Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.83K | Year: 2015
DESCRIPTION provided by applicant The goal of this project is to test the feasibility of targeted delivery of andquot re programmingandquot liposomal drugs to tumor associated macrophages TAMs TAMs are the major component of tumor microenvironment that generally supports tumor growth and interferes with anti tumor therapy These effects are significantly mediated by about of TAMs that are located in tumor perivascular areas and are the major source of pro tumorigenic and pro angiogenic mediators specifically implicated in promotion of tumor angiogenesis and metastatic dissemination There is evidence that various re programming cues can be used to reduce the pro tumorigenic potential of TAMs creating an opportunity for more efficient anti cancer therapy To target perivascular TAMs we selected liposomal formulations of a TLR ligand poly I C that we named Lip PIC The TLR activation stimulates re polarization in TAMs which appears to be relatively safe as it is being developed for various vaccination protocols and at the same time rather efficient in tumor growth inhibition at least in animal tumor models We reasoned that Lip PIC would extravasate through the leaky tumor vasculature to perivascular space the very area of the location of perivascular TAMs To further increase the probability of targeted drug delivery to TAMs we propose to test Lip PIC decorated with annexin V that targets tumor cells undergoing apoptosis Pro tumorigenic TAMs are the known andquot eatersandquot of tumor apoptotic cells presenting an opportunity to use tumor apoptotic cells as andquot Trojan Horseandquot to feed Lip PIC to TAMs Given the complexity of tumor microenvironment that is impossible to reconstruct in tissue culture we reasoned that only in vivo system would be adequate for the proposed proof of principle experiments Therefore we will test our approach in orthotopic T luc mouse breast tumor xenografts in immunocompetent Balb c mice Our Specific Aims are Specific Aim Evaluate the effects of delivery of liposomal poly I C formulation to perivascular TAMs in a breast cancer tumor model Specific Aim Establish if delivery of liposomal poly I C to TAMs could be enhanced by recruitment of apoptotic cells indoxorubicin treated breast cancer model Accomplishing these Specific Aims will provide a proof of principle for using liposomal formulations for delivery of re programming drugs to perivascular TAMs in vivo We envision that the eventual commercial product will be a proprietary optimized liposomal formulation for targeting perivascular TAMs in primary tumor as a part of combination anti cancer therapy PUBLIC HEALTH RELEVANCE The goal of this project is to test the feasibility of targeted delivery of andquot re programmingandquot liposomal drugs to specific cells in tumor microenvironment in order decrease their tumor supporting potential and increase their tumor fighting capabilities Two strategies will be tested one based on delivering liposomal drugs to the same andquot neighborhoodandquot where tumor supporting cells reside and the other based on targeting liposomal drugs to dying tumor cells that are expected to serve as andquot Trojan Horseandquot in feeding pro tumorigenic cells in tumor microenvironment
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 286.38K | Year: 2009
DESCRIPTION (provided by applicant): Our goal is to develop a targeted anti-cancer 177Lu radiotherapeutic agent that localizes to a tumor via receptor- mediated uptake by endothelial cells in the tumor vasculature. Due to beta emission (1.5 mm max depth) 177Lu radiopharmaceutical is expected to be cytotoxic to the host endothelial cells and to surrounding tumor cells, but not to surrounding healthy tissue. In addition, targeted destruction of tumor vasculature can bring starvation to tumor areas outside of uptake areas, further amplifying the cytotoxic effects of the proposed radiopharmaceutical. To achieve selective accumulation of 177Lu in the tumor vasculature, we will target it to the receptors for vascular endothelial growth factor (VEGFR). These receptors are overexpressed in tumor vasculature and their critical role in tumor angiogenesis is underscored by the massive drive to develop drugs that selectively inhibit VEGFR activity. Although the significance of targeting VEGFR stems from their role in tumor angiogenesis, the inhibition approach has, so far, only achieved a modest success. Approved anti-angiogenic drugs (Avastin, Sunitinib, Sorafenib) in combination with established chemo- or radiotherapy prolong life only for several months in a small and unpredictable set of patients. Because of these issues, we propose a different approach to VEGFR- targeted therapy. Instead of inhibiting these receptors, we propose to use VEGFR for targeted delivery of therapeutic radionuclides. We hypothesize that combination of destruction of tumor vasculature and bystander killing of tumor cells will provide for a significantly larger therapeutic effect than VEGFR inhibition alone. For the targeting of 177Lu to the tumor vasculature, we will use a proprietary VEGFR ligand, an engineered single-chain (sc) VEGF developed in our company. According to our published data, scVEGF can be site- specifically derivatized with PEGylated chelators for VEGF receptor mediated delivery of imaging and therapeutic radionuclides to tumor vasculature. Our preliminary results indicate that such conjugates can be radiolabeled with 177Lu to a specific radioactivity that is sufficient for therapeutic efficacy in tumor models. Furthermore, these studies indicated several pathways to optimize the chemical design of scVEGF/177Lu radiopharmaceutical. In Phase I of this project we propose to optimize the composition of scVEGF/177Lu, calculate the dosimetry of optimized scVEGF/177Lu, and perform an initial test of single or divided dose treatment regimens. These are the critical tasks because the viability of any potential radiotherapeutic agent is determined by its therapeutic window, the balance between its therapeutic efficacy and non-specific radiotoxicity. In Phase II of the project we will test optimized scVEGF/177Lu in metastatic models of breast cancer and models of poorly treatable liver, pancreatic, and brain cancer. The second major Phase II task will be the development of GMP production of scVEGF conjugate optimized in Phase I. PUBLIC HEALTH RELEVANCE: The developing a targeted radiotherapeutic agent for delivery of 177Lu to tumor vasculature. We expect that this therapeutic agent will be internalized by tumor endothelial cells and will be cytotoxic to such cells and surrounding tumor cells. In Phase I of this project, we will optimize targeted radiotherapeutic agent, establish its radiotoxicity and therapeutic efficacy mouse model of breast cancer. The results of Phase I will provide a rational basis for clinical development of targeted radiotherapeutic agent in Phase II.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2015
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 222.92K | Year: 2014
The overall goal of this collaborative Fast-Track project is clinical development of a novel 18F PET tracer for molecular imaging of receptors for vascular endothelial growth factor (VEGFR). This receptor is the major anti-angiogenic drug target in oncology patients. Critically, VEGFR prevalence decreases when VEGF/VEGFR anti-angiogenic inhibitors work , and increases when these drugs stop working . These findings provide a rationale for VEGFR imaging for image-guided anti-angiogenic therapy. To provide for high selectivity, specificity, and VEGFR-mediated intracellular accumulation, the 18F PET tracer will be targeted by VEGFR ligand, scVEGF. The protein will be site-specifically derivatized with a strained alkyne for copper-free click- chemistry radiolabeling with 18F-PEG(4)-azide. In Phase I of this project we will select the lead scVEGF/Alkyne conjugate, optimize conditions for 18F radiolabeling, and validate the use of lead tracer for monitoring anti- angiogenic therapy in a murine model of triple neg
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 385.46K | Year: 2010
DESCRIPTION (provided by applicant): Myocardial infarction is a disabling disease, with infarct size being a major determinant of mortality. To limit infarct size and improve functional recovery, the ischemic myocardium has to be reperfused. However, reperfusion itself causes irreversible damage to the previously ischemic myocardium. A significant part of cardiac injury is caused by apoptosis that starts immediately at the beginning of reperfusion. Therefore, reperfusion injury is considered an important new pharmacologic target for the treatment of patients with ongoing acute myocardial infarction. We propose to develop a targeted liposomal formulation of two drugs proven to protect myocardium through independent mechanisms. Drug-carrying liposomes will be decorated with human annexin V for targeting to phosphatidylserine exposed on the surface of cardiomyocytes at the early stages of apoptosis. Intravenous administration of such liposomes immediately before the beginning of reperfusion could serve as an adjunct therapy for angioplasty and/or thrombolytic administration, which are the standard of care for patients with myocardial infarction. The advantages of the proposed strategy are: 1) delivery of pharmacologically significant amounts of drugs in cardiomyocytes from the first moments of reperfusion, when apoptosis is still reversible, 2) avoiding adverse effects of high-dose regimens that are necessary for free drugs, and 3) intracellular delivery of two drugs working via independent mechanisms increases the probability of successful treatment. Targeted drug-loaded liposomes will be evaluated in primary cultures of cardiomyocytes. We will establish mechanism(s) of internalization in early apoptotic cells and evaluate the therapeutic potential of annexin-targeted drug-loaded liposomes. Biodistribution, targeted drug delivery and the protective effects of the liposomes in vivo will be studied in a mouse model of myocardial ischemia/reperfusion. If successful, the proposed strategy will establish the feasibility of using annexin- targeted therapeutic liposomes as an adjunct therapy for myocardial infarction. It will also advance new technologies in developing therapeutic liposomes for targeted delivery to early-stage apoptotic cells. PUBLIC HEALTH RELEVANCE: We propose to test feasibility of developing a targeted liposomal formulation for two drugs proven to protect ischemic myocardium from lethal reperfusion injury through independent mechanisms. Drug-carrying liposomes will be decorated with human annexin V for targeting to phosphatidylserine exposed on the surface of cardiomyocites at the early stages of apoptosis. Intravenous administration of such liposomes immediately before the beginning of reperfusion could serve as an adjunct therapy for angioplasty and/or thrombolytic administration, which are the standard of care for patients with acute myocardial infarction.