Photochemical internalization (PCI) in cancer therapy: from bench towards bedside medicine

PDT in cancer therapy has been reviewed several times recently and many published reports have been showing promising results. The clinical approvals for PDT include curative treatment of early or superficial cancers and palliative treatment of more advanced disease. Still PDT has yet to become a widely used cancer treatment. This may partly be due to limitations in current PDT regimens and partly due to effective alternative treatment modalities. If the specificity and selectivity of PDT could be improved, PDT would probably make substantial progress and comprise an even more competitive alternative in cancer treatment. The PCI technology is based on the same principles as PDT, the activation of a photosensitizer by light and subsequently followed by formation of reactive oxygen species. Unlike PDT, the photosensitizer used in PCI has to be located in the endocytic vesicles of the targeted cells and will, upon activation of light, induce a release of endocytosed therapeutic agents after a photochemically induced rupture of the endocytic vesicles. The endocytosed therapeutic agent will then be released and may reach their intracellular target of action before being degraded in lysosomes. This site-specific drug delivery induced by PCI will take place in addition to the well described cytotoxic, vascular and immunostimulatory effects of PDT. PCI has been shown to facilitate intracellular delivery of a large variety of macromolecules that do not otherwise readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), RIP-based immunotoxins, genes and some chemotherapeutic agents. Several animal models have been used for in vivo documentation of the PCI principle and more animal models of clinical relevance have recently been utilized for addressing clinical issues. This review will focus on the possibilities and limitations offered by PCI to overcome some of the challenges recognized in current PDT regimens in cancer treatment.