Minocycline and photodynamic priming significantly improve chemotherapy efficacy in heterotypic spheroids of pancreatic ductal adenocarcinoma

Shazia Bano; Jose Quilez Alburquerque; Harrison James Roberts; Sumiao Pang; Huang-Chiao Huang; Tayyaba Hasan

doi:10.1016/j.jphotobiol.2024.112910

Minocycline and photodynamic priming significantly improve chemotherapy efficacy in heterotypic spheroids of pancreatic ductal adenocarcinoma

J Photochem Photobiol B. 2024 Apr 16:255:112910. doi: 10.1016/j.jphotobiol.2024.112910. Online ahead of print.

Authors

Shazia Bano¹, Jose Quilez Alburquerque¹, Harrison James Roberts¹, Sumiao Pang², Huang-Chiao Huang², Tayyaba Hasan³

Affiliations

¹ Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, MA, USA.
² Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
³ Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, MA, USA; Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, MA, USA. Electronic address: thasan@mgh.harvard.edu.

PMID: 38663337
DOI: 10.1016/j.jphotobiol.2024.112910

Abstract

The prognosis for patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) remains dismal. It is generally accepted that combination cancer therapies offer the most promise, such as Folforinox, despite their associated high toxicity. This study addresses the issue of chemoresistance by introducing a complementary dual priming approach to attenuate the DNA repair mechanism and to improve the efficacy of a type 1 topoisomerase (Top1) inhibitor. The result is a regimen that integrates drug-repurposing and nanotechnology using 3 clinically relevant FDA-approved agents (1) Top1 inhibitor (irinotecan) at subcytotoxic doses (2) benzoporphyrin derivative (BPD) as a photoactive molecule for photodynamic priming (PDP) to improve the delivery of irinotecan within the cancer cell and (3) minocycline priming (MNP) to modulate DNA repair enzyme Tdp1 (tyrosyl-DNA phosphodiesterase) activity. We demonstrate in heterotypic 3D cancer models that incorporate cancer cells and pancreatic cancer-associated fibroblasts that simultaneous targeting of Tdp1 and Top1 were significantly more effective by employing MNP and photoactivatable multi-inhibitor liposomes encapsulating BPD and irinotecan compared to monotherapies or a cocktail of dual or triple-agents. These data are encouraging and warrant further work in appropriate animal models to evolve improved therapeutic regimens.

Keywords: Chemoresistance; Minocycline priming; Pancreatic ductal adenocarcinoma; Photoactivable multi-inhibitor liposomes; Photodynamic priming.