Photodynamic Therapy with Liposomal Zinc Phthalocyanine and Tirapazamine Increases Tumor Cell Death via DNA Damage.

Abstract

The efficacy of photodynamic therapy (PDT) in some solid tumors is limited by the poor biodistributive properties of conventional photosensitizers and a natural predisposition of tumor cells to survive hypoxia and oxidative stress. This study investigated the therapeutic potential of a third-generation photosensitizer, liposomal zinc phthalocyanine (ZnPC), in combination with the hypoxic cytotoxin tirapazamine (TPZ). TPZ induces DNA double strand breaks (DSBs) under hypoxic conditions and subsequent apoptosis via p53 signaling. Experiments were performed in tumor cells with functional p53 (Sk-Cha1) and dysfunctional p53 (A431). The combination therapy of TPZ and PDT induced DNA DSBs and cell cycle stalling and enhanced the cytotoxicity of PDT by exacerbating apopotic and non-apoptotic tumor cell death. These phenomena occurred regardless of oxygen tension and the mechanism of cell death differed per cell line. Liposomes containing both ZnPC and TPZ exhibited no dark toxicity but were more lethal to both cell types after PDT compared to ZnPC-liposomes lacking TPZ—an effect that was more pronounced under hypoxic conditions. In conclusion, TPZ is a suitable pharmaceutical compound to increase PDT efficacy by exploiting the post-PDT tumor hypoxia. The inclusion of TPZ and ZnPC into a single liposomal delivery system was feasible. The PDT strategy described in this study may be valuable for the treatment of PDT-recalcitrant tumors.

• Authors: Mans Broekgaarden, Ruud Weijer, Alebert C van Wijk, Ruud C Cox, Maarten R Egmond, Ron Hoebe, Thomas M van Gulik, Michal Heger
• Journal: Journal of biomedical nanotechnology (J Biomed Nanotechnol) Vol. 13 Issue 2 Pg. 204-20 (Feb 2017) ISSN: 1550-7033 [Print] United States
• PMID: 29377650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Isoindoles
• Liposomes
• Organometallic Compounds
• Photosensitizing Agents
• Reactive Oxygen Species
• Triazines
• Zinc Compounds
• Zn(II)-phthalocyanine
• Tirapazamine

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA Damage (drug effects)
• Humans
• Indoles (chemistry, pharmacology)
• Isoindoles
• Liposomes (chemistry, pharmacology)
• Neoplasms (metabolism)
• Organometallic Compounds (chemistry, pharmacology)
• Oxidative Stress (drug effects)
• Photochemotherapy (methods)
• Photosensitizing Agents (chemistry, pharmacology)
• Reactive Oxygen Species
• Tirapazamine
• Triazines (chemistry, pharmacology)
• Zinc Compounds