Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Patients with recurrent or metastatic HNSCC have a median overall survival of 10 months. Even with intensive surgery, radiotherapy and chemotherapy, the prognosis is still dismal. Completely removal (negative surgical margin) with surgery is the goal of the treatment, but it is difficult to achieve due to the infiltration of vital structures. Since positive surgery margin is associated with poor prognosis, there is a great need to develop novel treatments which could not only guide the surgery but also destroy the residual tumors while sparing important normal functions. Moreover, development of theranostic agents that can detect and eliminate early HNSCC lesions, particularly the aggressive sub-types, will have tremendous impact in many patients with HNSCC. We recently developed a set of highly innovative Transformable Nano-Theranostics (TNTs) that possess outstanding capability to circumvent the sequential biological barriers which have generally hindered drug delivery to tumors including oral squamous cell carcinoma (OSCC), the most common HNSCC worldwide. We have demonstrated that 1) the smart dual size/charge- transformation of TNTs in response to ubiquitous hallmarks of tumors (e.g. tumor acidosis induced acidic extracellular pH, pHe) could dramatically increase the tumor accumulation and penetration of TNTs in oral cancer tissue, and facilitate uptake in cancer cells; 2) TNTs enabled effective visualization of tumor, drug delivery and therapeutic effect by magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIRFI); 3) the synergistic trimodal therapy via TNTs achieved a 100% complete cure rate in orthotopic oral cancer mouse models. These highly encouraging data suggest that such nano-platform can be translated into early detection and elimination of HNSCC lesions, which are readily accessible to illumination with light. The overall goal of this Phase I SBIR proposal is to develop highly effective, non-toxic yet easy-to-make TNTs for precision image-guided intervention of HNSCC in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to the FDA. We will integrate a series of ultrasensitive, pHe-cleavable crosslinkers on the surface of TNTs to further optimize their plasma stability, and their capability to effectively target tumor acidosis which would trigger the smart size/charge transformation to significantly improve imaging sensitivity and drug delivery efficiency. These strategies will ultimately enhance their capability to detect and eliminate early HNSCC lesions. Our long-term goal is to develop safe, highly efficacious and cost-effective theranostic agents for human HNSCC. The proposed transformable, tumor hallmark targeting yet easy-to- make nano-theranostic agents that are highly capable of overcoming the important barriers for drug delivery to HNSCC offer tremendous opportunities for precision image-guided intervention of HNSCC, therefore have great commercial potentials to lead to a marketable nanoformulation to improve the treatment of HNSCC.
Public Health Relevance Statement: Narrative The proposed transformable Nano-Theranostics are expected to be highly useful for primary treatment (phototherapy) of early localized HNSCC lesions. For larger HNSCC that require surgical resection, it can be used as a theranostic agent for (i) delineation of tumor margin for image-guided surgery, (ii) intra-operative phototherapy to treat any residual diseases at the surgical margin and adjacent sites that are accessible to illumination intra-operatively, and (iii) systemic treatment of lesions that are not accessible to illumination if using full dose anti-cancer drug within the transformable nano-theranostics. This project will lead to lower mortality among patients with HNSCC and will have a tremendous impact on the quality of life of these patients.
Project Terms: Acidosis; Acids; Alcohol consumption; ethanol use; ethanol product use; ethanol intake; ethanol ingestion; ethanol drinking; ethanol consumption; alcoholic drink intake; alcoholic beverage consumption; alcohol use; alcohol product use; alcohol intake; alcohol ingestion; EtOH use; EtOH drinking; Alcohol Drinking; Aminolevulinic Acid; d-Amino-Levulinic Acid; Delta-Aminolevulinic Acid; Amino-Levulinic Acid; 5-amino-4-oxo-pentanoic acid; 5-Aminolevulinic Acid; 5-Amino-4-oxopentanoic Acid; 5-ALA; Antineoplastic Agents; anticancer drug; anticancer agent; anti-cancer drug; Tumor-Specific Treatment Agents; Neoplastic Disease Chemotherapeutic Agents; Cancer Drug; Antineoplastics; Antineoplastic Drugs; Anti-Cancer Agents; Blood Circulation; Circulation; Bloodstream; Malignant Neoplasms; neoplasm/cancer; malignancy; Malignant Tumor; Cancers; Charge; Hydroxyldaunorubicin; Hydroxyl Daunorubicin; Doxorubicina; Adriamycine; 14-Hydroxydaunomycin; Doxorubicin; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Fluorescence; Goals; Modern Man; Human; immuno therapy; immune-based treatments; immune-based therapies; immune therapy; immune therapeutic strategy; immune therapeutic regimens; immune therapeutic interventions; immune therapeutic approach; immune drugs; Immunologically Directed Therapy; Immunotherapy; In Vitro; heavy metal lead; heavy metal Pb; Pb element; Lead; Photoradiation; Light; Illumination; Lighting; Zeugmatography; Nuclear Magnetic Resonance Imaging; NMR Tomography; NMR Imaging; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MRI; MR Tomography; MR Imaging; Magnetic Resonance Imaging; mortality; Patients; Permeability; Photosensitization; light treatment; Photoradiation Therapy; Light Therapy; Actinotherapy; Phototherapy; Reticuloendothelial System, Serum, Plasma; Plasma Serum; Blood Plasma; Plasma; Prognosis; outcome forecast; Publishing; QOL; Quality of life; treatment with radiation; radio-therapy; radiation treatment; Radiotherapy; Radiotherapeutics; Radiation therapy; Recurrent; Recurrence; Risk Factors; Sensitivity and Specificity; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Signal Transduction; Body Tissues; Tissues; Translating; virus-induced disease; virus infection; viral infection; Viral Diseases; Virus Diseases; 2-deacetyl-2-vinylbacteriopheophorbide; pheophorbide a; Generations; Drug Delivery; Drug Delivery Systems; Epstein-Barr viral infections; EBV Infections; Epstein-Barr Virus Infections; malignant mouth neoplasm; oral cavity cancer; malignant mouth tumor; Oral Cancer; Mouth Cancer; Malignant Oral Neoplasm; Malignant Oral Cavity Tumor; Malignant Oral Cavity Neoplasm; malignant oropharynx neoplasm; malignant oropharynx tumor; Oropharynx Carcinoma; Oropharynx Cancer; Oropharyngeal Carcinoma; Oropharyngeal Cancer; Oropharnyx Cancers; Malignant Oropharyngeal Tumor; Malignant Oropharyngeal Neoplasm; Malignant neoplasm of nasopharynx; Nasopharynx Cancer; Nasopharyngeal Cancer; Malignant Tumor of the Nasopharynx; Malignant Nasopharyngeal Tumor; Malignant Nasopharyngeal Neoplasm; Photosensitizing Agents; Photosensitizers; Imagery; Visualization; improved; Site; Surface; Clinical; premature; prematurity; Penetration; Phase; Biological; Physiological; Physiologic; Series; Lesion; Surgical margins; Stimulus; uptake; Infiltration; Cleaved cell; cleaved; cancer cell; Malignant Cell; Human papilloma virus infection; Human papillomavirus infection; HPV infection; Nature; subcutaneous; Head and neck structure; Head and Neck; extracellular; Tobacco use; Tobacco Consumption; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; Residual Tumors; residual disease; mouth squamous cell carcinoma; oral squamous carcinoma; oral squamous cancer; oral cavity SCC; mouth SCC; Oral squamous cell carcinoma; Oral Cavity Squamous Cell Carcinoma; Early Diagnosis; early detection; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; Structure; Therapeutic Index; novel; Modality; Excision; resection; Surgical Removal; Removal; Extirpation; Abscission; PUVA Photochemotherapy; neoplasm/cancer photoradiation therapy; Photodynamic Therapy; Photochemotherapy; PUVA; response; Image-Guided Surgery; surgical imaging; intraoperative imaging; intra-operative imaging; SCCHN; Head and Neck Carcinoma; HNSCC; Head and Neck Squamous Cell Carcinoma; Dose; Crosslinker; Data; Multimodal Imaging; multimodality imaging; multi-modality imaging; multi-modal imaging; Small Business Innovation Research Grant; Small Business Innovation Research; SBIR; Validation; Xenograft Model; Therapeutic Effect; Development; developmental; Image; imaging; pre-clinical; preclinical; nanoformulation; nano formulation; image guided intervention; image visualization; nanoparticle; nanosized particle; nano-sized particle; nano particle; Cancer cell line; cost effective; cancer type; innovation; innovative; innovate; chemotherapy; mouse model; murine model; tumor; FDA approved; phase 2 study; phase II study; theranostics; nanotheranostics; nano-theranostics; Near-infrared optical imaging; Near-infrared Fluorescence Imaging; NIR optical imaging; NIR imaging; clinical translation; image-guided drug delivery; anti-cancer; anticancer; photothermal therapy; nanotechnology platform; Nanotechnological platform; Nanoplatform; Nano-technology platform; Nano-technological platform; Nano platform
