This Phase II SBIR project seeks to demonstrate that novel, targetable nanoparticles can delivery therapeutic substances to human tumor cells and reduce tumor burden in cancer. The concept for these nanoparticles is based on the hybrid polymerized liposome nanoparticle (HPLN) that displays functional antibodies that target tumor cell surface markers. The therapeutic cargos are encapsulated cytotoxic drugs that comprise the front line treatment for Ewing sarcoma. Upon recognition by the tumor cell, the nanoparticle binds, gets taken into the cell (endocytosed) and the nanoparticle cargo is released, ultimately allowing availability of the drug to kill the cancer cell. This project fits well within the mission of the NCI, to develop new nanotechnology-based therapeutics. Treatment-resistant metastases are the ultimate cause of death in most cancer patients. Systemic therapy for metastases is generally ineffective. A reliable, low-toxic, highly effective therapy is urgently needed to treat both relapse patients and treatment- resistant metastases. The specific aims of this proposal are therefore to optimize the HPLN particle, carry out efficient encapsulation of cancer drugs inside the targeted HPLNs, demonstrate safety and efficacy in killing cancer cells in a humanized xenograft mouse model of human Ewing sarcoma. The first aim is to determine the maximal tolerated dose (MTD) in healthy animals and the PK-efficacy relationship in tumor- bearing mice. NanoValent's goal, at the conclusion of the Phase II is to have an optimized formulation that can be GMP manufactured and subsequently gather the necessary data for an IND submission to the FDA for approval of this novel therapy.
Public Health Relevance Statement: Project Narrative Toxicity of drugs used to treat cancer is the major limiting factor in effective chemotherapy. The collateral damage to bone marrow, GI tract, liver, heart, and other normal tissues limits the amount of chemotherapeutic agent a patient can receive. This project seeks to develop a method to encapsulate cancer drugs inside tiny particles and deliver these loaded particles directly and efficiently to cancer cells. This will widen the window of treatment by getting more drug to the tumor, preventing drug uptake by normal tissue, thereby reducing toxic side effects and saving patients lives.
Project Terms: Adverse effects; Aftercare; Animal Model; Animals; Antibodies; antibody conjugate; Antineoplastic Agents; arm; Autopsy; B-Lymphocytes; base; Binding; Bone Marrow; Cancer Biology; cancer cell; Cancer Patient; cancer therapy; Cause of Death; CD34 gene; Cell surface; Cells; chemotherapeutic agent; chemotherapy; Childhood; commercialization; Cytotoxic agent; Data; Documentation; Dose; Doxorubicin; Drops; Drug Formulations; Drug Kinetics; Drug toxicity; Drug usage; effective therapy; Encapsulated; Ewings sarcoma; Formulation; Frequencies; Funding; Gastrointestinal tract structure; Goals; Half-Life; Heart; high risk; Human; human model; humanized mouse; Hybrids; Implant; innovation; Intestines; irinotecan; Kidney; Late Effects; Liposomes; Liver; Malignant Neoplasms; Maximum Tolerated Dose; Methods; Mission; mouse model; Mus; nanoparticle; nanoparticle delivery; nanoparticle drug; Nanotechnology; Neoplasm Metastasis; neoplastic cell; Normal tissue morphology; novel; novel therapeutics; particle; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Polymers; pre-clinical; preclinical study; predicting response; prevent; Production; programs; Rare Diseases; Relapse; relapse patients; Research; Resistance; Safety; safety and feasibility; Salvage Therapy; sarcoma; Savings; SCID Mice; Small Business Innovation Research Grant; small molecule; Specificity; success; Survival Rate; System; Systemic Therapy; systemic toxicity; T-Lymphocyte; targeted treatment; Therapeutic; Tissues; Toxic effect; Translations; tumor; tumor ablation; Tumor Burden; tumor xenograft; uptake; Work; Xenograft procedure; young adult
