Objective
The purpose of this work is to design, synthesize and characterize a series of beta cell targeted phenylbutyrate (BTPBs). These BTPBs will be prepared by anchoring phenylbutyrate (PB) to targeting zinc-enriched granules on islet beta cells. These bioconjugates have potential as therapeutic agents for Type 1 Diabetes. Specifically, these bioconjugates will be designed to enrich PB in beta cells, so as to alleviate ER stress mediated by PB, thus preserving beta cell functional mass. We aim to optimize the beta cytotropic effect of prepared bioconjugates, as well as study their DMPK (drug metabolism and pharmacokinetic) properties to evaluate their potential to serve as therapeutics. We expect that prepared bioconjugates will have significant beta cytoprotective activity in vitro and in vivo. Upon fine design of BTPB derivatives, we anticipate that an optimal drug release and PK properties for designed prodrugs will result in significantly greater PB enrichment in islets beta cells than in other tissues, which can provide a general guidance for prodrug design in our unique BTM target delivery system.
Background Rationale
In spite of extensive research effort in the identification of therapeutic targets, regular administration of insulin remains the only viable solution to the management of Type 1 Diabetes (T1D). Accumulating evidences indicate that phenylbutyrate (PB) may preserve beat cell function and survival. PB is safe and well-tolerated in humans and even children. However, its therapeutic potential in diabetes is limited by its short half-life in the circulation, and by the lack of targeting specificity to β-cells in vivo. Therefore, to unlock the therapeutic potential of PB to enhance beta cell fitness or robustness, there is an unmet need to develop novel delivery strategies to overcome the aforementioned limitations.
Description of Project
Diabetes mellitus type 1 (T1D) is becoming an increasing burden on socioeconomic resources with increasing patient numbers all over the world. In spite of extensive research efforts in the identification of therapeutic targets, regular administration of insulin remains the only viable treatment option for T1D. Mounting evidence indicates that phenylbutyrate (PB) can preserve beta cell function and survival, can be applied safely, and is well tolerated in humans. However, the therapeutic potential of PB in diabetes is limited by its short half-life in circulation, and the lack of targeting specificity to beta cells in vivo. Therefore, to unlock the therapeutic potential of PB to enhance beta cell robustness, in this Advanced JDRF Postdoctoral Fellowship application, I plan to address an unmet need to develop an efficient drug delivery strategy to overcome these aforementioned limitations. By exploiting a Beta Cell-Targeting Motif (BTM), whose zinctropic property accounts for the selective uptake of ZIGIR by pancreatic beta cells as shown previously, I hereby propose the development and characterization of beta cell-targeting phenylbutyrate (BTPB) derivatives. In particular, I have already shown that our BTM moiety conjugated with different dyes or small molecules, the resulting conjugates exhibit exquisite efficacy and selectivity to target pancreatic beta cells. Through targeted delivery of these prodrugs to beta cells, the reported benefits of PB on reducing endoplasmatic reticulum stress and promoting cell survival were augmented, ultimately resulting in the preservation of beta cell function and the improvement of physiological glycemic control.
Anticipated Outcome
We expect that the designed beta cell targeted phenylbutyrate (PB) have a significant beta cytotropic activity in vitro and in vivo. Upon fine design of BTPB derivatives, we anticipate that an optimal drug release and PK properties for designed prodrugs will result in significantly greater PB enrichment in islets beta cells than in other tissues, which can provide a general guidance for prodrug design in our unique BTM target delivery system in the future.
Relevance to T1D
This work is highly relevant to Type 1 Diabetes as it aims to develop beta cell targeted delivery of potential therapeutics. The proposed molecules are expected to not only protect existing beta cells, but also investigate the synergetic treatment effect of combination of BTPB (beta cell protection) with an anti-CD3 antibody (immune regulation). Beta cell-targeting cytotoxic agents have the potential to act on their intended targets while avoiding unwanted systemic activation of phenylbutyrate, thus reducing potential side effects and increasing therapeutic utility. Restoration and maintenance of functional beta cell mass is an ultimate goal to relieve Type 1 diabetic patients from insulin dependence.