Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma.
Caitlin UngMaria TsoliJie LiuDomenico CassanoSalvador Pocoví-MartínezDannielle H UptonAnahid EhtedaFriederike M MansfeldTimothy W FailesAnnafranca FarfallaChristopher KatsinasMaria KavallarisGreg M ArndtOrazio VittorioGiuseppe CirilloValerio VolianiDavid S ZieglerPublished in: Cancers (2021)
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.
Keyphrases
- drug delivery
- cancer therapy
- cell death
- end stage renal disease
- induced apoptosis
- newly diagnosed
- emergency department
- dna damage
- high resolution
- low grade
- oxidative stress
- chronic kidney disease
- multiple sclerosis
- high grade
- radiation therapy
- dna repair
- cell cycle arrest
- silver nanoparticles
- cell proliferation
- radiation induced
- cerebral ischemia