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

Chengqiong Mao,Yan Zhao,Fang Li,Zibo Li,Shaomin Tian,W. Debinski,Xin Ming

Published 2018 in Journal of Controlled Release

ABSTRACT

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. Graphical abstract Figure. No caption available. HighlightsPgp‐targeted PDT was developed to achieve high cancer specificity via antibody targeting plus locoregional light ablation;Antibody‐photosensitizer conjugates provided Pgp‐specific delivery in chemoresistant tumors;Locoregional light activation of photosensitizer further enhanced cancer specificity;Pgp‐targeted PDT produced rapid tumor shrinkage, and significantly prolonged survival of tumor‐bearing mice.

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