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.
Subject(s)
Carcinoma, Pancreatic Ductal , Irinotecan , Minocycline , Pancreatic Neoplasms , Photochemotherapy , Humans , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Cell Line, Tumor , Minocycline/pharmacology , Minocycline/therapeutic use , Irinotecan/pharmacology , Irinotecan/therapeutic use , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Phosphoric Diester Hydrolases/metabolism , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/therapeutic use , Topoisomerase I Inhibitors/chemistry , Liposomes/chemistryABSTRACT
This review describes nanoparticle and dye diffusion in bacterial biofilms in the context of antimicrobial photodynamic inactivation (aPDI). aPDI requires the diffusion of a photosensitizer (Sens) into the biofilm and subsequent photoactivation of oxygen for the generation of reactive oxygen species (ROS) that inactivate microbes. Molecular diffusion in biofilms has been long investigated, whereas this review is intended to draw a logical link between diffusion in biofilms and ROS, a combination that leads to the current state of aPDI and superhydrophobic aPDI (SH-aPDI). This review should be of interest to photochemists, photobiologists and researchers in material and antimicrobial sciences as is ties together conventional aPDI with the emerging subject of SH-aPDI.
