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Principal Investigator: Tamara Minko
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2023
Award: $581,249
Funding agency: National Cancer Institute
Project Title: Bio-nanotechnology approach for treatment of lung cancer
Project Summary
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small Cell Lung Carcinoma
(NSCLC) is the most common type of lung cancer, accounting for more than 80% of all lung cancer cases.
Chemotherapy is the primary pre-operative and post-operative treatment of NSCLC. However, the efficiency of
chemotherapy remains relatively low in most patients and is limited by insufficient specificity, low drug
accumulation, and retention in the lungs with severe adverse side effects of treatment. Recently, small
molecule Tyrosine Kinase (TK) inhibitors which act on the Epidermal Growth Factor Receptors (EGFRs) were
introduced for treatment of NSCLC. However, even the latest generation of EGFR inhibitors cause severe
systemic toxicities and are ineffective in preventing non-canonical EGFR signaling. As a result, only
approximately 10% of patients with NSCLC benefit from this therapy. In order to overcome these limitations, a
novel multi-tier biotechnology treatment approach is proposed that includes: (1) suppression of all four types of
EGFR-TKs by a pool of small interfering RNAs (siRNAs); (2) induction of cell death by an anticancer drug, (3)
enhancing the efficiency of the treatment by the local inhalatory delivery of therapeutic agents to the lungs
(passive targeting), (4) active receptor-mediated targeting of the therapy specifically to cancer cells and (5)
increasing the stability, solubility, and cellular penetration of siRNA and drug by using Nanostructured Lipid
Carriers (NLC). We hypothesize that the application of this nanotechnology-based tumor-targeted,
multifunctional approach will substantially enhance the efficiency of the treatment of NSCLC and
reduce adverse side effects of chemotherapy. The main objective of the current research is to test the
stated hypothesis and develop a novel nanoscale-based technology to carry out proof-of-concept of the
proposed strategy. The specific aims of the proposed research are: (1) to engineer, synthesize, and
characterize a multifunctional, multicomponent Delivery System (DS) containing NLC, a pool of siRNAs
targeted to EGFR-TKs, paclitaxel (TAX) as an anticancer drug, and a Luteinizing Hormone-Releasing
Hormone (LHRH) peptide as a targeting moiety specific to receptors overexpressed in lung cancer cells; (2) to
examine efficiency of active (LHRH receptor-mediated) and passive (local inhalation delivery) dual tumor
targeting of NLC-based DS; (3) to characterize the efficiency of combinatorial gene and chemotherapy for
silencing of EGFR-TK signaling pathways and cell death induction; (4) to evaluate in vivo antitumor activity and
adverse side effects of targeted and non-targeted NLC-based DS in clinically relevant orthotopic mouse
models of primary human NSCLC xenografts. It is expected that the proposed approach and the use of the
developed multifunctional NLC-based DS will substantially enhance the efficiency of therapy of NSCLC and
limit adverse side effects of the treatment. Experimental data obtained will provide the proof-of-concept of the
proposed approach, and can potentially make a considerable impact on the field of drug delivery and improve
the efficiency of therapy for lung and other types of cancer.
Terms: <Abscission><Accounting><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Asotax><Biotech><Biotechnology><Blood Serum><Breast Cancer><Bristaxol><Buffers><Cancer Cause><Cancer Drug><Cancer Etiology><Cancers><Cell Communication and Signaling><Cell Death Induction><Cell Growth in Number><Cell Isolation><Cell Line><Cell Multiplication><Cell Proliferation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><CellLine><Cellular Proliferation><Cessation of life><Charge><Colon Cancer><Colon Carcinoma><DNA Therapy><Data><Death><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Targeting><Drug resistance><Drug usage><Drugs><EGF Receptor><EGFR><EGFR Blocker><EGFR Inhibitor><EGFR Tyrosine Kinase Inhibitor><EGFR-TK Inhibitor><ERBB Protein><Engineering><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Inhibitor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor><Epidermal Growth Factor-Urogastrone Receptors><Excision><Extirpation><Follicle Stimulating Hormone-Releasing Hormone Receptors><GNRH><GNRH1><GNRH1 gene><Gene Expression><Gene Transfer Clinical><Generations><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><GnRH Receptors><Gonadoliberin Receptors><Gonadorelin Receptors><Gonadotropin Releasing Hormone 1><Gonadotropin-Releasing Hormone Receptor><HER1><Heterograft><Heterologous Transplantation><Histology><Human><Immune response><Immunodeficient Mouse><Immunological response><In Vitro><Induction of Apoptosis><Inhalation><Inhaling><Intracellular Communication and Signaling><Intravenous><Invaded><LHRH Receptors><LNRH><Length of Life><Longevity><Luliberin Receptors><Lung><Lung Respiratory System><Luteinizing Hormone Releasing-Hormone Receptor><Luteinizing Hormone-Releasing Hormone><Lytotoxicity><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Prostate><Malignant neoplasm of lung><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Nanostructures><Nanotechnology><Nebulizer><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Normal Tissue><Normal tissue morphology><Operative Procedures><Operative Surgical Procedures><Organ><PTK Inhibitors><PTK Receptors><Paclitaxel><Paclitaxel (Taxol)><Patients><Penetration><Peptide Hormone Gene><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Post-Operative><Postoperative><Postoperative Period><Praxel><Primary Neoplasm><Primary Tumor><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protein Tyrosine Kinase Inhibitors><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Signaling><Receptor Tyrosine Kinase Gene><Removal><Research><Resistance><Secondary Neoplasm><Secondary Tumor><Serum><Shapes><Short interfering RNA><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Solubility><Specificity><Strains Cell Lines><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><TGF-alpha Receptor><TK Inhibitors><Taxol><Taxol A><Taxol Konzentrat><Technology><Testing><Therapeutic><Therapeutic Agents><Transforming Growth Factor alpha Receptor><Transmembrane Receptor Protein Tyrosine Kinase><Treatment Effectiveness><Treatment Efficacy><Treatment Side Effects><Treatment-related side effects><Tumor Cell><Tumor Tissue><Tumor-Specific Treatment Agents><Tyrosine Kinase Inhibitor><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><United States><Urogastrone Receptor><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer drug><anticancer agent><anticancer drug><biological signal transduction><bionano technology><bionanotechnology><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer in the colon><cancer metastasis><cancer type><cell sorting><chemotherapy><clinical relevance><clinically relevant><combination gene therapy><combinatorial><cultured cell line><cytotoxicity><drug resistant><drug use><drug/agent><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><established cell line><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genome mutation><genomic therapy><genotoxicity><host response><human model><immune system response><immunoresponse><improved><in vivo><innovate><innovation><innovative><intervention efficacy><life span><lifespan><lung Carcinoma><lung cancer><lung cancer cell><malignancy><malignant breast neoplasm><malignant breast tumor><model of human><molecular mass><mouse model><murine model><nano biotechnology><nano meter scale><nano meter sized><nano particle><nano scale><nano tech><nano technology><nano-sized particle><nano-sized structures><nano-structures><nano-technological><nanobiotechnology><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><nanotech><nanotechnological><nebulization><nebulize><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><particle><peptide hormone><prevent><preventing><proto-oncogene protein c-erbB-1><pulmonary><receptor><resection><resistance to Drug><resistant><resistant to Drug><response to therapy><response to treatment><siRNA><side effect><site targeted delivery><small molecule><structured lipid><surgery><systemic toxicity><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic response><therapy efficacy><therapy response><treatment response><tumor><tumor cell metastasis><xeno-transplant><xeno-transplantation>