Molecular imaging-directed bioengineering of nanoconjugates as adaptable tumor targeting platforms - PROJECT SUMMARY
Through cohesive advancements in protein engineering, bioconjugation chemistry and sophisticated
nanotechnology, innovations in targeted nanotherapeutics have made significant progress in increasing the
specificity of anticancer nanomedicines. However, as a consequence of the complexity of modular targeted
nanoconjugates (TNCs), in vivo selectivity, and subsequent treatment outcomes, frequently suffer setbacks.
The capacity to accurately resolve intratumoral molecular and cellular selectivity of TNCs in vivo is oftentimes
thwarted by dominant macrophysiological factors. Such factors include macro-scale quantification of TNC
tumor delivery, which provides little insight into micro-scale cancer cell-specific molecular binding events and
internalization of TNCs present within the interstitium. Additional factors include variable pharmacokinetics of
non-selective nanoconjugate controls, and unparalleled physiologies of target-null tumors; both which hamper
the accurate experimental comparisons needed to evaluate novel TNCs. To this end, Dual-Tracer
Fluorescence Imaging (DT-FI) will be deployed, which provides accurate in vivo quantitation of tumor target
molecular binding of TNCs via a Binding Potential metric, a combined measure of binding affinity and
respective tumor target receptor concentration. Head and neck squamous cell carcinoma (HNSCC) is
debilitating and manifests at critical anatomical sites, requiring highly selective treatments to preserve function
and aesthetics. Aside from indiscriminate surgery, chemo- and radiotherapy, confined spatiotemporal control of
cytotoxicity of HNSCC can be imparted by photodynamic therapy (PDT), a promising modality used to manage
cancers by the light-activation of photosensitizer (PS) agents. In an effort to improve the cellular selectivity of
HNSCC therapy, PS-embedded, chemo-loaded liposomes will be employed in this proposal as a model
nanoplatform to surface-graft engineered recombinant targeting moieties. DT-FI will be leveraged as a critical
means of directing the engineering of the photoactive TNCs to improve outcomes of PDT-based treatments in
HNSCC. To guide Dr. Obaid's transition to independence, a mentoring committee has been assembled to
complement his training in chemical nanoscience. Mentorship by Dr. Tayyaba Hasan will train Dr. Obaid on
PDT-based cancer nanomedicines and tumor biology response. Co-mentorship by Dr. Brian Pogue will train
Dr. Obaid in quantitative in vivo DT-FI. Additional distinguished members include Dr. Brian Seed, a specialist in
protein engineering, Dr. Andrew Tsourkas, a nanoconjugation expert, Dr. Eben Rosenthal, Otolaryngologist
and pioneer in HNSCC imaging, and Dr. William Faquin, a HNSCC pathophysiology expert. As a well-defined
and distinct transition to independence, the infrastructure established in the mentored phase will be adapted to
the engineering of multi-specific photo-chemotherapeutic nanoplatforms tailored for in vivo heterogeneity of
HNSCC models. The approach established in this K99/R00 mechanism will enable future designs of various
TNCs, as directed by in vivo DT-FI, with the capacity for targeting dynamic disease-specific molecular targets.
