Photochemical Internalization Of Bleomycin Research Articles

SCIDOT-25. ENHANCING THE EFFICACY OF DRUG RELEASED FROM LOADED FIBRIN GLUE BY PHOTOCHEMICAL INTERNALIZATION (PCI)

Abstract Although gross total resection of gliomas is often possible with current available techniques, almost all tumors recur due to the infiltrative nature of these tumors. Infiltrative tumor cells in normal brain are consequently protected by the blood brain barrier (BBB), greatly reducing the efficacy of chemotherapy. Localized per-operative methods of slow-release drug delivery, that bypass the BBB altogether, are therefore of considerable interest. Fibrin glue (FG) is a FDA approved compound often used during surgery. FG loaded with drugs has been studied as a localized controlled release vehicle but the quantity and release kinetics attainable for some drugs using FG are often inadequate. Photochemical internalization (PCI) has been demonstrated to significantly enhance the efficacy of several chemo-theraputic agents such as bleomycin (BLM) and doxorubicin (DOX). In particular PCI of BLM has been shown to be effective in sterilizing the tumor bed after marginal cytoreductive surgery. We have evaluated the ability of PCI to enhance the ability of BLM and DOX, released from loaded FG, to inhibit the growth of multi-cell glioma spheroids in vitro. Spheroid growth was monitored for 14 days. The results of the present study show that drug was released for up to 72 hours. The growth inhibition caused by either BLM or DOX was significantly enhanced by PCI. The photosensitizer AlPcS2a could also be loaded and released from FG allowing local delivery at the tumor site.

Abstract 1606: Photochemical internalization (PCI): a novel technology for site-specific drug delivery.

Abstract The utilization of macromolecules in therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. To achieve the expected biological effect of these macromolecules in many cases internalisation to the cell cytosol is crucial. At an intracellular level, the most fundamental obstruction for cytosolic delivery of therapeutic macromolecule is the membrane-barrier of the endocytic vesicles. Photochemical internalisation (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 rupture of the endocytic vesicles and thereby release of the macromolecules into the cytosol. 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 chemotherapeutic agent bleomycin. For clinical utilization a novel photosensitizer has been developed and evaluated for PCI of bleomycin. Preclinical results with this combination will be presented. Furthermore, a phase I/II dose-escalating clinical trial has been finalized and results from this trial will also be presented. Citation Format: Kristian Berg, Colin Hopper, Anette Weyergang, Pål K. Selbo, Anders Høgset. Photochemical internalization (PCI): a novel technology for site-specific drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1606. doi:10.1158/1538-7445.AM2013-1606

591 THE EFFECT OF PHOTOCHEMICAL INTERNALIZATION OF BLEOMYCIN IN THE TREATMENT OF UROTHELIAL CARCINOMA: AN IN VITRO STUDY

You have accessJournal of UrologyBladder Cancer: Basic Research (I)1 Apr 2013591 THE EFFECT OF PHOTOCHEMICAL INTERNALIZATION OF BLEOMYCIN IN THE TREATMENT OF UROTHELIAL CARCINOMA: AN IN VITRO STUDY Harm C. Arentsen, Jos Falke, Anders Høgset, Egbert Oosterwijk, and J. Alfred Witjes Harm C. ArentsenHarm C. Arentsen Nijmegen, Netherlands More articles by this author , Jos FalkeJos Falke Nijmegen, Netherlands More articles by this author , Anders HøgsetAnders Høgset Oslo, Norway More articles by this author , Egbert OosterwijkEgbert Oosterwijk Nijmegen, Netherlands More articles by this author , and J. Alfred WitjesJ. Alfred Witjes Nijmegen, Netherlands More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1987AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Photochemical internalization (PCI) is a novel light-directed drug delivery system. It triggers the release of endocytosed drugs into the cytosol. Thus the drugs can reach their intracellular target of action, realizing their therapeutic potential, instead of being degraded by lysosomal hydrolases. The PCI effect is achieved with photosensitizing compounds specifically localized in the membranes of endocytic vesicles, destroying these membranes by an oxidative process after illumination. Bleomycin is used in multiple standard cancer chemotherapy regimens. The relatively large and hydrophilic chemical structure limits its ability to penetrate membranes, which causes accumulation in endocytic vesicles. PCI of bleomycin can induce a synergistic inhibition of tumor growth in different animal tumor models. In this in vitro study we determined whether meso-tetraphenyl chlorin disulphonate (TPCS2a)-based photochemical delivery of bleomycin was able to potentiate the cytotoxicity of bleomycin on bladder cancer cell lines. Epirubicin, gemcitabine and mitomycin C were used as controls. METHODS The human RT4, RT112, 253J, T24 and rat AY-27 urothelial carcinoma cell lines were used in this study. Cells were seeded in 96-well plates. TPCS2a was added to the growth medium and the plates were incubated overnight. Cells were then resuspended in TPCS2a-free culture medium and incubated for 3 h. Subsequently, cells were treated for 60 min with increasing doses of epirubicin, gemcitabine, mitomycin C or bleomycin followed by illumination for different periods (0-5 min) to obtain dose-response curves. Cell viability was measured with a colorimetric assay after 72 hours. RESULTS For the single treatments, in all five cell lines a dose dependent inhibition of cell proliferation was observed. This was seen both after treatment with TPCS2a-based PDT alone as well as after treatment with either bleomycin or one of the control chemotherapeutic agents alone. For the combination treatments, a significant (p<0,001) synergistic effect, i.e. photochemical internalization effect, was only observed for PDT combined with bleomycin in the human T24 cell line and the rat AY-27 cell line. CONCLUSIONS TPCS2a-based photochemical internalization of bleomycin showed a significant synergistic antiproliferative activity against human and rat urothelial carcinoma cells in vitro. Thus, PCI may have therapeutic potential as an intravesical strategy against NMIBC. Since the effect is heterogeneous, further animal studies to investigate the in vivo effects seem justified. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e242 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Harm C. Arentsen Nijmegen, Netherlands More articles by this author Jos Falke Nijmegen, Netherlands More articles by this author Anders Høgset Oslo, Norway More articles by this author Egbert Oosterwijk Nijmegen, Netherlands More articles by this author J. Alfred Witjes Nijmegen, Netherlands More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

153 The effect of photochemical internalization of bleomycin in the treatment of urothelial carcinoma of the bladder: An in vitro study

153 The effect of photochemical internalization of bleomycin in the treatment of urothelial carcinoma of the bladder: An in vitro study

Photochemical Internalization of Bleomycin Before External-Beam Radiotherapy Improves Locoregional Control in a Human Sarcoma Model

The aim of this study was to explore the tumor growth response of the combination photochemical internalization and external-beam radiotherapy. Photochemical internalization is a technology to improve the utilization of therapeutic macromolecules in cancer therapy by photochemical release of endocytosed macromolecules into the cytosol. A human sarcoma xenograft TAX-1 was inoculated subcutaneously into nude mice. The photosensitizer AlPcS(2a) and bleomycin were intraperitoneally administrated 48 h and 30 min, respectively, before diode laser light exposure at 670 nm (20 J/cm(2)). Thirty minutes or 7 days after photochemical treatment, the animals were subjected to 4 Gy of ionizing radiation. Using photochemical internalization of bleomycin as an adjunct to ionizing radiation increased the time to progression for the tumors from 17 to 33 days as compared with that observed with photodynamic therapy combined with ionizing radiation as well as for radiochemotherapy with bleomycin. The side effects observed when photochemical internalization of bleomycin was given shortly before ionizing radiation were eliminated by separating the treatment modalities in time. Photochemical internalization of bleomycin combined with ionizing radiation increased the time to progression and showed minimal toxicity and may therefore reduce the total radiation dose necessary to obtain local tumor control while avoiding long-term sequelae from radiotherapy.

Photochemical internalization as an adjunct to marginal surgery in a human sarcoma model

Local recurrences after inadequate surgery are a major challenge in many cancers. Photochemical internalization (PCI) is a new technology to release endocytosed macromolecules into the cytosol by a photochemical rupture of the endocytic vesicles. A recent study on an invasive human fibrosarcoma xenograft HT1080 indicated low sensitivity of the tumour periphery to disulfonated aluminium phthalocyanine (AlPcS(2a))-based photochemical treatment. The main goal of the present study was to evaluate the sensitivity of the remaining tumour after marginal resection of the HT1080 tumour to the photochemical treatment alone and PCI of bleomycin. AlPcS(2a) and bleomycin was systemically administrated 48 h and 30 min, respectively, prior to surgery and immediately followed by intra-operative light exposure at 670 nm (15 J cm(-2)). PCI of bleomycin as an adjunct to surgery did significantly delay tumour growth in contrast to the photochemical treatment alone. The results indicate that PCI of bleomycin may be an efficient intra-operative technique to eradicate cancer cells in the wound bed after inadequate surgery.

Photochemical Internalization of Bleomycin is Superior to Photodynamic Therapy Due to the Therapeutic Effect in the Tumor Periphery

Photochemical internalization (PCI) is under development for clinical use in treatment of soft tissue sarcomas and other solid tumors. PCI may release endocytosed bleomycin (BLM) into the cytosol by photochemical rupture of the endocytic vesicles. In this study, the human fibrosarcoma xenograft HT1080 was transplanted into the leg muscle of athymic mice. The photosensitizer disulfonated aluminum phthalocyanine (AlPcS(2a)) and BLM were systemically administrated 48 h and 30 min, respectively, prior to light exposure at 670 nm (30 J cm(-2)). The purposes of this study were to evaluate the treatment response to AlPcS(2a)-photodynamic therapy (PDT) and AlPcS(2a)-PDT in combination with BLM (i.e. PCI of BLM) in an orthotopic, invasive and clinically relevant tumor model and to explore the underlying response mechanisms caused by PDT and PCI of BLM. The treatment response was evaluated by measuring tumor growth, contrast-enhanced magnetic resonance imaging (CE-MRI), histology and fluorescence microscopy. The results show that PCI of BLM is superior to PDT in inducing tumor growth retardation and acts synergistically as compared to the individual treatment modalities. The CE-MRI analyses 2 h after AlPcS(2a)-PDT and PCI of BLM identified a treatment-induced nonperfused central zone of the tumor and a well-perfused peripheral zone. While there were no differences in the vascular response between PDT and PCI, the histological analyses showed that PDT caused necrosis in the tumor center and viable tumor cells were found in the tumor periphery. PCI caused larger necrotic areas and the regrowth in the peripheral zone was almost completely inhibited after PCI. The results indicate that PDT is less efficient in the tumor periphery than in the tumor center and that the treatment effect of PCI is superior to PDT in the tumor periphery.