Transformable nano-theranostics for image-guided interventions in head and neck squamous cell carcinoma

Summary Abstract Head and neck squamous cell carcinomaHNSCCis the seventh most common cancer worldwidePatients with recurrent or metastatic HNSCC have a median overall survival ofmonthsEven with intensive surgeryradiotherapy and chemotherapythe prognosis is still dismalCompletely removalnegative surgical marginwith surgery is the goal of the treatmentbut it is difficult to achieve due to the infiltration of vital structuresSince positive surgery margin is associated with poor prognosisthere 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 functionsMoreoverdevelopment of theranostic agents that can detect and eliminate early HNSCC lesionsparticularly the aggressive sub typeswill have tremendous impact in many patients with HNSCCWe recently developed a set of highly innovative Transformable Nano TheranosticsTNTsthat possess outstanding capability to circumvent the sequential biological barriers which have generally hindered drug delivery to tumors including oral squamous cell carcinomaOSCCthe most common HNSCC worldwideWe have demonstrated thatthe smart dual size chargetransformation of TNTs in response to ubiquitous hallmarks of tumorse gtumor acidosis induced acidic extracellular pHpHecould dramatically increase the tumor accumulation and penetration of TNTs in oral cancer tissueand facilitate uptake in cancer cellsTNTs enabled effective visualization of tumordrug delivery and therapeutic effect by magnetic resonance imagingMRIand near infrared fluorescence imagingNIRFIthe synergistic trimodal therapy via TNTs achieved acomplete cure rate in orthotopic oral cancer mouse modelsThese highly encouraging data suggest that such nano platform can be translated into early detection and elimination of HNSCC lesionswhich are readily accessible to illumination with lightThe overall goal of this Phase I SBIR proposal is to develop highly effectivenon toxic yet easy to make TNTs for precision image guided intervention of HNSCC in preclinical animal modelsproviding validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to the FDAWe will integrate a series of ultrasensitivepHe cleavable crosslinkers on the surface of TNTs to further optimize their plasma stabilityand their capability to effectively target tumor acidosis which would trigger the smart size charge transformation to significantly improve imaging sensitivity and drug delivery efficiencyThese strategies will ultimately enhance their capability to detect and eliminate early HNSCC lesionsOur long term goal is to develop safehighly efficacious and cost effective theranostic agents for human HNSCCThe proposed transformabletumor hallmark targeting yet easy tomake 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 HNSCCtherefore have great commercial potentials to lead to a marketable nanoformulation to improve the treatment of HNSCC Narrative The proposed transformable Nano Theranostics are expected to be highly useful for primary treatmentphototherapyof early localized HNSCC lesionsFor larger HNSCC that require surgical resectionit can be used as a theranostic agent foridelineation of tumor margin for image guided surgeryiiintra operative phototherapy to treat any residual diseases at the surgical margin and adjacent sites that are accessible to illumination intra operativelyandiiisystemic treatment of lesions that are not accessible to illumination if using full dose anti cancer drug within the transformable nano theranosticsThis project will lead to lower mortality among patients with HNSCC and will have a tremendous impact on the quality of life of these patients