Huang, H-C;
Rizvi, I;
Liu, J;
Anbil, S;
Kalra, A;
Lee, H;
Baglo, Y;
... Hasan, T; + view all
(2018)
Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery.
Cancer Research
, 78
(2)
pp. 558-271.
10.1158/0008-5472.CAN-17-1700.
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Abstract
Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (1) increase intratumoral drug accumulation by >10-fold, (2) increase the duration of drug exposure above a critical therapeutic threshold, and (3) attenuate surges in CD44 and CXCR4 expression which mediate chemoresistance often observed after multi-cycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression and drug resistance and to extend patient survival.
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