Multifunctional Nanotechnology Platform for Triple Negative Breast Cancer Treatment

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: EMMANUEL O AKALA
Organization: HOWARD UNIVERSITY
Fiscal Year: 2024
Award: $154,500
Funding agency: National Institute of General Medical Sciences

Project Summary: Triple-negative breast cancer (TNBC) accounts for approximately 15% of invasive breast
cancers and is associated with aggressive tumor biology, poor prognosis, resistance, visceral metastases and
earlier disease recurrence. TNBC is more common in younger women than in older women and in African-
American and Hispanic women. Platinum-based drugs showed higher sensitivity in TNBC compared to non-
TNBC patients and recently there has been a renewed interest for platinum therapy in TNBC, especially
combination of carboplatin with paclitaxel (PTX). Sacituzumab govitecan is made up of an anti–Trop-2 antibody
linked to the chemotherapy drug (SN-38) and was cleared by the FDA for TNBC patients who have
undergone at least two prior chemotherapies. The FDA granted an accelerated approval for the
immunotherapy drug atezolizumab in combination with chemotherapy (nab-paclitaxel) for the treatment of
TNBC (for tumors positive for PD-L1). Thus chemotherapy is important in the therapeutic management of
TNBC even in the advent of immunotherapy and targeted therapy. However, chemotherapies are known
to cause fatal peripheral neuropathy in addition to poor response, metastasis, relapse and development of
multidrug resistance. The goal of this application is the development of multifunctional targeted nanoparticles
capable of achieving better outcomes for TNBC patients: (a) targeted delivery of large doses of multiple drugs
into cancer cells (per a single biorecognition event compared to a single immunotargeted drug (e.g.
sacituzumab govitecan-hziy)) to maximize therapeutic effects while reducing systemic toxicity (off target
toxicity); (b) EGFR-receptor targeted nanoparticles that promote intracellular drug delivery and release and
which can bypass multidrug resistant protein (p-glycoprotein) which mediates efflux of drug molecules; (c)
capable of long circulation without being sequestered into the liver. EGFR is overexpressed by TNBC and
literature is replete with examples of the use of cetuximab in therapy by targeting EFGR. We hypothesize that
the development of biodegradable polymeric nanotechnology platform containing carboplatin and paclitaxel
in the core and using cetuximab (tagged on nanoparticle surface) as a targeting moiety will improve TNBC
patients’ outcomes, unlike repeated chemotherapy cycles with high doses of cytotoxic drugs. We hypothesize
that the dual-loaded multifunctional targeted nanoparticles will be active in vitro and show in vivo efficacy in
mouse xenograft models of TNBC positive tumors. Aim #1: Fabrication of polymeric dye-loaded and-paclitaxel
and carboplatin-loaded stealth hydrolysable crosslinked cetuximab surface-targeted polylactide (PLL)
nanoparticles. Aim #2: Characterization of anti-EGFR mAb (cetuximab) surface-targeted-PLL-nanoparticles
containing carboplatin and paclitaxel in the core. Aim #3: Biodistribution and efficacy studies in tumor-bearing
mice. This work will bring to bear the combined power of chemotherapeutic agents, molecular targeted therapy
and nanotechnology to overcome EGFR positive TNBC resistance and improve efficacy with minimal toxicity.

Terms: <ABC20><ABCB1><ABCB1 gene><Abraxane><Acceleration><Adjuvant><African American><Afro American><Afroamerican><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Antibodies><Anzatax><Asotax><Athymic Mice><Athymic Nude Mouse><B7-H1><B7H1><Biodistribution><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Cancer Treatment><Breast Cancer cell line><Breast Tumor Patient><Breast tumor cell line><Bristaxol><Bypass><CBDCA><CD274><Carboplatin><Carboplatino><Cell Body><Cells><Cetuximab><Circulation><Clinic><Clinical Research><Clinical Study><Clinical Treatment Moab><Coloring Agents><Combination Drug Therapy><Confocal Microscopy><Coupled><Cytotoxic agent><Cytotoxic drug><Data Reporting><Development><Disease><Disorder><Dose><Drug Combinations><Drug Delivery><Drug Delivery Systems><Drug Efflux><Drug Kinetics><Drugs><Dyes><EGF Receptor><EGFR><ERBB Protein><ERBB2><ERBB2 gene><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Ethnic Group><Ethnic People><Ethnic Population><Ethnic individual><Ethnicity People><Ethnicity Population><Event><FDA approved><Female><Fluorescence Agents><Fluorescent Agents><Fluorescent Dyes><GP170><Goals><Grant><HER -2><HER-2><HER1><HER2><HER2 Genes><HER2/neu><Hispanic Females><Hispanic Women><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Implant><In Vitro><In complete remission><Induction Therapy><Label><Link><Literature><Liver><Loss of Sensation><Lytotoxicity><MDA MB 231><MDA-231><MDA-MB231><MDR-1><MDR1><MDR1 Protein><Malignant Breast Neoplasm><Malignant Cell><Mediating><Medical><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Molecular><Monoclonal Antibodies><Morphology><Multi-Drug Resistance><Multidrug Resistance><Multidrug Resistance 1><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Proteins><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><NEOADJ><NEU Oncogene><NEU protein><Nanoplatform><Nanotechnological platform><Nanotechnology><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><Nude Mice><Numbness><Oncogene ErbB2><Outcome><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><PD-L1><PDL-1><PDL1><PGY-1 Protein><PGY1><PNS Diseases><Paclitaxel><Paclitaxel (Taxol)><Pain><Painful><Particle Size><Pathologic><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peripheral Nerve Diseases><Peripheral Nervous System Diseases><Peripheral Nervous System Disorders><Peripheral Neuropathy><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phase><Platinum><Platinum Black><Polychemotherapy><Polymers><Praxel><Prior Chemotherapy><Prior Chemotherapy Regimens><Prognosis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><Pt element><Racial Group><Receptor Protein><Recurrent disease><Regimen><Relapse><Relapsed Disease><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Rhodamine 123><SN-38><Secondary Neoplasm><Secondary Tumor><Site><Spinal Column><Spine><Structure><Surface><TGF-alpha Receptor><TKR1><TNBC><Taxol><Taxol A><Taxol Konzentrat><Therapeutic><Therapeutic Effect><Time><Toxic effect><Toxicities><Transforming Growth Factor alpha Receptor><Tumor Biology><Urogastrone Receptor><Vertebral column><Visceral metastasis><Woman><Work><Xenograft Model><antibody conjugate><backbone><biodegradable polymer><bioresorbable polymer><breast tumor cell><c-erbB-1><c-erbB-1 Protein><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer metastasis><chemotherapeutic agent><chemotherapy><combination chemotherapy><combination pharmacotherapy><complete response><crosslink><cytotoxicity><data representation><data representations><degradable polymer><determine efficacy><developmental><drug efficacy><drug release kinetics><drug release rate><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><erbB-1><erbB-1 Proto-Oncogene Protein><erbB-2 Genes><erbBl><ethnic subgroup><ethnicity group><evaluate efficacy><examine efficacy><fabrication><fluorescent dye/probe><hepatic body system><hepatic organ system><herstatin><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vivo><induction therapies><interest><mAbs><malignant breast tumor><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><monoclonal Abs><multi-drug resistant><multidrug resistant><nano particle><nano polymer><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanopolymer><nanosized particle><nanotech><nanotechnological><nanotechnology platform><neu Genes><older women><overexpress><overexpression><patient oriented outcomes><poly(lactide)><polylactide><polymer><polymeric><prevent><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><proto-oncogene protein c-erbB-1><racial population><racial subgroup><receptor><resistant><response><site targeted delivery><standard of care><subcutaneous><subdermal><systemic toxicity><targeted agent><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><taxane><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><xenograft transplant model><xenotransplant model><young woman><zeta potential>