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The International Classification of Functioning Disability and Health (ICF) was approved in 2001 and, since then, several studies reported the increased interest about its use in different sectors. A recent overview that summarizes its applications is lacking. This study aims to provide an updated overview about 20 years of ICF application through an international online questionnaire, developed by the byline authors, and sent to each World Health Organization Collaborating Centers of the Family of International Classifications (WHO-FIC CCs). Data was collected during October 2020 and December 2021 and descriptive content analyses were used to report main results. Results show how, in most of the respondent countries represented by WHO-FIC CCs, ICF was mainly used in clinical practice, policy development and social policy, and in education areas. Despite its applications in different sectors, ICF use is not mandatory in most countries but, where used, it provides a biopsychosocial framework for policy development in health, functioning and disability. The study provides information about the needs related to ICF applications, that can be useful to organize targeted intervention plans. Furthermore, this survey methodology can be re-proposed periodically to monitor the use of the ICF in the future.

Photochemical internalization (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induces a release of macromolecules from their compartmentalization in endocytic vesicles. PCI has been shown to enhance the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus, oligonucleotides, and the chemotherapeuticum bleomycin. PCI has also been shown to enhance the treatment effect of targeted therapeutic macromolecules. The results show that PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that PCI may have a variety of useful applications for site-specific drug delivery, e.g., in gene therapy, vaccination, and cancer treatment. Our studies also indicate that PCI of bleomycin is superior to PDT in targeting the tumor periphery and that this is partly the cause of the improved treatment effect of PCI as compared to PDT.

Targeting cancer vasculature is an emerging field in cancer treatment. Photochemical internalization (PCI) is a drug delivery technology based on photochemical lysis of drug-bearing endocytic vesicles originally designed to target cancer cells. Recent investigations have revealed a lower PCI efficacy in vascular endothelial cells (HUVECs) in vitro than in HT1080 fibrosarcoma cells. This manuscript aims to explore the limiting factor for the PCI effect in HUVECs. Cellular uptake of the photosensitizers AlPcS(2a) and TPPS(2a), and a model compound for macromolecular drugs taken up by fluid phase endocytosis, Alexa⁴⁸⁸-dextran, was explored by flow cytometry. The uptake of AlPcS(2a) and TPPS(2a) was 3.8-fold and 37-fold higher in HUVECs than in HT1080 cells, respectively, while the Alexa⁴⁸⁸-dextran uptake was 50% lower. AlPcS(2a) (but not TPPS(2a)) was shown to reduce Alexa⁴⁸⁸-dextran uptake in a concentration-dependent manner, resulting in 66% and 33% attenuation of Alexa⁴⁸⁸-dextran uptake at 20 μg/ml AlPcS(2a) in HUVECs and HT1080 cells respectively. Studies of intracellular localization of Alexa⁴⁸⁸-dextran and AlPcS(2a) by confocal microscopy in HUVECs uncovered a concentration-dependent AlPcS(2a)-induced inhibition of Alexa⁴⁸⁸-dextran trafficking into AlPcS(2a)-stained and acidic vesicles. The localization of Alexa⁴⁸⁸-dextran to AlPcS(2a)-localizing compartments was reduced by 40% when the AlPcS(2a) concentration was increased from 5 to 20 μg/ml. The treatment dose of AlPcS(2a) was found to influence on the efficacy of PCI of saporin, but to a lesser extent than expected considering the data from cellular uptake and intracellular trafficking of Alexa⁴⁸⁸-dextran. The implications of these results for further development of vascular targeting-PCI are discussed.

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. PCI of saporin was performed on endothelial human umbilical vein endothelial cell (HUVEC) and fibrosarcoma cells (HT1080) using two PCI-relevant photosensitizers, TPPS2a and AlPcS2a. A 22- and 13-fold higher photosensitizer uptake was detected in the endothelial cells compared with the HT1080 cells for AlPcS2a and TPPS2a, respectively. PCI of saporin was, however, found more effective in HT1080 cells. For HT1080 cells, PCI with saporin increased cell killing 1.9-fold over photodynamic therapy alone, but under the same conditions, only increased HUVEC cell killing by 1.6- and 1.3-fold with AlPcS2a and TPPS2a , respectively. Saporin uptake was higher in HUVECs than in the HT1080 cells, hence did not reflect the cell line differences in PCI efficacy. This is the first report on PCI-mediated kill of endothelial cells and lays the foundation for further preclinical evaluation of the PCI technology as an antivascular strategy to ablate tumors.

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. The principle of PCI has been demonstrated in >80 different cell lines and 10 different xenograft models of various cancers in different laboratories demonstrating its broad application potential. PCI-induced endosomal escape of protein- or nucleic acid-based therapeutics and some chemotherapeutics will be presented in this review. With a joint effort by life scientists the PCI technology is currently in a Phase I/II clinical trial with very promising initial results in the treatment of solid tumors.