| Autor: |
Jeena K; Amrita Centre for Nanosciences and Molecular Medicine, ‡Central Lab Animal Facility, and §Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Manju CA; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and §Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Sajesh KM; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Gowd GS; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Sivanarayanan TB; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Mol C D; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Manohar M; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Nambiar A; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Nair SV; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India., Koyakutty M; Amrita Centre for Nanosciences and Molecular Medicine, Central Lab Animal Facility, and Department of Pathology, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences, Ponekkara, Kochi 682 041, India. |
| Abstrakt: |
Glioma stem cells (GSC) present a critical therapeutic challenge for glioblastoma multiforme (GBM). Drug screening against GSC demands development of novel in vitro and in vivo platforms that can mimic brain microenvironment and support GSC maintenance and tumorigenesis. Here, we report, a 3-dimensionel (3D) biomimetic macro-porous scaffold developed by incorporating hyaluronic acid, porcine brain extra cellular matrix (ECM) and growth factors that facilitates regeneration of GBM from primary GSCs, ex vivo and in vivo. After characterizing with human and rat GBM cell lines and neurospheres, human GSCs expressing Notch1, Sox-2, Nestin, and CD133 biomarkers were isolated from GBM patients, cultured in the 3D scaffold, and implanted subcutaneously in nude mice to develop patient derived xenograft (PDX) models. Aggressive growth pattern of PDX with formation of intratumoral vascularization was monitored by magnetic resonance imaging (MRI). Histopathological and phenotypial features of the original tumors were retained in the PDX models. We used this regenerated GBM platform to screen novel siRNA nanotherapeutics targeting Notch, Sox-2, FAK signaling for its ability to inhibit the tumorigenic potential of GSCs. Current clinical drug, Temozolomide and an anticancer phytochemical, nanocurcumin, were used as controls. The siRNA nanoparticles showed excellent efficacy in inhibiting tumorigenesis by GSCs in vivo. Our study suggests that the brain-ECM mimicking scaffold can regenerate primary gliomas from GSCs in vitro and in vivo, and the same can be used as an effective platform for screening drugs against glioma stem cells. |
