This collaborative application seeks to create an image-guided platform for the treatment of glioblastoma multiforme (GBM) by combining drug delivery using novel nanoconstructs with our unique magnetic resonance guided optical imaging quantification (MROQ) system for image analysis. We use targeted photodynamic therapy (PDT), a photochemistry-based technology to effectively treat GBM. PDT is in clinical studies for GBM treatment and PDT agents can also fluoresce thus enabling online imaging of drug for both image-guided drug delivery (IGDD) and light dosimetry (IGLD). The basic thesis being tested here is that treatment outcomes are superior when targeted delivery of therapeutic and imaging agents is combined with quantitative imaging to provide pharmacokinetic binding (PKB) models that guide treatment planning for PDT. The strategy is to fabricate nanotechnology-based, epidermal growth factor receptor (EGFR) targeting, fluorescent nanocells (TNC) that incorporate a PDT agent (benzoporphyrin derivatve, BPD), a biologic agent, Avastin and a surface conjugated MRI contrast agent Gadolinium-DTPA (Gd-DTPA). The EGFR is targeted using the monoclonal antibody (Mab) Cetuximab, C225, which is fluorescently labeled with an NIR dye LICOR 800CW for enabling IGDD and subsequent development of PK models of binding of the imaging and therapeutic agents to tumor cells. BPD fluorescence will provide the basis for IGLD. EGFR, overexpressed in >50% of GBMs is used as a molecular target primarily for delivering high payloads of probes. The TNC will be compared with non-specifically targeted nanocells (NNC) where the C225 is replaced by an irrelevant Mab targeted to prostate specific membrane antigen (PSMA) not expressed on U87 GBM cells. The study goals will be achieved in 4 specific aims that include TNC/NNC fabrication, 2D cell culture, newly developed 3D GBM models (recapitulating tumor architecture) and in vivo orthotopic tumor models combined with quantitative imaging using MROQ.
Aim 1 will synthesize and characterize TNC and NNC.
Aim 2 : will test the TNC/NNC selectivity and phototoxicity in 3D cellular models of GBM (U87 cells) in vitro for establishing the basis for IGDD/IGLD by determining cell associated fractions.
Aim 3 will develop predictive PKB models in vivo using our MROQ system for quantifying drug delivery and establishing cell-associated fractions of TNC in vivo to guide Aim 4, which will establish the impact of quantitative IGDD/IGLD and PKB models in vivo on treatment outcomes in orthotopic murine models of GBM in short-term (tumor burden) and long-term (survival) studies. The significance of this study is that it provides new multifunctional drug delivery constructs, new 3D GBM models, a dual modality system for quantitative imaging, establishes the impact of IGDD/IGLD on treatment outcome and resolves the controversy of the value of targeting of macromolecular carriers by direct comparative studies with TNC and NNC. If IGDD/IGLD show superior outcomes, the study forms the basis for patient-customized treatments where the timing and amount of illumination is adjusted to individuals.
The outcomes of the proposed studies will impact patients with early and advanced GBM by allowing the eradication of small volume disease by PDT beyond the primary tumors which are resectable. This is already in clinical studies. It will also benefit GBM patients with unresectable disease. Quantitative imaging will also accelerate fluorescence-guided resections for GBM already in advanced clinical trials. Finally, the approach developed here will be adaptable to treating a broad range of diseases.
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