title: Foscan and foslip based photodynamic therapy in osteosarcoma in vitro and in intratibial mouse models.
abstract: Current osteosarcoma therapies cause severe treatment-related side effects and chemoresistance, and have low success rates. Consequently, alternative treatment options are urgently needed. Photodynamic therapy (PDT) is a minimally invasive, local therapy with proven clinical efficacy for a variety of tumor types. PDT is cytotoxic, provokes anti-vascular effects and stimulates tumor cell targeting mechanisms of the immune system and, consequently, has potential as a novel therapy for osteosarcoma patients. This study investigated the uptake and the dark- and phototoxicity and cytotoxic mechanisms of the photosensitizer (PS) 5,10,15,20-tetrakis(meta-hydroxyphenyl) chlorine (mTHPC, Foscan) and a liposomal mTHPC formulation (Foslip) in the human 143B and a mouse K7M2-derived osteosaroma cell line (K7M2L2) in vitro. Second, the tumor- and metastasis-suppressive efficacies of mTHPC formulations based PDT and associated mechanisms in intratibial, metastasizing osteosarcoma mouse models (143B/SCID and syngeneic K7M2L2/BALB/c) were studied. The uptake of Foscan and Foslip in vitro was time- and dose-dependent and resulted in mTHPC and light dose-dependent phototoxicity associated with apoptosis. In vivo, the uptake of both i.v. administered mTHPC formulations was higher in tumor than in healthy control tissue. PDT caused significant (Foscan p < 0.05, Foslip p < 0.001) tumor growth inhibition in both models. A significant (Foscan p < 0.001, Foslip p < 0.001) immune system-dependent suppression of lung metastasis was only observed in the K7M2L2/BALB/c model and was associated with a marked infiltration of T-lymphocytes at the primary tumor site. In conclusion, mTHPC-based PDT is effective in clinically relevant experimental osteosarcoma and suppresses lung metastasis in immunocompetent mice with beneficial effects of the liposomal mTHPC formulation Foslip.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Meier
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Botter
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Campanile
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Robl
authors.affiliation: Biolitec Research GmbH, Otto-Schott-Straße 15, Jena, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Gräfe
authors.affiliation: Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pellegrini
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007107:Immune System; D008081:Liposomes / Q000737:chemistry; D008652:Mesoporphyrins / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use; D013977:Tibia / Q000473:pathology
chemical_list: D008081:Liposomes; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; C072269:temoporfin
keywords: Foscan; Foslip; metastasis; osteosarcoma; photodynamic therapy