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Principal Investigator: Qiaobing Xu
Organization: TUFTS UNIVERSITY MEDFORD
Fiscal Year: 2022
Award: $348,007
Funding agency: National Institute of Biomedical Imaging and Bioengineering
PROJECT SUMMARY
Intracellular protein therapies are tremendously appealing, promising treatments for many heretofore untreatable
diseases, including genetic diseases and cancers. However, the safe, efficient intracellular delivery of proteins
remains a challenge. Here we propose the development of an effective cytoplasmic delivery strategy for
therapeutic proteins for cancer treatment: A combination of reversible chemical modification of proteins and
nanocomplexation with cationic lipid-based nanoparticles. The chemical modification will inactivate the cytotoxic
proteins, making them effectively nontoxic to normal cells. However, upon encountering increased level of
reactive oxygen species (ROS), i.e. inside the cancer cells, the modified chemical moiety will be cleaved and the
biological function of the proteins will be restored, resulting in cytotoxic action. Simultaneously, chemical
modification reduces the surface charge of proteins, leading to more efficient nanocomplexation and delivery by
bioreducible cationic lipid-like molecules. This protein delivery platform may thus serve as an efficient tumor-
specific targeting system for cancer treatment.
To accomplish the objective of this application, we propose the following three Specific Aims:
Specific Aim 1: ROS-responsive modification of saporin and its characterization. To develop an approach
for chemical modification of saporin, characterize the modification, and investigate the cleavage of the modified
moieties at elevated ROS levels.
Specific Aim 2: Intracellular delivery of saporin-NBC using synthetic lipids. To study a new class of
synthetic lipid-based nanoparticles for intracellular saporin-NBC delivery in both cancerous and non-cancerous
cells, and to study the synergistic effect of intracellular delivery of saporin-NBC and ROS-inducing anticancer
drugs in suppressing triple-negative breast cancer cells.
Specific Aim 3: Studying the in vivo saporin-NBC delivery in mouse breast cancer model.
To study the therapeutic efficacy of bioreducible lipids in delivering proteins to inhibit tumor growth in murine
breast cancer mouse models.
Terms: <4T1><Active Oxygen><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Arsenic (III) Oxide><Arsenic Sesquioxide><Arsenic Trioxide><Arsenous Acid Anhydride><Arsenous Oxide><Asotax><Behavior><Binding><Biodistribution><Biologic Products><Biological Agent><Biological Function><Biological Process><Biological Products><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast tumor model><Bristaxol><Cancer Drug><Cancer Treatment><Cancerous><Cancers><Carbonates><Cations><Cell Body><Cell Surface Receptors><Cells><Charge><Chemicals><Clinical Treatment Moab><Cytoplasm><Development><Disease><Disorder><Drug Kinetics><Electrostatics><Experimental Designs><Formulation><Genetic Diseases><Goals><Growth Agents><Growth Factor><Growth Substances><H2O2><Human><Hydrogen Peroxide><Hydroperoxide><Hydrophobicity><In Vitro><Intravenous><Libraries><Lipids><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measurement><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modern Man><Modification><Molecular Interaction><Monitor><Monoclonal Antibodies><Murine><Mus><Nature><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Normal Cell><Organ><Oxygen Radicals><Paclitaxel><Paclitaxel (Taxol)><Peptides><Pharmacokinetics><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Praxel><Pro-Oxidants><Property><Protein Modification><Proteins><Proteins Growth Factors><Reactive Oxygen Species><Scheme><Secondary Neoplasm><Secondary Tumor><Surface><System><TNBC><Tail><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic Studies><Therapy Research><Toxic effect><Toxicities><Treatment Efficacy><Tumor-Specific Treatment Agents><White Arsenic><anti-cancer drug><anti-cancer therapy><anticancer agent><anticancer drug><anticancer therapy><arsenous anhydride><base><biologics><biopharmaceutical><biotherapeutic agent><breast tumor cell><cancer cell><cancer metastasis><cancer therapy><cancer type><cancer-directed therapy><cytokine><cytotoxic><developmental><diarsenic trioxide><disulfide bond><genetic condition><genetic disorder><improved><in situ imaging><in vivo><intervention efficacy><lipid based nanoparticle><lipid nanoparticle><mAbs><malignancy><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor model><mouse model><murine model><nano complexes><nano formulation><nano particle><nano-sized particle><nanocomplexes><nanoformulation><nanoparticle><nanosized particle><native protein drug><neoplasm/cancer><novel><pharmaceutical protein><physical property><protein complex><protein drug agent><protein function><protein-based drug><public health relevance><refractory cancer><resistant cancer><side effect><site targeted delivery><small molecule><success><targeted cancer therapy><targeted delivery><therapeutic efficacy><therapeutic protein><therapy efficacy><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth>