Objective
The objective of this research is to develop a multi-targeted nanomedicine for comprehensive treatment of T1D. An injectable nanoparticle drug delivery system will be designed to selectively transport drugs to islet cells of the pancreas, improve the condition in the pancreas friendly to insulin-generating beta-cells, thus protecting them from damage and restoring their functions. We will exploit nanoparticle technology to synergize drug combination therapy, stabilize large drug molecules (e.g., peptides), and direct them to the site of action in the pancreas after injection or infusion. In doing so, maximized drug efficacy and lowered risk of unwanted side effects will be anticipated as compared to monotherapies administer via conventional ways (e.g., oral ingestion). For some patients, the restoration of islet functions may be significant enough to reduce reliance on exogenous insulin administration. This new nanomedicine may furthermore aid in the viability of islet transplantation, thus offering a greater hope to T1D patients for a ‘cure’.
Background Rationale
The objective of this research is to develop a multi-targeted nanomedicine for comprehensive treatment of T1D. An injectable nanoparticle drug delivery system will be designed to selectively transport drugs to islet cells of the pancreas, improve the condition in the pancreas friendly to insulin-generating beta-cells, thus protecting them from damage and restoring their functions. We will exploit nanoparticle technology to synergize drug combination therapy, stabilize large drug molecules (e.g., peptides), and direct them to the site of action in the pancreas after injection or infusion. In doing so, maximized drug efficacy and lowered risk of unwanted side effects will be anticipated as compared to monotherapies administer via conventional ways (e.g., oral ingestion). For some patients, the restoration of islet functions may be significant enough to reduce reliance on exogenous insulin administration. This new nanomedicine may furthermore aid in the viability of islet transplantation, thus offering a greater hope to T1D patients for a strategy more resemblant of a ‘cure’.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease where the pancreatic cells responsible for producing insulin (i.e., beta-cells in the islets of Langerhans) are destroyed, hence individuals lose the ability to regulate blood glucose levels. Unlike Type 2 diabetes (T2D), which can be managed by diet, exercise, or oral medication, people living with T1D relies on exogenous insulin administration to survive. Although insulin therapy has been the primary, invaluable treatment of T1D for a century and has saved millions of lives, for many T1D patients, it is a life-long treatment. Resent years, efforts have been made to stop T1D by innovative ways to cure the disease, including islet cell transplantation. Despite the success of cell transplantation therapy, the limited donor source and immunosuppression medication hinder its broad application. Recent advances in the knowledge of multifactorial drivers of T1D has led to a new redirection of exploring medications that may improve the population, survival, and function of insulin-releasing beta-cells. However, these medications may cause undesired side effects when taken by conventional ways, such as oral ingestion or injection. Therefore, we propose to develop a new nanocarrier (a tiny particle with a diameter about one-thousandth of thickness of a human hair) that can carry the drugs to target islet cells to restore damaged beta-cells. We will employ pharmaceutically acceptable materials to encapsulate the candidate drugs in the nanocarrier and evaluate the treatment outcomes in preclinical T1D models. We will also test the new nanoformulations in an islet cell transplant model to study if they can prolong the life of the cells and/or reduce the number of cells for transplantation to achieve the desirable therapeutic outcomes. If successful, this new nanomedicine will be transformative in the field of T1D therapies, eliminating the need for daily injection of insulin and its associated economic and social burdens to both the patients and healthcare system.
Anticipated Outcome
Our long-term goal is to develop nanomedicine products for T1D (and insulin dependent T2D) patients using the multi-targeted nanoparticle delivery platform designed and validated in this project. We anticipate harnessing the ability to deliver therapeutic agents alone or in combination for restoring islet beta-cell functions and improving survival of beta-like/islet cell transplantation in T1D. Compared to other forms and routes of administration, we hypothesize that the drug combination delivered by our targeted nanoparticle delivery system will successfully concentrate within the target site (pancreatic islets) of appropriate animal models, lead to increased beta-cell mass, reduce beta-cell destruction, and restore endogenous insulin production. Furthermore, we anticipate that targeted delivery of drug combinations will provide an adjuvant effect when administered alongside islet cell transplantation, thus reducing the ‘dose’ required for therapeutic effect.
Upon demonstrating the proof-of-concept of our targeted-NP systems at the end of this project, we intend to expand our research to evaluate their safety and efficacy using various preclinical models. By this means of therapy, we anticipate enhanced therapeutic efficacy, while minimizing unwanted side-effects. Subsequent research will be geared towards human clinical trials of targeted-NPs, evaluating the pharmacokinetics and toxicity of the formulations based on FDA guidance for nanomedicine. We would also further develop the manufacturing process of the targeted-NPs so they may be scalable for commercialization.
Relevance to T1D
Type 1 diabetes (T1D) accounts for 10% of all diabetes cases. It can be distinguished from Type 2 diabetes (T2D), such that the treatment options and margin for error when using these treatments are significantly more restricted. Hence, there is an urgent need for better T1D therapies. The major limitations of the currently offered treatments include: 1) scarcity of islet transplant donors and inflammatory response, and 2) inadequate efficacy and unwanted side effects of some promising therapeutic agents, which are addressed in this research. By proposing an injectable nanoparticle drug delivery system that can selectively target islet cells of the pancreas to deliver these promising drug candidates, we aim to maximize their efficacy to improve, protect, and/or restore the function of islet beta-cells, which may furthermore improve the viability of islet cell transplantation.