In vivo documentation of photochemical internalization, a novel approach to site specific cancer therapy

Abstract

Photochemical internalization (PCI) is a unique procedure for site‐specific delivery of several types of membrane‐impermeable molecules to the cytosol of target cells. The technology is based on photochemical‐induced release of endocytosed macromolecules from endosomes and lysosomes into the cytosol. The purpose of this study was to evaluate the therapeutic potential of PCI of the type I ribosomal‐inactivating protein gelonin in an animal model. The photosensitizer aluminum phthalocyanine disulfonate (AlPcS2a) was injected intraperitoneally (10 mg/kg) into athymic female BALB/c (nu/nu) nude mice (8–9 mice per group) with subcutaneously growing human adenocarcinoma (WiDr) tumors 48 hr before exposure to 135 J/cm2 of red light focused on the tumor. Six hours before light exposure a single dose of 50 μg gelonin was administrated intratumorally. Tumor growth was measured at least twice a week. After immunomagnetic separation of in vivo growing tumor cells the subcellular localization of the photosensitizer was evaluated by fluorescence microscopy. The photosensitizer localized in endocytic vesicles in in vivo growing WiDr cells. Furthermore, it was found that in vitro gelonin treatment of WiDr cells isolated from photosensitizer‐treated mice potentiated a light‐induced decrease of clonal survival. Complete remission in 6 of 9 (67%) of the treated mice were induced. Our findings indicate that photochemical treatment with the photosensitizer AlPcS2a activates the cytotoxic potential of gelonin in vivo. These results demonstrate that the synergistic effect of combining photoactivation of photosensitizer located in endocytic vesicles and gelonin is indeed a result of PCI of gelonin. © 2001 Wiley‐Liss, Inc.

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

“…This drug delivery system is based on photosensitizers that localize to the cells endosomes and lysosomes such as meso-tetraphenylporphine with 2 sulfonate groups on adjacent phenyl rings (TPPS 2a ) and aluminium phtalocyanine with two sulfonate groups on adjacent phthlates (AlPcS 2a ) (Berg et al 1990b, Berg & Moan 1994, Berg & Moan 1997, Selbo et al 2001b. These PSs are amphiphilic and are, upon administration, first adsorbed to the plasma membrane (Berg et al 1990b) before they are endocytosed into the membranes of the endocytic vesicles (Fig.4).…”

PCI-enhanced adenoviral transduction employs the known uptake mechanism of adenoviral particles

“…6,7 Furthermore, the enhanced gene expression will only take place in tissue exposed to light, and thus the light treatment increases the specificity of the virus improving the therapeutic index. The PCI technology has already been implemented in animal models, and promising results have been obtained combining photochemical treatment with gelonin, a type I ribosomal-inactivating protein, 43 implying that the combination of adenoviral vectors and photochemical treatment has the potential to be successful in vivo.…”

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

“…The potentiating effects of PCI have previously been demonstrated in vitro (Engesaeter et al, 2006) and in vivo (Selbo et al, 2001;Dietz et al, 2005) and these results have been reviewed by Høgset (Høgset et al, 2004). While most studies have been carried out using amphiphilic photosensitisers (eg, TPPS 2a ) PCI has also been demonstrated using a membrane localising sensitiser, ALAinduced photoporphyrin IX.…”

“…While most studies have been carried out using amphiphilic photosensitisers (eg, TPPS 2a ) PCI has also been demonstrated using a membrane localising sensitiser, ALAinduced photoporphyrin IX. Selbo et al, 2001 administered the photosensitiser aluminium disulphonated phthalocyanine by intraperitoneal injection into athymic mice, followed (48 h later) by a single intratumoural injection of the protein toxin gelonin. The findings indicated that the photosensitiser could become localised in endosomes, in vivo, within the tumour cells and that upon illumination it could be relocalised to the cytoplasm.…”

“…(Høgset et al, 2004;Ndoye et al, 2004;Dietze et al, 2005). Consequently, PCI enables a more efficient delivery of drug to their intracellular targets (Berg et al, 1999;Selbo et al, 2001;Høgset et al, 2004). In cancer treatment, PCI as a more selective procedure than systemic chemotherapy will have reduced systemic effects and its activity can be restricted to irradiated tissues.…”