Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery.

Abstract

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.Significance: A biophysical priming approach overcomes key treatment barriers, significantly reduces metastases, and prolongs survival in orthotopic models of human pancreatic cancer. Cancer Res; 78(2); 558-71. ©2017 AACR.

• Authors: Huang-Chiao Huang, Imran Rizvi, Joyce Liu, Sriram Anbil, Ashish Kalra, Helen Lee, Yan Baglo, Nancy Paz, Douglas Hayden, Steve Pereira, Brian W Pogue, Jonathan Fitzgerald, Tayyaba Hasan
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 2 Pg. 558-571 (01 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29187403 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• CXCR4 protein, human
• Liposomes
• Receptors, CXCR4
• Irinotecan
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Camptothecin (administration & dosage, analogs & derivatives, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Drug Delivery Systems
• Humans
• Irinotecan
• Liposomes (administration & dosage, chemistry)
• Male
• Mice
• Mice, Nude
• Nanoparticles (administration & dosage, chemistry)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Photochemotherapy
• Receptors, CXCR4 (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays