Glioblastoma is the most common and aggressive malignant brain tumor with extremely poor prognosis. Current standard care for glioblastoma treatment consists of maximal surgical resection followed by chemotherapy and radiation therapy. Unfortunately, it hardly produces long-term control on tumor progression. Due to the highly heterogeneous, infiltrating and recurring natures of glioblastomas, chemotherapy plays a crucial role in clinical management of glioblastomas. However, existing chemotherapies in brain tumor treatment are mostly disappointing, often due to poor delivery of chemotherapy agents stemming from their low water solubility and/or inability of crossing the blood brain barrier (BBB) or blood tumor barrier (BTB). Although nanomaterial-based drug delivery systems have shown advantages by enhancing the delivery efficiency and improving the safety profile of therapeutics over conventional chemotherapy formulations in treating many cancers, their development and applications in brain tumor treatment are largely limited, because of delivery challenges in current nano-delivery systems with sizes of 10-200 nm. Supported by the premises that: 1) ferumoxytol (Feraheme®), an FDA approved iron oxide nanoparticle for treating iron deficiency anemia, can be used for imaging brain tumor with magnetic resonance imaging (MRI) in patients, and 2) our sub-5 nm ultrafine iron oxide nanoparticle (uIONP) can reach brain tumors in the intracranial glioma mouse model to enhance tumors in MRI with T1 contrast, this STTR Phase I project aims to develop a new class of drug-carrying and glioblastoma targeted IONP for delivering highly potent yet water-insoluble chemotherapy agent SN38, the active and much more potent form of chemotherapy agent Irinotecan (CPT-11) used in treating many other cancers in oncology clinic, for treating intracranial brain tumors. We will incorporate our patented amphiphilic poly(ethylene glycol)-block-(allyl glycidyl ether) (PEG-b-AGE) coating polymer for uIONPs to encapsulate hydrophobic SN38, which has not been used for treating brain tumors due to poor intracranial delivery. Tri-peptide RGD with well-documented functions and safety profile is selected as the ligand for functionalizing uIONPs to target ?v?3 integrin overexpressed in glioblastomas. In the proposed project, we will prepare and optimize the RGD-conjugated uIONP with SN38 loading (RGD-uIONP/SN38) with consistent physiochemical and biological properties, including SN38 loading efficiency, surface charge, density of conjugated the targeting ligand, glioblastoma cell targeting, intracellular drug release and cytotoxicity, and stability (Aim 1). We will then use an intracranial mouse model to investigate the blood half-life, biodistribution, clearance, and tumor uptake and intra-tumoral distribution of developed RGD-uIONP/SN38 as well as the stability of this platform in blood and organs in Aim 2, followed by determining the efficacy of RGD- uIONP/SN38 in inhibiting the tumor growth based on MRI in vivo and histopathological analysis. The results will lead to the further development of this system towards clinical translation in the Phase II project. Public Health Relevance Statement PROJECT NARRATIVE Effectively delivering chemotherapeutics to malignant and infiltrative brain tumors remains the one of the biggest obstacles in current clinical oncology due to the challenges in delivering therapeutics to the intracranial tumors. The goal of this Phase I STTR project is to develop a sub-5 nm nanocarrier capable of delivering highly potent yet water-insoluble chemotherapy agent to treat glioblastoma, the most common type of brain tumors. The successful development will lead to further efficacy assessment in the Phase II project towards potential clinical translation.
Project Terms: Blood ; Blood Reticuloendothelial System ; Blood Circulation ; Bloodstream ; Circulation ; Brain Neoplasms ; Brain Neoplasia ; Brain Tumors ; tumors in the brain ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Charge ; Chemistry ; Combination Drug Therapy ; Polychemotherapy ; combination chemotherapy ; combination pharmacotherapy ; combined drug therapy ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; ethylene glycol ; 1,2-Ethanediol ; 2-Hydroxyethanol ; Dihydroxyethanes ; Ethanediols ; Ethylene Glycols ; Monoethylene Glycol ; Glioblastoma ; Grade IV Astrocytic Neoplasm ; Grade IV Astrocytic Tumor ; Grade IV Astrocytoma ; glioblastoma multiforme ; spongioblastoma multiforme ; Glioma ; Glial Cell Tumors ; Glial Neoplasm ; Glial Tumor ; Neuroglial Neoplasm ; Neuroglial Tumor ; glial-derived tumor ; neuroglia neoplasm ; neuroglia tumor ; Goals ; Half-Life ; In Vitro ; Integrins ; Integrins Extracellular Matrix ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Ligands ; Liposomes ; Liposomal ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Legal patent ; Patents ; Patients ; Cyclic Peptides ; Drug Kinetics ; Pharmacokinetics ; Play ; Polymers ; Radiation therapy ; Radiotherapeutics ; Radiotherapy ; radiation treatment ; radio-therapy ; treatment with radiation ; Role ; social role ; Safety ; Technology ; Tissues ; Body Tissues ; Universities ; Water ; Hydrogen Oxide ; RGD (sequence) ; Arg-Gly-Asp ; Arginine-Glycine-Aspartic Acid Cell Adhesion Domain ; RGD Cell Adhesion Domain ; RGD Domain ; RGD Motif ; RGD Tripeptide Sequence ; RGD peptide ; RGD tripeptide ; arginyl-glycyl-aspartic acid ; glycidyl ethers ; Ultrafine ; Drug Delivery Systems ; Drug Delivery ; irinotecan ; Campto ; camptosar ; Malignant neoplasm of brain ; Brain Cancer ; Malignant Tumor of the Brain ; Iron deficiency anemia ; analytical method ; base ; density ; Organ ; tumor progression ; cancer progression ; neoplasm progression ; neoplastic progression ; improved ; Surface ; Clinical ; Encapsulated ; Malignant - descriptor ; Malignant ; Phase ; Biological ; uptake ; chemical property ; Oncology ; Oncology Cancer ; Therapeutic ; Therapeutic Agents ; Morphology ; Malignant Cell ; cancer cell ; Nature ; Investigation ; Clinic ; subdermal ; subcutaneous ; System ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; amphiphilicity ; biocompatibility ; biomaterial compatibility ; Lytotoxicity ; cytotoxicity ; physical property ; success ; water solubility ; Hydrophobicity ; tumor growth ; Toxicities ; Toxic effect ; Reporting ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; chemotherapeutic agent ; Property ; Integrin aVBeta3 ; Integrin alpha-v beta-3 ; Integrin αVβ3 ; aVBeta3 ; alpha-v beta-3 Integrin Receptors ; Integrin alphaVbeta3 ; Clinical Oncology ; image-based method ; imaging method ; imaging modality ; preventing ; prevent ; nano medicinal ; nano medicine ; nanomedicinal ; nanomedicine ; Feraheme ; ferumoxytol ; Reproducibility ; in vivo ; Clinical Management ; Small Business Technology Transfer Research ; STTR ; Preparation ; Development ; developmental ; Intracranial Neoplasms ; Intracranial Central Nervous System Neoplasms ; Intracranial Central Nervous System Tumors ; Intracranial Tumor ; efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; nanomaterials ; nano materials ; nanocarrier ; nano carrier ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Biodistribution ; Outcome ; targeted delivery ; site targeted delivery ; chemotherapy ; mouse model ; murine model ; stem ; tumor ; overexpression ; overexpress ; FDA approved ; standard care ; standard treatment ; Systems Development ; theranostics ; Drug Targeting ; in vivo imaging ; imaging in vivo ; contrast enhanced ; Magnetic nanoparticles ; contrast imaging ; targeted biomarker ; Formulation ; novel drug class ; new drug class ; clinical translation ; nanoparticle delivery ; nano particle delivery ; nanoparticle delivered ; Nano delivery ; Nanodelivery ; iron oxide nanoparticle ; iron oxide nano particle ; side effect ; pharmacokinetics and pharmacodynamics ; PK/PD ; Chemotherapy and/or radiation ; Chemotherapy and Radiation ; blood-brain tumor barrier ; blood-tumor barrier ; bloodbrain tumor barrier ; blood-brain barrier crossing ; BBB crossing ; bloodbrain barrier crossing ; brain tumor imaging ; therapeutically effective ; Prognosis ;
