2017 — 2020 |
Gu, Zhen |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Engineering Biomimetic Glucose-Responsive Vesicles For Self-Regulated Insulin Delivery @ North Carolina State University
Non-technical: Diabetes is a disorder in glucose regulation, and is characterized by increase in blood glucose. Globally, an estimated 422 million people had diabetes. In the United States, about 8.3% of the population currently has diabetes and that number is projected to grow to 1 in 3 adults by 2050. The current treatment for high blood sugar is frequent self-administration of insulin injections and monitoring of blood sugar levels throughout the day is necessary to sustain life for patients with type 1 or advanced type 2 diabetes. Lack of tight control of blood sugar levels accounts for many chronic complications of diabetes, such as limb amputation, blindness and kidney failure; while low blood sugar levels result in life disruption and the risk of seizures, unconsciousness, brain damage, or possible death. Current insulin infusion approaches, however, cannot mimic normal physiological conditions in which the pancreatic cells quickly releases insulin in response to increase in blood sugar levels, and insulin levels are shut down once the blood sugar is normal. This proposal is to develop the next-generation blood glucose-responsive insulin delivery systems that are based on synthetic vesicles in a biomimetic manner, inspired by the vesicles (or granules) of pancreatic celIs. The planned insulin delivery system will be able to automatically regulate insulin release continuously and repeatedly according to blood sugar levels. Towards this goal, the PI proposes to develop transformative glucose-responsive insulin nanoparticles (GRINs) for intelligently regulating blood sugar levels with fast and repeatable responsiveness. The activation of GRINs and subsequent release of insulin are expected to be triggered at a high blood sugar level, and the release is inhibited with a normal blood sugar range, thereby mimicking pancreatic cells to "secrete" insulin in response to fluctuating blood sugar levels. The GRINs prepared will be further loaded into a painless microneedle array-based patch on the skin to achieve easy administration and enhanced biocompatibility. This project will develop novel materials, formulations and devices that may be of broad use for development of other bio-responsive smart drug delivery systems. In addition, the proposed research will create dynamic and sustainable education activities, including a K-12 based outreach module 'Engineering Our Way to Stop Diabetes', an interdisciplinary curriculum targeting undergraduates and graduates, together with hands-on lab research. Such activities are expected to inspire students to pursue careers in science, technology, engineering and mathematics (STEM) disciplines.
Technical: Diabetes is a major public health problem currently affecting about 422 million people across the world, and this number is expected to reach over 450 million by 2030. Current treatment for Type 1 and advanced Type 2 diabetic patients requires continuous monitoring of blood glucose (BG) levels and periodical insulin injections to maintain normal blood glucose levels. An artificial pancreas-like closed-loop insulin delivery system that continuously and intelligently releases insulin in response to changing blood glucose levels holds great promise for enhancing heath and improving quality of life for patients with type 1 and advanced type 2 diabetes. To date, mimicking the function of pancreatic cells, chemically-controlled closed-loop delivery strategy utilizing synthetic materials and/or modified insulin have been widely explored. This typically consisted of polymeric formulations that swell, shrink or dissociate to adjust the insulin release rate according to ambient glucose levels. However, challenges remain to demonstrate a system which would combine; i) fast response; ii) repeatable activation; iii) ease of administration; and iv) excellent biocompatibility. The proposed project aims to develop the next-generation glucose-responsive insulin delivery systems, inspired by the "natural" granules of pancreatic cells. The PI will explore 'artificial' glucose-responsive insulin nano-granules (GRINs) and their relevant devices. The activation of GRINs and subsequent release of insulin are expected to be rapidly triggered at high blood sugar state, and inhibited within a normal blood sugar levels in a repeatable manner. The GRINs developed will be further integrated into a painless microneedle array-based device for application on skin, and thus achieving easy administration and enhanced biocompatibility. This project will also guide the development of novel materials, formulations and devices for engineering other delivery systems which can be intelligently activated by the variation of physiological signals. Moreover, the proposed research program will be closely integrated with dynamic and sustainable educational activities, through development of a K-12 outreach module- 'Engineering Our Way to Stop Diabetes', a new interdisciplinary curriculum targeting undergraduates and graduates, as well as hands-on lab research. Students will be exposed to biomaterials, devices and micro-nanotechnology, inspiring them to pursue careers in science, technology, engineering and mathematics (STEM) disciplines.
|
1 |
2018 — 2020 |
Gu, Zhen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Towards Glucose Transporter-Mediated Glucose-Responsive Insulin Delivery With Fast Response @ North Carolina State University Raleigh
PROJECT SUMMARY Glucose-responsive delivery of insulin mimicking the function of pancreatic ?-cells to achieve meticulous control of blood glucose (BG) would revolutionize type 1 and advanced type 2 diabetes care. However, it is extremely challenging to demonstrate a system which would combine fast response, reversible activation, ease of administration and excellent biocompatibility. In this proposal, we aim to establish an innovative glucose-responsive insulin delivery system based on the interaction between the glucose derivative- modified insulin (Glu-insulin) and glucose transporters (GLUTs) on red blood cells (RBCs). This binding interaction is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of blood glucose levels. We will exploit two conjugation formulations of Glu-insulin and glucose transporters (GIGTer): 1) polymeric nanoparticles (NPs; ~100 nm in diameter) coated with the RBC membrane (with GLUTs) and loaded with Glu-insulin; and 2) liposomal NPs integrated with exogenously expressed glucose transporters and Glu-insulin. We will further integrate these two glucose-responsive formulations into a painless microneedle (MN)-array based transcutaneous patch to obtain the ?smart insulin patch? (SIP). Glu-insulin encapsulated NPs will also be incorporated inside SIP for serving as insulin reservoir to ?recharge? GIGTers for up to 48 h regulation within a normoglycemic range. In vivo potency of smart insulin patch will be evaluated using the streptozotocin (STZ)-induced type 1 diabetic male C57B6 mice and Sprague Dawley rats. In Aim 1, we will validate and optimize the glucose-responsive capability of the GIGTers based on our preliminary study. In Aim 2, we will evaluate the effectiveness of SIPs integrated with GIGTers, determining the feasibility of utilizing the GIGTer as a new administration modality. In Aim 3, we will optimize the physicochemical properties of the GIGTer-integrated patches in type 1 diabetic mouse and rat (implanted with the Continuous Glucose Monitoring System, CGMS) models; we will substantiate the glucose-responsive capability as well as the biocompatibility of SIPs with GIGTers. The proposed goal, when successfully realized, will be a significant upgrade over the current insulin-dependent diabetes therapy options and have a profound impact to improve health and quality of life of diabetic patients.
|
1 |
2019 |
Gu, Zhen |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Biotechnology Training in Biomedical Sciences and Engineering @ University of California Los Angeles
? DESCRIPTION (provided by applicant): The goal of the UCLA Biotechnology Training in Biomedical Science and Engineering (BTBSE) Program is to educate and to train the next generation of highly skilled scientists and engineers who will assume leadership roles in multidisciplinary biotechnology research. This goal is achieved through a cohesive 2-year training program entailing multidisciplinary research, a common curriculum composed of formal coursework in life science and engineering and of a cross-disciplinary laboratory rotation, and an industrial internship. The required coursework is comprised of a course in macromolecular synthesis and structure, a course on molecular biotechnology from an engineer's perspective, the Biotechnology Forum course, and a class in research ethics. Life science trainees must work in the research laboratory of an engineering mentor for at least three months; likewise the engineers spend time in the laboratory of their life science mentor. A biotechnology community is fostered principally through the monthly trainee lunch seminar series and the Annual Biotechnology Symposium, which brings together ~50 students, faculty and industry representatives. Trainees who complete this program will be equipped to function productively in the multidisciplinary teams of bioengineers and life scientists prevalent in the industry. The interface between the life/health sciences and engineering is extraordinarily rich in its diversity and this biotechnology program focuses broadly on molecular and cellular research. Faculty participants in the proposed BTBSE Program all mentor Ph.D. students who conduct research focused at the molecular and cellular level, and most have established cross-disciplinary collaborations. Three interconnected theme areas have been identified and are i) synthetic biology and metabolic engineering; ii) bionanotechnology and tissue engineering; and iii) Molecular, Cellular and Systems Biology. Such an array of research activities conducted by collaborating researchers provides an exciting menu of multidisciplinary research opportunities to trainees. Faculty participants in the proposed training program have had the opportunity to recruit from a pool of over 100 eligible Ph.D. students this academic year. The Director and faculty mentors are very active and successful in underrepresented minority student development and recruitment, especially from the very diverse, populous greater Los Angeles area. Several major changes are noted for this renewal application, including change of the program director to Prof. Yi Tang, turnover of ~20% of training faculty to increase collaboration and training participation, and reconstitution of the training committee members.
|
1 |
2019 — 2020 |
Gu, Zhen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Platelets-Mediated Delivery of Checkpoint Inhibitors For Post-Surgical Cancer Immunotherapy @ University of California Los Angeles
PROJECT SUMMARY Despite continual improvements in surgical techniques, cancer recurrence after surgical resection remains a significant challenge in cancer therapy. It has also been verified that surgery can induce promotion of cancer metastasis. In this proposal, utilizing platelet as a delivery vehicle, the team intends to develop a transformative platform for locally releasing immune checkpoint inhibitors toward post-surgical eradication of residual cancer cells. In a preliminary study, using the B16F10 melanoma tumor-bearing C57BL/6 mouse model, it has been demonstrated that the anti-PDL1 (aPDL1) attached platelets (designated P-aPDL1) could facilitate the accumulation of aPDL1 toward the surgical bed where the residual microtumors remain. Importantly, the loaded aPDL1 can be effectively released from the activated platelets mediated by the platelet-derived microparticles (PMPs) upon in situ platelet activation. Moreover, platelets can generate a local inflamed tumor microenvironment, which could boost T cells activity as well as other immune cells. Here, the team proposes to further substantiate, optimize and extend the capability of platelets as a delivery platform for checkpoints blockade-based cancer immunotherapy. The team will validate the detailed treatment mechanism of P-aPDL1 as well as optimize its physicochemical property. The capability of P-aPDL1 for treating circulating tumor cells (CTCs) will also be evaluated. In addition, the team will evaluate the potential of platelets to achieve combination delivery of aPDL1 and gemcitabine (GEM), which can upregulate both PDL1 and PD1 on tumor cells and tumor infiltrating immune cells, respectively. Furthermore, the twam will extend this platform to co-deliver different ?cells?- therapeutics-loaded platelets and specific chimeric antigen receptor (CAR) T cells. Three aims will be pursued: in Aim 1, the capability of platelets for delivering checkpoint inhibitors will be validated and optimized; in Aim 2, the effectiveness of combination delivery of aPDL1 and GEM using platelets will be evaluated; in Aim 3, the innovative combination cell immunotherapy with platelets and CAR-T cells will be developed and assessed. The synergistic immune responses as well as systemic toxicity of this combination cells-based immunotherapy will be evaluated. The proposed research, when successfully demonstrated in human studies, would significantly enhance the anticancer efficacy and improving the patients? survival. This novel in situ bio-responsive strategy may also inspire new treatments applying bio-particulates for targeting and bio-responsive release of therapeutics.
|
1 |
2020 |
Cheng, Ke Gu, Zhen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Surgical Microneedle Patch Delivery of Cmmp For Heart Repair @ North Carolina State University Raleigh
PROJECT SUMMARY Cell-based therapy represents a promising strategy in regenerative medicine. However, live cells need to be carefully preserved and processed before usage. In addition, as ?live drugs?, cell transplantation carries certain immunogenicity and/or tumorigenicity risks. The development of cell-free and non-living therapeutics has the potential to revolutionize current regenerative medicine practice. Mounting lines of evidences indicate that adult stem cells exert their beneficial effects mainly through the secretion of pro-regenerative factors. Based on this, the PI Cheng Lab fabricated cell mimicking microparticles (CMMPs) by encapsulating stem cell-secreted factors in a biodegradable polymer block. Our previous studies demonstrated that those ?synthetic cells? carried similar secreted proteins and membranes as their parental cells did. In a mouse model of myocardial infarction (MI), intramyocardial injection of CMMPs led to preservation of viable myocardium and augmentation of cardiac functions similar to cell therapy. Despite the successful proof of concept, a big challenge is the effective delivery of those therapeutic microparticles to the heart. Cardiac patches have been tested to deliver therapeutic cells to the surface of the heart. One caveat is that there is a lack of patch-host communication due to poor integration of the cardiac patch with the host myocardium. The MPI Gu Lab is experienced in the fabrication of microneedle (MN) patches. Our previous studies indicated that MN patch can deliver therapeutics to the tissue effectively. The present R01 proposal represents a logic progression from our previous work while bringing new technologies. Here we will be developing and testing a new entity: a MN-CMMP cardiac patch formed by embedding CMMPs into biodegradable and biocompatible microneedle cardiac patches. In addition, our studies will extend from the previous rodent acute MI model to a chronic MI model in both small/large animals. The overarching hypothesis is that MN-CMMP can further improve the efficacy of CMMP therapy in rats and pigs with chronic heart injury. AIM 1: Fabricate MN-CMMP comprised of microneedle patch loaded with CMMPs; Determine in vitro potency of MN-CMMP in cultured cells. AIM 2: Determine the safety and efficacy of MN-CMMP therapy in rat model of chronic MI. AIM 3: Translate the findings into clinically-relevant porcine models of heart injury. Our study will form the foundation for an innovative and ?off the shelf? therapy based on secreted factors and myocardium matrix that can be standardized from donor stem cell lines and xenogenic cardiac tissues. The cell-free nature of our approach is more readily translatable to the clinic. Although this particular grant application targets the heart and cardiac stem cells, our approach represents a platform technology that can be applied to the creation of multiple types of synthetic stem cell and organ matrices for the repair of various other organs.
|
0.93 |