Paras N. Prasad - US grants

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is the fourth most common cause of cancer-related mortality in the United States, accounting for nearly 31,000 deaths each year. The vast majority of patients present with locally advanced or unresectable disease, and currently available conventional therapeutic approaches have been minimally successful in ameliorating the dismal prognosis of this malignancy. Nanobiotechnology provides unprecedented opportunities for addressing many of the current pitfalls in the diagnosis and therapy of pancreatic cancer. The current proposal represents a multi-institutional platform partnership between groups with extensive expertise in nanomaterial synthesis and delivery, pancreatic cancer biology, and small animal imaging. Multifunctional hybrid ceramic-polymeric nanoparticles, specifically indium phosphide quantum dots (InP Q-DOTS) and organically modified silica (ORMOSIL) nanoparticles have been developed for comprehensive preclinical evaluation in pancreatic cancer models. Specific Aim 1 of this proposal entails the synthesis of long-circulating (PEGylated), surface-functionalized Q-DOTS and dye-doped ORMOSIL nanoparticles incorporating PET probes ("nanoPET"), for improved imaging of early and metastatic pancreatic cancer in vivo. Specific Aim 2 of this proposal entails synthesis of long-circulating, surface-functionalized ORMOSIL nanoparticles encapsulating the small molecule inhibitor rapamycin (nanorapamycin) for systemic drug delivery to pancreatic cancer. A systematic approach is proposed, including an "optimization" phase comprised of in vitro experiments using human pancreatic cancer cell lines and in vivo studies using conventional subcutaneous xenografts; these studies will then lead into an "application" phase utilizing two preclinical models that faithfully recapitulate human pancreatic cancer biology, including the development of intra-abdominal metastases: first, a novel KRAS-driven transgenic mouse model of pancreatic cancer and second, a spontaneously metastasizing orthotopic xenograft model of human pancreatic cancer established in athymic mice. It is anticipated that clinical translation of these "smart" nanomaterials will lead to improved staging of pancreatic cancer at diagnosis, early detection in "at risk" individuals, and more potent therapeutic benefits for patients with advanced disease. The long-term goal of this proposal remains improvement in patient outcome for a malignancy with near-uniform lethality.

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is the fourth most common cause of cancer-related mortality in the United States, accounting for nearly 31,000 deaths each year. The vast majority of patients present with locally advanced or unresectable disease, and currently available conventional therapeutic approaches have been minimally successful in ameliorating the dismal prognosis of this malignancy. Nanobiotechnology provides unprecedented opportunities for addressing many of the current pitfalls in the diagnosis and therapy of pancreatic cancer. The current proposal represents a multi-institutional platform partnership between groups with extensive expertise in nanomaterial synthesis and delivery, pancreatic cancer biology, and small animal imaging. Multifunctional hybrid ceramic-polymeric nanoparticles, specifically indium phosphide quantum dots (InP Q-DOTS) and organically modified silica (ORMOSIL) nanoparticles have been developed for comprehensive preclinical evaluation in pancreatic cancer models. Specific Aim 1 of this proposal entails the synthesis of long-circulating (PEGylated), surface-functionalized Q-DOTS and dye-doped ORMOSIL nanoparticles incorporating PET probes ("nanoPET"), for improved imaging of early and metastatic pancreatic cancer in vivo. Specific Aim 2 of this proposal entails synthesis of long-circulating, surface-functionalized ORMOSIL nanoparticles encapsulating the small molecule inhibitor rapamycin (nanorapamycin) for systemic drug delivery to pancreatic cancer. A systematic approach is proposed, including an "optimization" phase comprised of in vitro experiments using human pancreatic cancer cell lines and in vivo studies using conventional subcutaneous xenografts;these studies will then lead into an "application" phase utilizing two preclinical models that faithfully recapitulate human pancreatic cancer biology, including the development of intra-abdominal metastases: first, a novel KRAS-driven transgenic mouse model of pancreatic cancer and second, a spontaneously metastasizing orthotopic xenograft model of human pancreatic cancer established in athymic mice. It is anticipated that clinical translation of these "smart" nanomaterials will lead to improved staging of pancreatic cancer at diagnosis, early detection in "at risk" individuals, and more potent therapeutic benefits for patients with advanced disease. The long-term goal of this proposal remains improvement in patient outcome for a malignancy with near-uniform lethality.

DESCRIPTION: Human Immunodeficiency Virus (HIV) is ranked globally as the deadliest single most infectious agent, with Mycobacterium tuberculosis (TB) following a close second. At least one-third of HIV-positive people are infected with TB and it is a major cause of mortality among this patient population. On the other hand, HIV is a major co- morbidity in patients with TB, with this population 30 times more likely to develop active TB disease than people without HIV. In the absence of vaccines against these diseases, drug therapy approaches remain the only effective treatment options. The foundation of HIV therapy is based on the combination of multiple antiretroviral agents in a single regimen. However, several factors contribute to the continuing development of treatment failure and drug resistance, among them are suboptimal drug efficacy and/or variable pharmacokinetics, inadequate adherence to lifelong therapy, pre-existing drug resistance and acute or chronic drug toxicities. Standard TB management involves combination therapy for 6 to 9 months using 4 first-line drugs. Treatment failure and drug resistance are primarily related to the long duration of treatment, TB drug side effects and toxicity, various socioeconomic constraints, poor adherence to treatment, loss to follow up, human errors in prescribing inadequate regimens, inconsistent dosing and poor quality of drugs. An innovative alternative for both of these diseases would combine the antimicrobial drug effects with an augmented innate immune system to eradicate pathogens and overcome the problems associated with current therapies. We utilize nanoparticle carriers prepared from FDA approved, biodegradable and biocompatible polymers, with poly(lactic-co-glycolic) acid (PLGA) as the core and chitosan as the shell in a core-shell configuration that allows attachment of the immune stimulatory ligand, ?-glucan, to the surface of the shell and encapsulation of drugs (HIV and/or TB) in the core. These nanoparticles will deliver TB and/or HIV drugs specifically to macrophages while concomitantly inducing the production of cytokines and reactive oxygen molecules within the macrophage, with the goal of intracellular pathogen clearance. This innovative therapy represents a new and practical alternative to study targeted nanoparticle drug delivery combined with immunomodulation using a single ligand, ?-glucan. The study design utilizes an integrated physiologically-based, dynamic, hollow fiber macrophage cell culture system to determine the pharmacokinetics and immune-dynamics of this multi-modal nanoparticle. We will determine the optimal dose and method of delivery and the bio-distribution, pharmacokinetics and immune stimulation in a mouse model. We will then develop a physiological based-pharmacokinetic model that describes nanoparticle distribution based on chemical and biological parameters (in vitro and in vivo data). This approach will broaden our scientific knowledge of HIV and/or TB disease therapies and, by combining targeted drug delivery with immune augmentation, create new approaches that will facilitate reducing individual drug doses, reduce systemic drug toxicity and reduce the development of drug resistance.

? DESCRIPTION (provided by applicant): This application is in response to the President's Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. A central goal of the BRAIN Initiative is to understand how electrical and chemical signals code information in neural circuits and give rise to sensations, thoughts, emotions and actions. Existing technologies are not sufficient to accomplish this goal and have to be significantly improved or novel tools should be introduced to analyze circuit-specific processes in the brain, leading to transformative advances in our understanding of the brain function and behavior. RFA-EY-15-001 seeks technology at the very earliest stage of development, which can assist recording and/or manipulating neural circuit activity in human and animal experiments. The specific goal of the proposed work is to introduce and validate a new voltage-sensitive upconverting photoacoustic imaging (VSUPAI) technique. It is based on voltage-sensitive dye (VSD) imaging, which exploits change of optical properties of dye associated with a cell membrane with variation of a membrane potential, allowing for real-time probing of the neuronal activity via non-invasive optical methods. VSDs have limited use in deep brain imaging, because they require excitation in the visible range. This proposal addresses the current limitation of VSD imaging through the convergence of photoacoustic tomography (PAT), biocompatible upconversion (UC) nanoparticles, and VSDs. In the proposed method, we exploit the voltage-sensitive change in dye absorbance to produce a change in the photoacoustic signal, as opposed to fluorescence-based probing with conventional VSDs. In our proposal, the PAT technique will involve NIR excitation and ultrasound detection, while UCNPs will serve as nanotransformers that convert skull penetrating NIR light to VIS light, which will be absorbed by the locally administered VSDs, allowing us to monitor changes in their absorption, induced by changes in action potentials, and, correspondingly, map the deeper brain neuronal activity.