Controlled release microspheres loaded with BMP7 suppress primary tumors from human glioblastoma

// Pilar Gonzalez-Gomez 1 , Jose Crecente-Campo 2, * , Cristina Zahonero 1, * , Maria de la Fuente 3 , Aurelio Hernandez-Lain 4 , Helena Mira 1 , Pilar Sanchez-Gomez 1 , Marcos Garcia-Fuentes 2 1 UFIEC, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain 2 Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Pharmacy and Pharmaceutical Technology, and Health Research Institute (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, A Coruna, Spain 3 Nano-Oncologicals Laboratory, Translational Medical Oncology, Clinical University Hospital and Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain 4 Unidad Multidisciplinar de Neurooncologia, Hospital Universitario 12 de Octubre, Madrid, Spain * These authors have contributed equally to this work Correspondence to: Pilar Sanchez-Gomez, e-mail: psanchezg@isciii.es Helena Mira, e-mail: hmira@isciii.es Marcos Garcia-Fuentes, e-mail: marcos.garcia@usc.es Keywords: bone morphogenetic protein, glioblastoma, tumor initiating cells, microspheres, controlled release Received: February 18, 2015      Accepted: February 24, 2015      Published: March 26, 2015 ABSTRACT Glioblastoma tumor initiating cells are believed to be the main drivers behind tumor recurrence, and therefore therapies that specifically manage this population are of great medical interest. In a previous work, we synthesized controlled release microspheres optimized for intracranial delivery of BMP7, and showed that these devices are able to stop the in vitro growth of a glioma cell line. Towards the translational development of this technology, we now explore these microspheres in further detail and characterize the mechanism of action and the in vivo therapeutic potential using tumor models relevant for the clinical setting: human primary glioblastoma cell lines. Our results show that BMP7 can stop the proliferation and block the self-renewal capacity of those primary cell lines that express the receptor BMPR1B . BMP7 was encapsulated in poly (lactic-co-glycolic acid) microspheres in the form of a complex with heparin and Tetronic, and the formulation provided effective release for several weeks, a process controlled by carrier degradation. Data from xenografts confirmed reduced and delayed tumor formation for animals treated with BMP7-loaded microspheres. This effect was coincident with the activation of the canonical BMP signaling pathway. Importantly, tumors treated with BMP7-loaded microspheres also showed downregulation of several markers that may be related to a malignant stem cell-like phenotype: CD133 + , Olig2, and GFAPδ. We also observed that tumors treated with BMP7-loaded microspheres showed enhanced expression of cell cycle inhibitors and reduced expression of the proliferation marker PCNA. In summary, BMP7-loaded controlled release microspheres are able to inhibit GBM growth and reduce malignancy markers. We envisage that this kind of selective therapy for tumor initiating cells could have a synergistic effect in combination with conventional cytoreductive therapy (chemo-, radiotherapy) or with immunotherapy.