Managing diabetes with nanomedicine: challenges and opportunities

Abstract

Nanotechnology-based approaches hold substantial potential for improving the care of patients with diabetes. Nanoparticles are being developed as imaging contrast agents to assist in the early diagnosis of type 1 diabetes. Glucose nanosensors are being incorporated in implantable devices that enable more accurate and patient-friendly real-time tracking of blood glucose levels, and are also providing the basis for glucose-responsive nanoparticles that better mimic the body's physiological needs for insulin. Finally, nanotechnology is being used in non-invasive approaches to insulin delivery and to engineer more effective vaccine, cell and gene therapies for type 1 diabetes. Here, we analyse the current state of these approaches and discuss key issues for their translation to clinical practice.

Figure 1. Nanotechnology-based approaches to address challenges in the diagnosis and treatment of diabetes

a | The progression of diabetes results in a loss in β-cell mass, which can be subcategorized into three stages: primary, secondary and tertiary. As the disease progresses through each stage, new types of therapies are necessary to help slow advancement to the subsequent stage. b | Highlighted below the profile illustrating the progressive loss in β-cell mass are potential nanotechnology-based interventions that could be developed to address patient needs at the various stages of disease progression. A number of examples are highlighted, including: nanoparticle-based contrast agents to improve early diagnosis of the onset of type 1 diabetes; nanoparticle-based continuous glucose sensors that can facilitate frequent monitoring of blood glucose levels with improved accuracy and patient comfort; nanoparticles to improve the pharmacodynamics of insulin in order to better mimic the physiological needs of the body; and nanotechnology-based protection of transplanted pancreatic islet cells. These approaches can be used as highlighted to help maintain healthy normoglycaemic levels in patients with diabetes.

Figure 2. Nanotechnology-based glucose sensor technologies

Sensing devices are constructed by assembling a detector that measures blood glucose concentrations and a transducer that converts measurements into output signals. a | There are three main classes of glucose-sensing molecules that are being used to engineer nanoparticle-based glucose sensors: glucose oxidase, glucose-binding proteins and glucose-binding small molecules. Highlighted next to the description of each detection molecule are the strengths (green boxes) and weaknesses (red boxes) associated with each technology. b | These glucose-detecting molecules can be coupled to nanoparticles engineered as transducers with unique optical or electrical properties, as well as the ability to produce surface plasmon resonance. The strengths (green boxes) and weaknesses (red boxes) associated with each technology are shown. ConA, concanavilin A; hv, excitation light; IR, infrared; PBA, phenylboronic acid.

Figure 3. Development of glucose-responsive

a | There are several mechanisms by which glucose-sensing triggers can be integrated with nanoparticle design to facilitate glucose-responsive behaviour. Nanoparticles prepared using polymers that are molecularly imprinted with glucose and phenylboronic acid (PBA) could form supramolecular assemblies through reversible hydrogen-bonding interactions between glucose and PBA molecules. These nanoparticle assemblies would then be sensitive to glucose concentrations in their localized environment through the competitive binding of glucose from the environment to PBA. Alternatively, glucose-imprinted polymers could be combined with glucose-binding proteins such as concanavilin A (ConA) to form supramolecular assemblies that are similarly responsive to glucose. Glucose-sensitive nanoparticle systems can also be engineered by combining pH-sensitive polymers with the glucose-sensitive enzyme glucose oxidase, which enzymatically converts glucose to gluconic acid, producing a drop in pH in the nanoparticle microenvironment. b | The triggers can be integrated within a nanoparticle that is engineered to disassemble by either swelling or degrading in response to increased glucose levels, thus providing a mechanism by which the insulin cargo can be released and made bioavailable.

Figure 4. Development of patient-friendly insulin delivery nanoparticle formulations

Various properties of nanoparticles can be tailored to exploit transepithelial transport mechanisms to facilitate systemic insulin delivery. Nanoparticles prepared with bound ligands for specialized receptors expressed on epithelial cell surfaces can be transcytosed across epithelial barriers. Ultrasmall nanoparticles with hydrophilic coatings can exploit paracellular diffusion to bypass epithelial barriers. Nanoparticles with tuned lipophilic physicochemical properties can permeate across epithelial barriers through a transcellular pathway. Cationic charged nanoparticles can exploit the adsorption-mediated transcytosis pathway for transport across epithelial barriers. Finally, nanoparticles that are transported across epithelial barriers by antigen sampling Microfold cells (M cells) could be developed.