The lack of tumor specificity by photosensitizers often hampers the clinical application of photodynamic therapy (PDT). Delivery of photosensitizer to tumor based entirely on the enhanced permeability and retention effect could lead to nonspecific uptake of photosensitizer by normal tissue, causing adverse effect in patients. Accumulating evidence showed that the combination of antibody immunotherapy and PDT can complement each other to produce effective cancer-targeted photoimmunotherapy. IRDye 700DX (IR700) is a water-soluble phthalocyanine-based photosensitizer that can produce reactive oxygen species (ROS) efficiently upon light irradiation. Cadherin-17 (CDH17) is a cell surface antigen commonly overexpressed in gastrointestinal cancers. By conjugating IR700 to anti-CDH17 humanized monoclonal antibody (ARB102), the conjugate could target CDH17 positive cancer cells and achieve selective accumulation to induce potent cytotoxicity upon light irradiation.
Kwang Poo Chang, Bala K. Kolli, Chia-Kwung Fan, Dennis K. P. Ng, Clarence T. T. Wong, Laura Manna, Raffaele Corso, Neng-Yao Shih, Robert Elliott, X. P. Jiang, Shin-Hong Shiao, Guo-Liang Fu
Photodynamic therapy (PDT) uses photosensitizers (PS) that are excited with light to generate ROS in the presence of oxygen for treating various diseases. PS also has the potential use as photodynamic insecticides (PDI) and for light-inactivation of Leishmania for photodynamic vaccination (PDV). PDT-inactivated Leishmania are non-viable, but remain immunologically competent as whole-cell vaccines against leishmaniasis, and as a universal carrier for delivery of add-on vaccines against other infectious and malignant diseases. We have screened novel PS, including Zn- and Si-phthalocyanines (PC) for differential PDT activities against Leishmania, insect and mammalian cells in vitro to assess their PDI and PDV potential. Here, Zn-PC were conjugated with various functional groups. The conjugates were examined for uptake by cells as a prerequisite for their susceptibility to light-inactivation. PDT sensitivity was found to vary with cell types and PS used. PDI potential of several PS was demonstrated by their mosquito larvicidal PDT activities in vitro. PDT-inactivated Leishmania were stored frozen for PDV in several ongoing studies: [1] Open label trial with 20 sick dogs for immunotherapy of canine leishmaniasis after chemotherapy in Naples, Italy. Clinical follow-up for >3 years indicate that the PDV prolongs their survival; [2] PDV of murine models with a human lung cancer vaccine showed dramatic tumor suppression; [3] Open label trial of multiple PDV via compassionate access to 4 advanced cancer patients showed no clinically adverse effects. Two subjects remain alive. Genetic modifications of Leishmania are underway to further enhance their safety and efficacy for PDV by installation of activable mechanisms for self-destruction and spontaneous light-emission.
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