectious Diseases, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India.
² Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
³ Chemical Science and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India.
⁴ Department of Chemistry, School of Physical Sciences, Mizoram University, Aizawl 796004, Mizoram, India.

PMID: 39718458
DOI: 10.1021/acsabm.4c01426

Abstract

Glucose-dependent insulin delivery systems have been recognized as a promising approach for controlling blood sugar levels in individuals with diabetes mellitus (DM). Recently, titanium dioxide nanoparticles have garnered huge attention in scientific research for their small size and effective drug delivery capabilities. In this study, we developed alizarin (AL)-capped phenylboronic acid (PBA)-functionalized titanium dioxide nanoparticles (TiO₂) for glucose-sensitive insulin delivery (TiO₂-PBA-INS-AL) aiming to manage both blood sugar levels and its associated organ pathology in DM. The synthesized nanoparticles demonstrated favorable loading capacity as well as high insulin encapsulation efficiency. Initial studies demonstrated glucose-responsive insulin release from TiO₂-PBA-INS-AL in a cell-free environment upon exposure to different glucose concentrations. Notably, in vitro experiments revealed that insulin release from TiO₂-PBA-INS-AL was more effective in muscle cells (primary glucose storage cells) compared to lung cells when subjected to different glucose concentrations (5.5-25 mM), indicating a glucose-sensitive intracellular insulin delivery mechanism. Furthermore, treatment with TiO₂-PBA-INS-AL significantly enhanced GLUT4 translocation and glucose utilization in muscle cells treated with sodium palmitate (PA, 0.75 mM), compared to treatments with TiO₂ or insulin alone. In diabetic animal models, a single oral dose of TiO₂-PBA-INS-AL maintained normoglycemia for up to 12 h, indicating a significant improvement over subcutaneous or oral insulin treatment. Oral administration of TiO₂-PBA-INS-AL also increased insulin bioavailability in both serum and muscle tissue compared to other administration methods. Besides, TiO₂-PBA-INS-AL treatment showed no toxicity against both in vitro and in vivo models. Taken together, this nanocarrier-based drug delivery system mimics the natural regulation of insulin secretion in a noninvasive manner, enhancing patient adherence, reducing the risk of hyperglycemia, and improving diabetes management.

Keywords: GLUT4 translocation; biocompatible; diabetes management; glucose utilization; insulin delivery; titanium dioxide nanoparticles.