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Principal Investigator: Irina V Balyasnikova
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $533,757
Funding agency: National Cancer Institute
Project Abstract
Glioblastoma (GBM) is the most devastating and aggressive brain tumor in adults, with patients surviving a
median of only 14.6 months. Hidden behind the blood-brain and blood tumor-barrier (BBTB), the glioma cells
migrating away from the tumor and invading surrounding brain tissue, are the source of recurrence. The
invasive cells are not readily accessible to most drug therapeutics, and targeting these cells is an essential
goal for achieving better treatment outcomes. Nanoparticles hold promise for drug delivery, but their
penetration of the BBTB is limited, and the efficiency of targeting invasive cells remains unknown. We recently
discovered that fluorescent indocarbocyanine lipids (ICLs) formulated in PEGylated Lipid Nanoparticles (PLNs)
exhibit highly efficient glioma extravasation, with a single injection resulting in accumulation in ~60% of tumor
cells and up to 30% of injected dose per gram of brain tumor. Furthermore, data in highly invasive models
demonstrate PLNs reach invasive cells at the tumor/brain margin. These findings offer a unique opportunity to
comprehensively understand the mechanism of accumulation of lipid nanoparticles and improve drug delivery
to invasive gliomas. We will pursue the following specific aims: 1) Study the trafficking mechanism of ICLs
across the BBTB and in tumors. In this aim, we will test the hypothesis that lipids migrate in tumors via
extracellular vesicles; 2) Understand the role of lipid structure and formulation in targeting glioma cells
and the tumor immune microenvironment. This aim will test if accumulation in invasive cells and
immunosuppressive cells can be further improved through lipid chemistry, formulation and targeting to glioma
marker IL13R2; 3) Exploit ICLs to understand and improve small molecule delivery to invasive
gliomas. We will explore our previously developed chemistry to conjugate small molecules to ICLs to improve
their delivery, drug release, and therapeutic efficacy of cyclin-dependent kinase inhibitor dinaciclib in invasive
mouse and patient-derived glioma models. These studies will expand our understanding of the drug delivery
process and guide treatment of invasive gliomas with brain tumor-penetrating nanomedicine.
Terms: <21+ years old><Abbreviations><Adult><Adult Human><Animals><Antibodies><Antigens><Apoptosis><Apoptosis Pathway><Biodistribution><Blood><Blood Reticuloendothelial System><Blood Vessels><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CDK Inhibitor Protein><CDKI Protein><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cells><Cellular Migration><Cellular Motility><Chemistry><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cyclin Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor><Cyclin-Dependent Kinases><Cyclin-Dependent Protein Kinases><Data><Dextrans><Diffusion><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Precursors><Drug Therapy><Drugs><Encephalon><Endocytosis><Endothelial Cells><Endothelium><Exhibits><Exocytosis><Extravasation><FLIM imaging><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formulation><Foundations><GEM model><GEMM model><Genetically Engineered Mouse><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Image><In Situ><In Vitro><Injections><Invaded><Leakage><Libraries><Ligands><Lipid Chemistry><Lipids><Liposomal><Liposomes><Mediating><Medication><Mice><Mice Mammals><Modeling><Murine><Mus><Myeloid Cells><Neuroglial Neoplasm><Neuroglial Tumor><Organoids><Pathway interactions><Patients><Penetration><Perfusion><Pharmaceutical Preparations><Pharmacokinetics><Pharmacotherapy><Phosphatides><Phospholipids><Population><Pro-Drugs><Process><Prodrugs><Programmed Cell Death><Radiation therapy><Radiotherapeutics><Radiotherapy><Recurrence><Recurrent><Reporting><Resistance><Role><Solid Neoplasm><Solid Tumor><Source><Specificity><Spillage><Structure><Testing><Therapeutic><Treatment Efficacy><Treatment outcome><Tumor Cell><adulthood><blood-brain tumor barrier><blood-tumor barrier><bloodbrain tumor barrier><brain tissue><cdk Proteins><cell motility><clinical translation><clinically translatable><delivery vector><delivery vehicle><dextran><diffused><diffuses><diffusing><diffusions><drug treatment><drug/agent><extracellular vesicles><flow cytophotometry><fluorescence life-time imaging><fluorescence life-time imaging microscopy><fluorescence lifetime imaging><fluorescence lifetime imaging microscopy><fluorophore><genetically engineered mouse model><genetically engineered murine model><glial-derived tumor><glioblastoma multiforme><imaging><immune microenvironment><immunogen><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><inhibitor><innovate><innovation><innovative><intervention efficacy><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><lipid structure><lipophilicity><migration><nano formulation><nano medicinal><nano medicine><nano particle><nano particle delivery><nano-sized particle><nanoformulation><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neoplastic cell><neuroglia neoplasm><neuroglia tumor><new approaches><novel><novel approaches><novel strategies><novel strategy><particle><pathway><radiation treatment><resistant><small molecule><social role><spatiotemporal><spongioblastoma multiforme><success><therapeutic efficacy><therapy efficacy><tool><trafficking><transcytosis><treatment with radiation><tumor><tumor immune microenvironment><tumor-immune system interactions><tumors in the brain><uptake><vascular>