Photochemical Internalisation: A Novel Drug Delivery System

Abstract

The present report reviews a number of recently published papers on a novel technology for the cytosolic delivery of macromolecules named photochemical internalisation (PCI). PCI is based upon the light activation of a drug (a photosensitiser) specifically located in the membrane of endocytic vesicles. Light which is absorbed by the photosensitiser induces the formation of reactive oxygen species, of which singlet oxygen (¹O₂) is the predominant form. Singlet oxygen oxidises biomolecules in the membranes of endosomes and lysosomes, resulting in a subsequent release of the contents of these compartments into the cytosol. Photosensitisers have a higher affinity for tumour tissues than for most normal tissues and are used in photodynamic therapy of various types of cancers. We have taken advantage of the PCI strategy to enhance the delivery of a variety of macromolecules, including ribosome-inactivating toxins, an immunotoxin, horse radish peroxidase, a ras peptide, RNA, oligonucleotides and protein encoding DNA, to the cytosol. Normally, a major intracellular barrier to the application of therapeutically interesting peptides and proteins or the application of DNA and RNA in gene therapy is the degradation of the macromolecules in the endocytic vesicles after uptake by endocytosis. Therefore, a photochemically induced rupture of endocytic vesicles and the subsequent cytosolic release of the macromolecules aids these molecules in escaping attack by the lysosomal hydrolases, thereby maintaining their biological activity. Thus, PCI represents a novel principle for the cytosolic delivery of biologically active macromolecules which overcomes the pivotal intracellular barrier of endosomes and lysosomes. In addition to being utilised as a new site-specific cancer therapy method, PCI can also be applied as a research tool for macromolecule delivery both in vitro and in vivo.

Photodynamic Effects of Novel XF Porphyrin Derivatives on Prokaryotic and Eukaryotic Cells

“…A longer incubation with significantly lower photosensitizer concentrations yielded equal phototoxicities. Active uptake by mammalian cells via endocytosis may explain this observation (13,59).…”

Pheophorbide�a-mediated photodynamic therapy induces apoptotic cell death in murine oral squamous cell carcinoma in vitro and in vivo

“…PDT typically involves the systemic administration of a photosensitizer followed by its activation by light of an appropriate wavelength to create a photochemical reaction (6,7). Most types of cancers are especially active in both the uptake and accumulation of photosensitizer agents than normal tissues, which makes tumors especially vulnerable to PDT (8). PDT employs a photosensitizer and visible light to produce singlet oxygen and other reactive oxygen species, which cause an oxidative stress in cells and membrane damage which eventually leads to cell death and tumor ablation (9)(10)(11).…”

Enhanced photodynamic destruction of a transplantable fibrosarcoma using photochemical internalisation of gelonin

“…The endosomal escape of macromolecules such as transgene substances can be increased up to a 100-fold or more (Berg et al, 1999;Selbo et al, 2000). Recently, we have demonstrated a good effect of PCI on two sarcoma cell lines in vitro (Dietze et al, 2003), although the available in vivo data is limited (Selbo et al, 2002). The aim of this study was to determine whether PCI could improve the therapeutic effect of PDT on a human soft-tissue sarcoma in a mouse model, particularly to assess whether it might have value as an adjunct to surgical excision of this type of tumour.…”