Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery

Physiologic 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 wide...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2018-01, Vol.78 (2), p.558-571
Main Authors: Huang, Huang-Chiao, Rizvi, Imran, Liu, Joyce, Anbil, Sriram, Kalra, Ashish, Lee, Helen, Baglo, Yan, Paz, Nancy, Hayden, Douglas, Pereira, Steve, Pogue, Brian W, Fitzgerald, Jonathan, Hasan, Tayyaba
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Biomarkers, Tumor - metabolism
Camptothecin - administration & dosage
Camptothecin - analogs & derivatives
Camptothecin - chemistry
Camptothecin - pharmacology
CD44 antigen
Cell Proliferation - drug effects
Chemoresistance
Chemotherapy
CXCR4 protein
Cytotoxicity
Drug delivery
Drug Delivery Systems
Drug resistance
Humans
Irinotecan
Liposomes - administration & dosage
Liposomes - chemistry
Male
Metastases
Metastasis
Mice
Mice, Nude
Nanoparticles - administration & dosage
Nanoparticles - chemistry
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Photochemotherapy
Receptors, CXCR4 - metabolism
Surges
Survival
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Xenografts
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Summary:Physiologic 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, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by >10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle 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. A biophysical priming approach overcomes key treatment barriers, significantly reduces metastases, and prolongs survival in orthotopic models of human pancreatic cancer. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-17-1700