Transformable nano-theranostics for image-guided interventions in head and neck squamous cell carcinoma - Summary/Abstract
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.
