P-glycoprotein targeted and near-infrared light-guided depletion of chemoresistant tumors

Abstract

Drug resistance remains a formidable challenge to cancer therapy. P-glycoprotein (Pgp) contributes to multidrug resistance in numerous cancers by preventing accumulation of anticancer drugs in cancer cells. Strategies to overcome this resistance have been vigorously sought for over 3 decades, yet clinical solutions do not exist. The main reason for the failure is lack of cancer specificity of small-molecule Pgp inhibitors, thus causing severe toxicity in normal tissues. In this study, Pgp-targeted photodynamic therapy (PDT) was developed to achieve superior cancer specificity through antibody targeting plus locoregional light activation. Thus, a Pgp monoclonal antibody was chemically modified with IR700, a porphyrin photosensitizer. In vitro studies showed that the antibody-photosensitizer conjugates specifically bind to Pgp-expressing drug resistant cancer cells, and caused dramatic cytotoxicity upon irradiation with a near infrared light. We then tested our Pgp-targeted approach in mouse xenograft models of chemoresistant ovarian cancer and head and neck cancer. In both models, targeted PDT produced rapid tumor shrinkage, and significantly prolonged survival of tumor-bearing mice. We conclude that our targeted PDT approach produces molecularly targeted and spatially selective ablation of chemoresistant tumors, and thereby provides an effective approach to overcome Pgp-mediated multidrug resistance in cancer, where conventional approaches have failed.