Objective
The ultimate objective of the present proposal is to achieve improved immunosuppression for diabetic patients who have received an islet or stem cell-derived insulin secreting cell transplant by use of our novel nanomaterial-based drug delivery system DIANAs (Drug-Integrating Amphiphilic Nanomaterial Assemblies). They have been shown to be non-toxic, and they can achieve improved solubilization, easier administration, and stronger effect by delivering drugs in a targeted and localized manner only where their actions are needed; therefore, reducing or eliminating the undesired side effects of existing immunosuppressive drugs, which act in a non-specific manner thorough the entire body, and increasing the safety of the islet or cell transplantation procedure. With the expertise of Dr. Velluto, we are now able to produce in-house a variety of these nanomaterials, which are particles as small as a virus and can transport drugs only to the site of the body where they are required while also prolonging their actions there reducing the frequency of their administrations. By customizing the chemical preparation (synthesis), the properties of these nanomaterials can be fine-tuned for each drug of interest that needs to be transported. Therefore, we will explore and test two different types of nanomaterial-based systems, nanomicelles (nMICs) and nanofibers (nFIBs), for two different drug classes of interest, which are already approved for clinical use but whose widespread use in islet transplantation is hindered by their unavoidable side effects. Such nanomaterial-based local antiinflammatory and immunosuppression regimens should decrease or possibly eliminate the amount of immunosuppression that needs to be taken systemically (by mouth or by injection) and, therefore, make these treatments safer and more widely applicable so that they could make cell replacement therapies available to a much wider portion of T1D patients. Following preparation (synthesis) and characterization, we will test and optimize them, and we will select the most promising ones for detailed evaluation in animal models of islet transplantation including in combination that may provide additional benefits (synergy).
Background Rationale
People affected by type 1 (insulin-dependent or juvenile-onset) diabetes (T1D) lose their ability to produce insulin and must depend on administration of insulin for the rest of their lives. This is not only inconvenient, but, despite many improvements, it can still not fully reproduce normal physiological insulin production and can lead to health problems in long-term diabetic patients. Transplantation of insulin producing pancreatic islets could be a solution that has been shown to be safe and effective, and islet transplantation is about to become an approved clinical treatment in the US for a subgroup of high-risk patients. Stem cells have also become a recently emerging alternative as possible replacement for insulin producing cells, and they are now already in clinical trials with T1D patients. However, as in all transplantations, transplantation of insulin producing cells requires lifelong immunosuppression that is accompanied by many undesirable side effects, including the increased risk for infections and cancer. The existence of local immune privilege at some specialized sites, such as the pregnant uterus, supports the feasibility of localized immunomodulation, and such an approach could be particularly well-suited for islet / stem cell transplantation because in these cases, the transplanted cells are localized to a well-defined and confined space. Here, we propose to use nanomaterials (materials that are developed via recently emerging technologies and rely on very small, nano-sized components) developed in our laboratories (DIANAs; Drug-Integrating Amphiphilic Nanomaterial Assemblies) to achieve localized antiinflammatory and immunosuppressive activity by delivering drugs in a targeted and sustained manner to the vicinity of the insulin producing implant. This should provide local therapeutic effects, but without the undesired side effects that are produced in other organs by current therapies that are not localized to the transplant site. To ensure that our new therapies are quickly translated from animal test to use in patients, we will focus on drugs that are already FDA approved for use in humans and on our DIANA nanomaterial shown to be safe and nontoxic. We have already obtained some encouraging preliminary results with two drugs used as cargo including in mouse models and intend to extend this approach to others to select the best possible treatment regimen.
Description of Project
People affected by type 1 (insulin-dependent or juvenile-onset) diabetes (T1D) lose their ability to produce insulin and must depend on administration of insulin for the rest of their lives. Despite obvious clinical benefits, such insulin administration does not provide proper metabolic control and does not prevent the long-term complications of T1D. Transplantation of insulin producing pancreatic islets or, more recently, stem cell-derived insulin-secreting cells emerged as alternatives that can restore function, and islet transplantation is likely to become an approved clinical treatment in the US for certain high-risk T1D patients. However, as in all transplantations, this will require lifelong immunosuppression, and such treatments are accompanied by many undesirable side effects including the increased risk for infections and cancer. If immunosuppression could be limited only to the site of the transplant and its immediate neighborhood, one could have a much safer regimen that could be used in a much larger numbers of patients with T1D, including children. This, however, is challenging, as it is difficult to deliver and maintain immunosuppressive drugs at effective levels only in certain parts of the body. Nanomaterials, emerging technologies that have already been applied successfully in several medical fields, could provide innovative solutions for such targeted and localized drug delivery. Nanomaterials are materials with extremely small, nano-sized dimensions (as small as viruses) that can be used as drug carriers that travel through the body delivering their cargos. They can protect the drugs from premature degradation increasing their efficacy and avoiding toxicity. Because of their extremely small size, such nanocarriers can be efficiently taken up by the cells in organs and tissues. Accordingly, here, we propose to use our DIANA nanomaterials designed and produced in-house as drug delivery systems (Drug-Integrating Amphiphilic Nanomaterial Assemblies) to achieve localized immunosuppression and anti-inflammatory treatments that can delay or avoid rejection of transplanted islets without side effects, making the cure available to a much wider range of T1D patients.
At the University of Miami’s Diabetes Research Institute, we can now produce (synthesize) in-house a variety of nanomaterials that have been shown to be able to solubilize, deliver, and provide passively targeted and sustained release for drugs currently used in clinical islet transplantation. These nanomaterials are nontoxic, and their drug delivery and release properties can be fine-tuned by adjusting their chemistry in-house. We propose to use them to deliver highly effective and clinically already used drugs locally by using two complementary approaches to dampen both the inflammatory and the immune responses at and around the transplant site by (repeatedly) injecting a targeted delivery drug form. Preliminary results with two different compounds and two different DIANAs are encouraging indicating that these nanomaterial-based systems can deliver and maintain sufficient drug concentrations to achieve local activity while avoiding high concentrations at other sites, which will reduce the systemic toxicity of clinically used drugs. Since for this work we will combine the expertise in drug development, medicinal chemistry, pharmacology, immunology, and islet biology of Dr. Buchwald with that in nanomaterials, polymer chemistry, and drug delivery of Dr. Velluto, we are well-positioned to achieve considerable progress along the proposed research lines.
Anticipated Outcome
We anticipate our DIANA nanomaterial-based local delivery (Drug-Integrating Amphiphilic Nanomaterial Assemblies) to produce targeted antiinflammatory and immunosuppressive effects and, thus, improve islet engraftment and long-term function. This will reduce or minimize the undesired side effects of current therapies needed in all transplant recipients and will allow a much wider applicability of islet and stem cell transplantation procedures. Since achieving local effect is challenging, we will explore two different nanomaterial-based DIANA systems, so-called nanomicelles (nMIC) and nanofibers (nFIB) and use two different drug classes that both include clinically approved drugs as cargos to allow fast clinical translatability. After initial testing, we will pursue only the most promising DIANA-formulated candidates. While all experiments here will be done in preclinical (animal) models, to ensure that our approach is relevant for clinical applicability, we will use as cargo only drugs that are already approved for clinical use and as delivery system only nanomaterials known to be safe and nontoxic. Furthermore, the safety and efficacy of DIANAs will also be assessed using human islets. For this work, we will combine the expertise in drug development, medicinal chemistry, pharmacology, immunology, and islet biology of Dr. Buchwald with that in nanomaterials, polymer chemistry, and drug delivery of Dr. Velluto; thus, we are well-positioned to achieve considerable progress along the proposed research lines.
To summarize, we anticipate that by fine-tuning the size and morphology of our nanomaterials for drug delivery (DIANAs) they will be able to • efficiently load different drugs, • deliver them to the cell transplant and relevant immune-response sites (draining lymph nodes) • achieve localized inflammatory- and immune-modulation at reduced doses and/or frequencies of administration than traditional drugs. We also expect our innovative DIANAs to • increase the survival and function of transplanted islet cells in diabetic mice and rats used as animal model and • minimize or possibly eliminate the need for systemically administered immunotherapies and their undesirable side effects. Overall, we anticipate identifying at least two new DIANA-based drug formulations that can be injected to provide improved islet engraftment and long-term function minimizing or even eliminating the undesirable side effects of current systemically administered therapies. Therefore, our DIANAs will make possible a wider applicability of pancreatic islet and stem cell-derived insulin secreting cell transplantation procedures for existing high-risk T1D patients.
Relevance to T1D
People affected by type 1 (insulin-dependent or juvenile-onset) diabetes lose their ability to produce insulin and must depend on administration of insulin for the rest of their lives. This is not only inconvenient, but, despite many improvements, it can still not fully reproduce normal physiological insulin production and can lead to long-term complications especially in patients with uncontrolled T1D. Transplantation of insulin producing pancreatic islets or stem cell-derived insulin-secreting cells, which are showing increasing promise, could be a solution, especially in those patients who do not respond well to insulin injections. Islet transplantation is about to become an approved clinical treatment in the US for a subgroup of high-risk patients and insulin producing stem cells have now also reached the clinical development phase. However, as all transplantations, these require lifelong immunosuppression, and such treatments are accompanied by many undesirable side effects including the increased risk for infections and cancer. If immunosuppression could be limited only to the site of the transplant and its immediate neighborhood, one could have a much safer regimen that could be used much more widely. Here, we propose to use nanomaterials (novel materials that rely on very small, nano-sized components, which are as small as viruses) delivered in our laboratories and designated as DIANAs (Drug-Integrating Amphiphilic Nanomaterial Assemblies) to achieve localized immunosuppression by delivering drugs in a targeted and prolonged manner to the vicinity of the insulin producing implant. This should provide local therapeutic effects without the undesired side effects that are produced in other organs by current immunosuppressive therapies that are not localized at or around the transplant site. Ultimately, by minimizing or maybe even eliminating the need for systemically administered immunosuppressive therapies together with their undesirable side effects, our novel nanomaterials can make cell transplantation a therapy available to a much wider portion of T1D patients, including children.