All-trans retinoic acid enhances the anti-tumour effects of fimaporfin-based photodynamic therapy.

The vitamin A metabolite all-trans retinoic acid (ATRA; tretinoin) has anticancer potential. However, lack of clinical success has prevented its approval for solid tumours. Herein, we propose combining short-term low-dose ATRA with fimaporfin-based photodynamic therapy (ATRA+PDT) for the improved treatment of solid cancers.

Inhibiting autophagy increases the efficacy of low-dose photodynamic therapy.

Rupture and permeabilization of endocytic vesicles can be triggered by various causes, such as pathogenic invasions, amyloid proteins, and silica crystals leading to cell death and degeneration. A cellular quality control process, called lysophagy was recently described to target damaged lysosomes for autophagic sequestration within isolation membranes in order to protect the cell from the consequences of lysosomal leakage. This protective process, however, might interfere with treatment conditions, such as photodynamic therapy (PDT) and the intracellular drug delivery method photochemical internalization (PCI).

Light-controlled elimination of PD-L1+ cells.

The programmed death ligand-1 (PD-L1), also known as CD274 or B7-H1, is mainly expressed on cancer cells and/or immunosuppressive cells in the tumor microenvironment (TME) and plays an essential role in tumor progression and immune escape. Immune checkpoint inhibitors (ICIs) of the PD-1/PD-L1 axis have shown impressive clinical success, however, the majority of the patients do not respond to immune checkpoint therapy (ICT). Thus, to overcome ICT resistance there is a high need for potent and novel strategies that simultaneously target both tumor cells and immunosuppressive cells in the TME.

Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers.

Background And Aims: Photochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol a light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site.

High aldehyde dehydrogenase activity does not protect colon cancer cells against TPCS-sensitized photokilling.

Aldehyde dehydrogenases (ALDH) are detoxifying enzymes that are upregulated in cancer stem cells (CSCs) and may cause chemo- and ionizing radiation (IR) therapy resistance. By using the ALDEFLUOR assay, CD133 + human colon cancer cells HT-29, were FACSorted into three populations: ALDH, ALDH and unsorted (bulk) and treated with chemo-, radio- or photodynamic therapy (PDT) using the clinical relevant photosensitizer disulfonated tetraphenyl chlorin (TPCS/fimaporfin). Here we show that there is no difference in cytotoxic responses to TPCS-PDT in ALHD, ALDH or bulk cancer cells.

Photochemical Internalization for Intracellular Drug Delivery. From Basic Mechanisms to Clinical Research.

Photochemical internalisation (PCI) is a unique intervention which involves the release of endocytosed macromolecules into the cytoplasmic matrix. PCI is based on the use of photosensitizers placed in endocytic vesicles that, following light activation, lead to rupture of the endocytic vesicles and the release of the macromolecules into the cytoplasmic matrix. This technology has been shown to improve the biological activity of a number of macromolecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus and oligonucleotides and certain chemotherapeutics, such as bleomycin.

Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines.

Photochemical internalization (PCI) is a further development of photodynamic therapy (PDT). In this report, we describe PCI as a potential tool for cellular internalization of chemotherapeutic agents or antigens and systematically review the ongoing research. Eighteen published papers described the pre-clinical and clinical developments of PCI-mediated delivery of chemotherapeutic agents or antigens.

Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization.

The objective of this study was to develop and explore a novel CD133-targeting immunotoxin (IT) for use in combination with the endosomal escape method photochemical internalization (PCI). scFvCD133/rGelonin was recombinantly constructed by fusing a gene (scFvCD133) encoding the scFv that targets both non-glycosylated and glycosylated forms of both human and murine CD133/prominin-1 to a gene encoding the ribosome-inactivating protein (RIP) gelonin (rGelonin). RIP-activity was assessed in a cell-free translation assay.

Photochemical internalization enhances cytosolic release of antibiotic and increases its efficacy against staphylococcal infection.

Bacterial pathogens such as Staphylococcus aureus and Staphylococcus epidermidis can survive in different types of cells including professional phagocytes, causing intracellular infections. Antibiotic treatment of intracellular infections is often unsuccessful due to the low efficacy of most antibiotics inside cells. Therefore, novel techniques which can improve intracellular activity of antibiotics are urgently needed.

5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin.

Background: Development of resistance to 5-fluorouracil (5-FU) is a major problem in treatment of various cancers including pancreatic cancer. In this study, we reveal important resistance mechanisms and photochemical strategies to overcome 5-FU resistance in pancreatic adenocarcinoma.

Methods: 5-FU resistant (5-FUR), epithelial-to-mesenchymal-like sub-clones of the wild type pancreatic cancer cell line Panc03.

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance.

Here we report on the induction of resistance to photodynamic therapy (PDT) in the ABCG2-high human breast cancer cell line MA11 after repetitive PDT, using either Pheophorbide A (PhA) or di-sulphonated meso-tetraphenylchlorin (TPCS) as photosensitizer. Resistance to PhA-PDT was associated with enhanced expression of the efflux pump ABCG2. TPCS-PDT-resistance was neither found to correspond with lower TPCS-accumulation nor reduced generation of reactive oxygen species (ROS).

Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics.

Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs.

Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization - A minimally invasive cancer stem cell-targeting strategy.

The cancer stem cell (CSC) marker CD133 is an attractive target to improve antitumor therapy. We have used photochemical internalization (PCI) for the endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin (PCIAC133-saporin). PCI employs an endocytic vesicle-localizing photosensitizer, which generates reactive oxygen species upon light-activation causing a rupture of the vesicle membranes and endosomal escape of entrapped drugs.

177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

Background: CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.

Light-triggered, efficient cytosolic release of IM7-saporin targeting the putative cancer stem cell marker CD44 by photochemical internalization.

We have used the site specific and light-depended drug delivery method photochemical internalization (PCI) to release an immunotoxin (IT), targeting the CD44 receptor, into the cytosol of target cells. The IT consisted of a pan CD44 mAb (clone IM7) bound to the ribosome inactivating protein (RIP) saporin by a biotin-streptavidin linker named IM7-saporin. PCI is based upon photosensitizing compounds localized in the membrane of endosomes and lysosomes causing membrane rupture upon illumination followed by release of the IT into the cytosol.

Intradermal photosensitisation facilitates stimulation of MHC class-I restricted CD8 T-cell responses of co-administered antigen.

The protection or treatment of several immunological disorders is dependent on the antigen-specific and cytotoxic CD8 T cells. However, vaccines aimed at stimulating CD8 T-cell responses are typically ineffective because vaccine antigens are primarily processed by the MHC class-II and not the MHC class-I pathway of antigen presentation: the latter requires cytosolic delivery of antigen. In order to facilitate targeting of antigen to cytosol, the antigen was combined with the photosensitiser TPCS2a (disulfonated tetraphenyl chlorin) and administered intradermally to mice.

Circumvention of resistance to photodynamic therapy in doxorubicin-resistant sarcoma by photochemical internalization of gelonin.

A wide range of anti-cancer therapies have been shown to induce resistance upon repetitive treatment and such adapted resistance may also cause cross-resistance to other treatment modalities. We here show that MES-SA/Dx5 cells with adapted resistance to doxorubicin (DOX) are cross-resistant to photodynamic therapy (PDT). A DOX-induced increased expression of the reactive oxygen species (ROS)-scavenging proteins glutathione peroxidase (GPx) 1 and GPx4 in MES-SA/Dx5 cells was indicated as the mechanism of resistance to PDT in line with the reduction in PDT-generated ROS observed in this cell line.

Vascular endothelial cells as targets for photochemical internalization (PCI).

Cancer treatment can be exerted by targeting both cancer cells and the vasculature supplying solid tumors. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, but recent data on contrast-enhanced MRI have indicated that the method also reduces blood perfusion in HT1080 fibrosarcoma xenografts. The present report aims to investigate if PCI may exert direct cytotoxic effects on endothelial cells.

Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity.

Background: The normal stem cell marker CD133 is also a putative marker of cancer stem cells (CSCs) in different types of cancers. Hence, a major challenge when targeting CD133-expressing CSCs is to prevent depletion of the normal stem cell pool. We hypothesized that the site-specific and light-controlled drug delivery method photochemical internalization (PCI) may have the potential to enhance selectivity and endosomal escape of CD133-targeting immunotoxins in stem-like sarcoma cells.

Strongly amphiphilic photosensitizers are not substrates of the cancer stem cell marker ABCG2 and provides specific and efficient light-triggered drug delivery of an EGFR-targeted cytotoxic drug.

A wide range of anti-cancer drugs are substrates of the ATP-binding cassette transporter ABCG2/CD338/BCRP/MXR, which is thought to play an important role in multi-drug resistance (MDR) and protection of cancer stem cells (CSC) against chemotherapeutics and photodynamic therapy (PDT). Hence, it is of importance to develop drugs that are not substrates of ABCG2. The aim of this study was to elucidate if photosensitizers utilized for the endo-lysosomal release drug delivery method photochemical internalization (PCI) are substrates for ABCG2.

Disulfonated tetraphenyl chlorin (TPCS2a), a novel photosensitizer developed for clinical utilization of photochemical internalization.

Photochemical internalisation (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers that locate in endocytic vesicles, and that upon activation by light induce a release of macromolecules from the endocytic vesicles. PCI has been shown to stimulate delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane.

Photochemical internalization provides time- and space-controlled endolysosomal escape of therapeutic molecules.

A successful cure of cancer by biopharmaceuticals with intracellular targets is dependent on both specific and sufficient delivery of the drug to the cytosol or nuclei of malignant cells. However, cytosolic delivery and efficacy of membrane-impermeable cancer therapeutics are often hampered by the sequestration and degradation of the drugs in the endolysosomal compartments. Hence, we developed photochemical internalization (PCI) as a site-specific drug delivery technology, which bursts the membrane of endocytic vesicles inducing release of entrapped drugs to the cytosol of light exposed cells.

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.