2013 - CTS 2013 Congress


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Oral Communications 7

15.3 - Mesenchymal Stem cells as delivery vehicle of porphyrin loaded nanoparticles: effective photoinduced in vitro killing of osteosarcoma

Presenter: Serena, Duchi, Bologna, Italy
Authors: Serena Duchi1,2,3,4, Giovanna Sotgiu1,2,3,4, Enrico Lucarelli1,2,3,4, Marco Ballestri1,2,3,4, Barbara Dozza1,2,3,4, Augusto Pessina1,2,3,4, Davide Donati1,2,3,4, Greta Varchi1,2,3,4

Mesenchymal Stem cells as delivery vehicle of porphyrin loaded nanoparticles: effective photoinduced in vitro killing of osteosarcoma

Serena Duchi1,2,3,4, Giovanna Sotgiu1,2,3,4, Enrico Lucarelli1,2,3,4, Marco Ballestri1,2,3,4, Barbara Dozza1,2,3,4, Augusto Pessina1,2,3,4, Davide Donati1,2,3,4, Greta Varchi1,2,3,4

1Osteoarticolar Regeneration Laboratory, Rizzoli Orthopaedic Institute (IOR) , Bologna, Italy; 2Institute for the Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy; 3Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum University of Bologna, Bologna, Italy; 4Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

Osteosarcoma (OS) is the most common primary tumor of human bone and the most frequent bone sarcoma in children and adolescents [1]. Current treatments consist of multiple modalities, traditionally including amputation or limb sparing surgery as well as chemotherapy. The estimated 5-year survival is 65%. Unfortunately, most of the current drugs are infused systemically and cause harsh side effects. The poor outcome in the efficacy of therapy is due in part to an inability to deliver the drugs to the infiltrative tumor cells. Therefore, significant efforts need to be undertaken to develop new delivering strategies. One approach is to dispense therapeutic agents using mesenchymal stem cells (MSC) which have the unique ability to home and engraft in the tumor stroma. The therapeutic potential of MSC is in fact not only linked to a broad spectrum of biological activities such as anti-inflammatory, immunomodulative and tissue reparative activities thanks to expression of genes encoding a large variety of important growth factors and cytokines.They also could represent an ideal vehicle for targeted drug delivery, since they can be loaded with therapeutic agents, while maintaining their ability to migrate to sites of disease [2].
In this study we evaluated the efficacy of a combined strategy in which MSC are used as a delivery vehicle for photodynamic therapy (PDT), an approach that applies light and molecular oxygen in combination with a photosensitizing agent [3], to selectively eliminate cells.
For our purposes, we used biocompatible multi-functional core-shell poly(methylmethacrylate) (PMMA)-based core-shell nanoparticles (NPs) loaded with meso-tetrakis(4-sulfonatophenyl) porphyrin (TPPS). In addition, NPs are fluorescently labeled by incorporation of fluorescein (FNPs) in the inner hydrophobic core, while the external shell is decorated with amino groups and a number of ammonium salts, able to electrostatically bind TPPS (TPPS@NPs). These molecules are well known to exhibit a high photo-activity and to generate ROS after excitation with 405nm emission wavelength source. ROS species represent the cytotoxic agents responsible of cell death. The very stable and light-activable TPPS@NPs are then efficiently loaded into MSC.
Our results demonstrate that TPPS@FNPs are efficiently taken up by MSC at a concentration of 45µg/ml without evident sign of toxicity, as shown by cytofluorimetric analyses and different proliferation/cytotoxicity assays.  Then, through laser confocal microscopy and time lapse imaging of TPPS@FNPs-MSCco-cultured with OS cells in vitro, we tested the ability of this system to induce cell death when stimulated with laser light.In order to roughly mimicin vivo conditions, we carried out the co-culture experiment with a 1:5 (MSC vs OS cells) ratio, demonstrating the high effectiveness of our system even in this environment. TPPS@FNPs loaded MSC can in fact induce controlled and massive cells death of themselves and of OS cells in a short time frame right after stimulation with laser light. Collectively these encouraging preliminary data indicate that our bio-system could represent an efficient targeted delivery strategy in killing human OS cells. Our results proponea novel yet therapeutic option for the treatment of bone sarcomas and other tumors, such as breast cancer and gliomas, all of which currently require different therapeutic approaches to overcome recurring and drug treatment failures.
[1] J.B. Hayden, B.H. Huang, Osteosarcoma: Basic Science and Clinical Implications, Orthopedic Clinics of North America 37 (2006) 1-5.
[2] Y.L. Hu, Y.H. Fu, Y. Tabata, J.Q. Gao, Mesenchymal stem cells: a promising targeted-delivery vehicle in cancer gene therapy, J. Control. Release 147(2010) 154-162.
[3] P. Agostinis, K. Berg, K.A. Cengel, T.H. Foster, A.W. Girotti, S.O. Gollnick, et al., Photodynamic therapy of cancer: an update, CA: a Cancer Journal for Clinicians. 61 (2011) 250–81.


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