Journal
JOURNAL OF CONTROLLED RELEASE
Volume 286, Issue -, Pages 289-300Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.08.005
Keywords
P-glycoprotein; Antibody conjugates; Cancer multidrug resistance; Cancer targeted therapy; Photodynamic therapy
Funding
- NIH [5R01CA194064]
- National Cancer Institute's Cancer Center Support Grant [P30CA012197]
- NATIONAL CANCER INSTITUTE [P30CA012197, R01CA194064] Funding Source: NIH RePORTER
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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.
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