(496f) Nanocarrier-Enhanced Photoimmunotherapy for Cancer

Photoimmunotherapy (PIT) involves light activation of an antibody–photosensitizer conjugate (APC) to generate cytotoxic molecular species that kill or modulate targets cells. The fluorescence signal generated from the excited-state photosensitizer can be useful for image-guided tumor resection and light dosimetry. PIT was first reported by Levy et al. in 1983 and later developed by several teams for treatment and imaging of different tumors. With the advances of APC, targeted photosensitizer (or fluorophore) delivery to solid tumors and disseminated micrometastasis has already achieved notable preclinical success and clinical progress. But this approach has also met with limitations. PIT minimizes damage to surrounding tissues when the photosensitizer localization is cancer-selective, but requires a threshold intracellular APC concentration to be effective. We focus on leveraging nanoparticle engineering strategies to improve the pharmacokinetics and biodistribution of APC, as well as to enable PIT-based combination therapies. The platform being developed by us attaches APCs onto nanoparticles to improve the biodistribution and accumulation of these conjugates in target cells. We demonstrate multiple benefits to this APC-Nanocarrier (APC-NC) platform. Using the APC-NC platform, the selectivity and intracellular accumulation of APCs were doubled in EGFR-overexpressing human ovarian cancer and glioblastoma multiforme cell lines (OVCAR-5 and U87) but not in macrophages (J774), compared to free APC alone. Subsequently, the highly self-quenched photosensitizers (nontoxic) on the APC-NC can be de-quenched (activated) by cancer cells via lysosomal proteolysis of the antibody. De-quenched photosensitizers (phototoxic) enabled both fluorescence imaging and effective PIT of tumor cells. Animal studies are underway and preliminary results will be presented. Our findings show strong evidence that APC-NC as a viable tactic to overcome the limited effectiveness of APC, and this strategy will be further explored for image-guided, PIT-based combination treatment of ovarian cancer and glioblastoma multiforme.