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Principal Investigator: Jeff W. Bulte
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $519,965
Funding agency: National Institute of Biomedical Imaging and Bioengineering
Our overall aim is to develop a precision-based nanotheranostic platform where the imaging signal may
serve as an early predictive imaging biomarker for intracellular nanoparticle accumulation and therapeutic
response. New anti-cancer agents continue to be developed, but many fail due to the tumor developing (multi-)
drug resistance. Cellular membrane proteins acting as a drug efflux pump have been identified, and while
some promising agents enter tumor cells, they cannot always be retained long enough to be effective. We aim
to exploit the enzyme legumain (an asparaginyl endopeptidase) that is overexpressed in prostate cancer cells
for specific cleavage of an olsalazine (Olsa)-conjugated peptide substrate, following which the substrate self-
assembles into intracellular nanoparticles. This enzyme-driven self-assembly serves several purposes: 1)
intracellular entrapment with minimal drug efflux; 2) prolonged tumor drug exposure; and 3) minimal toxicity to
normal organs due to rapid blood clearance of non-assembled single molecules. We have preliminary data
demonstrating this concept to be feasible in vivo. Since it does not only serve as an anti-cancer drug through
inhibition of DNA methylation, but also as a non-metallic, label-free contrast agent for chemical exchange
saturation transfer magnetic resonance imaging (CEST MRI), olsalazine is a unique theranostic agent. The
drug can be visualized without modification, allowing direct imaging without pharmacological alterations that
may affect self-assembly and/or biodistribution. Following in vitro selection of an optimal Olsa-CBT-800CW-Rn-
AAN substrate with maximum tumor cell penetration and retention in legumain-overexpressing DU145 cells
(Aim 1), we will test this compound for its in vivo nanotheranostic properties in an orthotopic mouse prostate
tumor model (Aim 2) and a transgenic mouse model (TRAMP mouse) where normal prostate cells undergo a
malignant transformation over time (Aim 3). If successful, this approach may be extended to other enzyme-
targeted CEST MRI-detectable theranostic platforms for imaging tumor aggressiveness, drug accumulation,
and predicting therapeutic response.
Terms: <2-Hydroxybenzoic Acid><Acetylsalicylic Acid><Affect><Anti-Cancer Agents><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Arginine><Aspirin><Biodistribution><Blood><Blood Reticuloendothelial System><Cancer Drug><Cancers><Caspase><Caspase Gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell division><Cell membrane><Cell-Death Protease><Cells><Cellular Membrane><Chemical Agents><Chemicals><Colon Cancer><Colon Carcinoma><Contrast Agent><Contrast Drugs><Contrast Media><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Cytoplasmic Membrane><DNA Methylation><DNA Methylation Inhibition><DU-145><DU145><Data><Detection><Drug Efflux><Drug Exposure><Drug resistance><Drugs><Enzyme Gene><Enzymes><FDA approved><Failure><Formulation><Glutathione><Goals><H+ element><Hour><Human><Hydrogen Ions><Hydroxyl><Hydroxyl Radical><ICE-like protease><Image><Image Enhancement><In Vitro><Injectable><Intracellular Communication and Signaling><Intravenous><Kidney><Kidney Urinary System><L-Arginine><LNCaP><Label><Length><Liver><MR Imaging><MR Tomography><MRI><MRI Scans><MRIs><Magnetic Resonance Imaging><Magnetic Resonance Imaging Scan><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measurement><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Modeling><Modern Man><Modification><Murine><Mus><NIR dye><NIR imaging><NIR optical imaging><NMR Imaging><NMR Tomography><Nanostructures><Near-infrared Fluorescence Imaging><Near-infrared optical imaging><Neoplastic Disease Chemotherapeutic Agents><Nuclear Magnetic Resonance Imaging><Optics><Organ><Penetration><Peptides><Permeability><Pharmaceutical Preparations><Physical condensation><Plasma Membrane><Prediction of Response to Therapy><Property><Proprotein Convertases><Prostate><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Gland><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Protons><Radiopaque Media><Reaction><Salicylic Acids><Signal Transduction><Signal Transduction Systems><Signaling><Spleen><Spleen Reticuloendothelial System><Surface Proteins><TRAMP mouse><Testing><Therapeutic><Time><Toxic effect><Toxicities><Transgenic Mice><Treatment Efficacy><Tumor Cell><Tumor-Specific Treatment Agents><Validation><Visualization><Xenograft Model><Zeugmatography><anti-cancer drug><asparaginyl endopeptidase><asparaginylendopeptidase><biocompatibility><biological signal transduction><biomaterial compatibility><cancer cell><cancer imaging><cancer in the colon><chemical reaction><clinical relevance><clinical translation><clinically relevant><clinically translatable><condensation><contrast enhanced><cystein protease><cystein proteinase><cysteine endopeptidase><drug resistant><drug/agent><efflux pump><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><hepatic body system><hepatic organ system><imaging><imaging biomarker><imaging marker><imaging platform><imaging-based biological marker><imaging-based biomarker><imaging-based marker><in vivo><inhibitor><intervention efficacy><legumain><malignancy><mouse model><murine model><nano formulation><nano particle><nano-sized particle><nano-sized structures><nano-structures><nano-theranostics><nanoformulation><nanoparticle><nanosized particle><nanotheranostics><near IR dye><near infrared dye><near infrared imaging><neoplasm/cancer><neoplastic cell><new anti-cancer agent><new anticancer agent><new anticancer drug><new antineoplastic><new cancer drug><novel><novel anti-cancer agent><novel anti-cancer drug><novel anticancer agent><novel anticancer drug><novel antineoplastic><novel cancer drug><o-Hydroxybenzoic Acid><oncologic imaging><oncology imaging><optical><ortho-Hydroxybenzoic Acid><overexpress><overexpression><peptide aminoacid sequence><peptide sequence><pharmacologic><plasmalemma><predict therapeutic response><predict therapy response><prognostic><prostate cancer cell><prostate cancer cell line><prostate cancer model><prostate cancer treatment><prostate tumor cell><prostate tumor model><protein aminoacid sequence><renal><resistance to Drug><resistant to Drug><response to therapy><response to treatment><salicylate><self assembly><single molecule><small molecule><subcutaneous><subdermal><success><theranostics><therapeutic efficacy><therapeutic response><therapy efficacy><therapy prediction><therapy response><transgenic adenocarcinoma of mouse prostate><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><tumor><tumor growth><tumor imaging><tumor initiation><uptake><validations><xenograft transplant model><xenotransplant model>