Objective
To develop a tailorable drug delivery vehicle that specifically targets the β-cell for delivery a therapeutic cargo for the treatment of T1D.
Background Rationale
While β-cell death has been well characterized in T1D, there are currently no therapies to prevent or halt existing β-cell death. Strategies under development to prevent β-cell death or induce expansion of remaining β-cells show promise in halting T1D; however, lack of specific targeting to the β-cell results in off-target effects and reduced therapeutic efficacy. Targeted drug delivery using nanoparticles has emerged as a promising technology for prolonged release of therapeutics; however, delivery across biological barriers, such as cell membranes, remains a challenge limiting the effectiveness of these treatments. Designer nanoparticles coated with targeting peptides are being developed to overcome biological barriers and achieve cell-specific drug delivery. Several studies have successfully employed Exendin-4 to target diagnostic imaging nanoparticles to the β-cell, but this strategy has not been applied to targeted delivery of small peptides to the β-cell to date. Additionally, new β-cell specific surface proteins have recently been identified that hold potential as targets for β-cell specific drug delivery; however, they are currently untested for this application. In T1D, immune destruction of β-cells is partly mediated by high levels of pro-inflammatory cytokines in the pancreas. Previous studies, including from our lab, have indicated a role for protein kinase c δ (PKCδ) in mediating cytokine-induced β-cell death. Our preliminary studies show that the PKCδ inhibitor δV1-1 protects both mouse and human islets from cytokine-induced death in vitro; however, a targeted delivery method is needed to determine if inhibiting PKCδ in T1D can prevent β-cell death.
Description of Project
T1D is characterized by immune-mediated destruction of insulin producing β-cells in the pancreatic islet. Current T1D treatments use exogenous insulin to manage symptoms, but this is not a cure. Strategies to prevent β-cell death show promise in halting T1D; however, lack of specific targeting to the β-cell results in off-target effects and reduced treatment efficacy. Targeted drug delivery using nanocapsules (NCs) has emerged as a promising technology for prolonged release of therapeutics in targeted cell types. Several studies have successfully employed Exendin-4 to target diagnostic imaging nanoparticles to the β-cell, but this strategy has not been applied to targeted delivery of small peptides to the β-cell to date. Additionally, new β-cell specific surface proteins have recently been identified that hold potential as targets for β-cell specific drug delivery; however, they are currently untested for this application. In T1D, immune destruction of β-cells is partly mediated by high levels of pro-inflammatory cytokines in the pancreas. Previous studies, including from our lab, have indicated a role for protein kinase c δ (PKCδ) in mediating cytokine-induced β-cell death. Our preliminary studies show that δV1-1 protects both mouse and human islets from cytokine-induced death in vitro; however, a targeted delivery method is needed to determine if inhibiting PKCδ in T1D can prevent β-cell death. The goal of this study is to develop a novel nanocapsule (NC) drug delivery system that can specifically target the human pancreatic β-cell and deliver small peptides and/or therapeutics. While we anticipate wide applicability of our innovative nanotechnology approach, we propose to deliver a therapeutic peptide for protection against β-cell death in T1D as a proof of principle demonstration. Specifically, we hypothesize that nanocapsules loaded with the PKCδ inhibitor δV1-1 and tagged with a targeting peptide will selectively be taken up by β-cells and will protect against β-cell death. To achieve this goal, we propose the following three aims: 1. Determine the selectivity and efficacy of targeted NC uptake into human islets and human stem cell derived β-cell clusters, 2. Determine if targeted NCs can specifically target the β-cell in vivo, and 3. Determine if NCs can target and improve survival of human β-cell grafts in an auto immune competent humanized mouse model. Overall, this study will utilize a novel NC design to target the human β-cell and deliver a small peptide therapeutic to protect against β-cell death. The results from this study will provide the necessary proof of concept data to verify stability and selectivity of NC targeting in human tissues and a humanized mouse model of T1D. Future studies will test the efficacy of this drug delivery treatment using non-human primates to provide necessary validation to allow safe translation to human patients in a timely manner.
Anticipated Outcome
We anticipate that our NC drug delivery system will successfully target to the human β-cell both in isolated islets and in NC treated mice. Furthermore, we anticipate that our targeted NCs will be selectively taken up by β-cells in a humanized mouse model of T1D and release the small therapeutic peptide δV1-1 to protect against β-cell death. The results from this study will provide a novel strategy to the diabetes research field that will allow targeted delivery of any peptide or small molecule therapeutic to the β-cell with minimal off target effects. Future studies will test the efficacy of this drug delivery treatment using non-human primates to provide necessary validation to allow safe translation to human patients in a timely manner.
Relevance to T1D
This work will have a direct impact on improving targeted delivery of small peptides to the β-cell to treat at risk individuals as well as those with established T1D. As of now, the inability to specifically target the pancreatic β-cell is a critical bottleneck that prevents effectively intervening with disease progression. Current strategies to promote β-cell survival during the onset of T1D rely on systemic administration of therapeutics, which leads to reduced efficacy and off target effects. The proposed work will provide a mechanism to target delivery of any peptide or small molecule therapeutic specifically to the β-cell and thus reduce current off target effects. Our preliminary results have confirmed that targeting of the β-cell and delivery of cargo using our NC system is feasible using human islets. We further show that PKCδ regulation of β-cell death is a novel mechanism that may be exploited to regulate β-cell fate in T1D. We anticipate that our proposed work will lay the foundation for employing nanoparticle technology to deliver therapeutics specifically to the β-cell in vivo in non-human primates, providing critical proof of principle data and validating safety and efficacy for future translation into clinical trials.