Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma
| Autor: | Anahid Ehteda, Greg M. Arndt, Annafranca Farfalla, Domenico Cassano, Valerio Voliani, Caitlin Ung, Maria Tsoli, Jie Liu, Giuseppe Cirillo, Timothy W. Failes, Dannielle Upton, Salvador Pocoví-Martínez, Maria Kavallaris, David S. Ziegler, Friederike M. Mansfeld, Orazio Vittorio, Christopher J. Katsinas |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
orthotopic animal models Cell nanoarchitectures Caspase 3 02 engineering and technology doxorubicin lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine Western blot Neurosphere polycyclic compounds Medicine Cytotoxic T cell Doxorubicin medicine.diagnostic_test business.industry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 021001 nanoscience & nanotechnology In vitro paediatric brain tumours medicine.anatomical_structure Oncology Apoptosis gold nanoparticles 030220 oncology & carcinogenesis DIPG Cancer research 0210 nano-technology business medicine.drug |
| Zdroj: | Cancers, Vol 13, Iss 1278, p 1278 (2021) Cancers Volume 13 Issue 6 |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Diffuse intrinsic pontine gliomas (DIPGs) are the most aggressive high-grade gliomas known to affect children. Due to the infiltrative nature of the DIPG tumours in the brainstem, they are very difficult to treat. Unfortunately, children succumb to their disease within 1–2 years from their diagnosis. Novel therapeutic treatments are, thus, urgently needed. Using primary cultures and orthotopic models of DIPG, we evaluated the therapeutic efficacy of passionfruit like nanoarchitectures functionalized with human serum albumin and loaded with doxorubicin (NA-HSA-Dox). We found that NA-HSA-Dox were significantly effective at penetrating DIPG spheroids and subsequently at reducing the proliferation and colony formation in DIPG cells. Although an antitumour effect was not observed in orthotopic models of DIPG, NA-HSA-Dox was well tolerated. These study demonstrates the importance of employing brain tumour orthotopic models for the identification of novel therapies and the need to develop treatments that effectively cross the blood brain barrier. Abstract Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG. |
| Databáze: | OpenAIRE |
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