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Principal Investigator: Jing Wen
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $281,781
Funding agency: National Cancer Institute
It is estimated that around 15% to 40% of cancers spread to the central nervous system (CNS). The treatment
of cancers with brain metastases, however, has been limited by the inefficient deliver of therapeutics to the CNS.
We propose herein a novel strategy, which enables effective delivery of monoclonal antibodies (mAbs), a class
of highly specific and potent protein therapeutics, to the CNS, for the treatment of cancers with brain metastases.
This strategy is based on a nano-encapsulating technology, where mAbs molecules are encapsulated within
nanocapsules of which the surface contains abundant choline and acetylcholine analogues. Such nanocapsules
can be effectively transported across the BBB and deliver the mAbs to the CNS upon systemic administration.
Furthermore, the nanocapsules can be targeted by conjugation with ligands which recognize cell surface markers
on tumor cells. We recently published effective delivery into the CNS of rituximab (anti-CD20) mAbs through
intravenous route using the nanocapsule technology. The nanocapsules were targeted to CXCR5 on the surface
of the tumor cells via conjugation with CXCL13. This therapeutic approach significantly reduced the tumor burden
in the brains of mice xenografted with B-cell lymphomas in comparison with direct native mAbs. In this proposal,
we will further improve the therapeutic efficacy by optimizing the design of the rituximab nanocapsules based on
understanding of the mechanisms of BBB passage and tumor clearance. Success of this project could potentially
enable effective delivery of many other therapeutic mAbs to the CNS, opening a new avenue for treatments of
cancers with CNS metastases.
Terms: <Acetylcholine><Address><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Antibodies><Antibody Therapy><B lymphoma><B-Cell Attracting Chemokine 1><B-Cell Lymphomas><B-Lymphocyte Chemoattractant><BBB crossing><BBB penetration><BCA1><BLC gene><BLC protein><BLR1><BLR1 gene><Binding><Biodistribution><Biologic Factor><Biological><Biological Factors><Biomedical Engineering><Blood - brain barrier anatomy><Blood-Brain Barrier><Brain><Brain Metastasis><Brain Nervous System><Breast Cancer><C2B8 Monoclonal Antibody><CNS Cancer><CNS Lymphoma><CNS Metastasis><CNS Nervous System><CNS Tumor><CNS neoplasm><CXCL13><CXCL13 gene><CXCR-5><CXCR5><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell surface><Cells><Central Nervous System><Central Nervous System Cancer><Central Nervous System Lymphoma><Central Nervous System Metastasis><Central Nervous System Neoplasms><Central Nervous System Tumors><Cerebrospinal Fluid><Chemical Engineering><Chemokine, CXC Motif, Ligand 13><Choline><Circulation><Clinical><Clinical Treatment Moab><Collaborations><Crosslinker><DNA><Data><Deoxyribonucleic Acid><Discipline><Disease><Disorder><Drug Kinetics><Drugs><Encapsulated><Encephalon><Environment><Failure><Formulation><Gene Delivery><Genes><Germinoblastic Sarcoma><Germinoblastoma><HER2 Monoclonal Antibody><Hemato-Encephalic Barrier><Herceptin><Heterograft><Heterologous Transplantation><History><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Situ><Individual><Intravenous><Intraventricular><Investigators><Leanness><Ligands><Lymphoma><MAb Therapeutics><MDR15><MabThera><Malignant Breast Neoplasm><Malignant CNS Neoplasms><Malignant Lymphoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the CNS><Malignant Tumor of the Central Nervous System><Malignant neoplasm of central nervous system><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Brain><Metastatic Neoplasm to the CNS><Metastatic Neoplasm to the Central Nervous System><Metastatic Tumor><Metastatic Tumor to the Brain><Metastatic Tumor to the CNS><Metastatic Tumor to the Central Nervous System><Metastatic malignant neoplasm to brain><Mice><Mice Mammals><MoAb HER2><Modeling><Molecular Interaction><Molecular Target><Monoclonal Antibodies><Monoclonal Antibody Therapy><Murine><Mus><Nanoplatform><Nanotechnological platform><Nanotechnology><Nature><Neoplasm Metastasis><Neuraxis><Non-Hodgkin's Lymphoma><Non-Polyadenylated RNA><Nonhodgkins Lymphoma><Oncology><Oncology Cancer><Pharmaceutical Preparations><Pharmacokinetics><Polymers><Position><Positioning Attribute><Property><Proteins><Publishing><RNA><RNA Gene Products><Reagent><Receptor Protein><Recording of previous events><Relapse><Reporting><Research Personnel><Researchers><Reticulolymphosarcoma><Ribonucleic Acid><Risk><Rituxan><Rodent><Rodentia><Rodents Mammals><Route><SCYB13><Secondary Neoplasm><Secondary Tumor><Small Inducible Cytokine Subfamily B, Member 13><Surface><Systemic disease><Technology><Therapeutic><Therapeutic Effect><Therapeutic Monoclonal Antibodies><Thinness><Time><Trastuzumab><Treatment Efficacy><Tumor Burden><Tumor Cell><Tumor Load><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><analog><anti-CD20><anti-cancer therapy><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><authority><bio-engineered><bio-engineers><bioengineering><biologic><biological engineering><blood-brain barrier crossing><blood-brain barrier penetration><bloodbrain barrier><bloodbrain barrier crossing><bloodbrain barrier penetration><brain micrometastasis><c-erb-2 Monoclonal Antibody><cancer metastasis><cancer of the central nervous system><cancer therapy><cancer-directed therapy><cerebral spinal fluid><chemical property><chemical substitution><choline analog><controlled release><design><designing><drug/agent><effective therapy><effective treatment><experience><histories><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><ineffective therapies><ineffective treatment><innovate><innovation><innovative><intervention efficacy><mAB-based therapy><mAb therapy><mAb-based therapeutics><mAbs><macromolecule><malignancy><malignant CNS lymphoma><malignant breast tumor><materials science><monoclonal Abs><monoclonal antibody drugs><monomer><nano tech><nano technology><nano-technological><nanocapsule><nanoencapsulated><nanoencapsulation><nanotech><nanotechnological><nanotechnology platform><native protein drug><neoplasm/cancer><neoplastic cell><neuron toxicity><neuronal toxicity><neuropathologic><neuropathological><neuropathology><neurotoxicity><new approaches><new technology><non-Hodgkins disease><non-human primate><nonhuman primate><novel><novel approaches><novel strategies><novel strategy><novel technologies><pharmaceutical protein><polymer><polymeric><polymerization><protein drug agent><protein-based drug><receptor><rhuMAb HER2><rituximab><site targeted delivery><spinal fluid><success><targeted delivery><therapeutic efficacy><therapeutic evaluation><therapeutic mAbs><therapeutic protein><therapeutic testing><therapy efficacy><tumor><tumor cell metastasis><tumor growth><tumors in the central nervous system><virtual><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>