Immobilization of Photo-Immunoconjugates on Nanoparticles Leads to Enhanced Light-Activated Biological Effects

摘要

The past three decades have witnessed notable advances in establishing photosensitizer- antibody photo-immunoconjugates for photo-immunotherapy and imaging of tumors. Photo-immunotherapy minimizes damage to surrounding healthy tissue when using a cancer-selective photo-immunoconjugate, but requires a threshold intracellular photosensitizer concentration to be effective. Delivery of immunoconjugates to the target cells is often hindered by I) the low photosensitizer-to-antibody ratio of photo-immunoconjugates and II) the limited amount of target molecule presented on the cell surface. Here, a nanoengineering approach is introduced to overcome these obstacles and improve the effectiveness of photo-immunotherapy and imaging. Click chemistry coupling of benzoporphyrin derivative (BPD)-Cetuximab photo-immunoconjugates onto FKR560 dye-containing poly(lactic-co-glycolic acid) nanoparticles markedly enhances intracellular photo-immunoconjugate accumulation and potentiates light-activated photo-immunotoxicity in ovarian cancer and glioblastoma. It is further demonstrated that co-delivery and light activation of BPD and FKR560 allow longitudinal fluorescence tracking of photoimmunoconjugate and nanoparticle in cells. Using xenograft mouse models of epithelial ovarian cancer, intravenous injection of photo-immunoconjugated nanoparticles doubles intratumoral accumulation of photo-immunoconjugates, resulting in an enhanced photoimmunotherapymediated tumor volume reduction, compared to "standard" immunoconjugates. This generalizable "carrier effect" phenomenon is attributed to the successful incorporation of photo-immunoconjugates onto a nanoplatform, which modulates immunoconjugate delivery and improves treatment outcomes.