Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma

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.

Focused Delivery of Chemotherapy to Augment Surgical Management of Brain Tumors

“…Similarly, a lysine-methotrexate conjugate showed enhanced brain delivery using the endogenous BBB lysine transport system in an in vitro and pre-clinical rodent study [ 22 ]. Rodent studies indicate that gold nanoparticles can serve as a vehicle for targeted hydrophobic drug delivery through the BBB [ 62 , 63 ]. This was demonstrated using doxorubicin loaded gold nanoparticles in pre-clinical studies [ 64 , 65 ].…”

Advanced biomaterials for human glioblastoma multiforme (GBM) drug delivery

“…185 effects. 188 Cheng et al modified Au NPs with a transactivator of transcription (TAT) peptide (5 nm core size), in which DOX was linked to a pH-dependent reversible hydrazone. TAT-Au-DOX doubled the intracellular penetration of DOX in U87 GBM cells compared to unloaded DOX.…”

“…However, although in vitro studies indicated a that significant enhancement in apoptotic markers cleaved Parp, cleaved caspase 3, and phosphorylated H2AX expression in the treated cells by NAs-HSA-DOX, treatment of a pediatric GBM xenograft mouse model did not demonstrate NAs-HSA-DOX antitumor effects. 188 Cheng et al modified Au NPs with a transactivator of transcription (TAT) peptide (5 nm core size), in which DOX was linked to a pH-dependent reversible hydrazone. TAT-Au-DOX doubled the intracellular penetration of DOX in U87 GBM cells compared to unloaded DOX.…”

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

“…Doxorubicin and doxorubicin-loaded NAs-HSA had a similar effect on DIPG neurospheres. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on inhibiting colony formation compared to doxorubicin [ 78 ]. Shargh et al developed three nanodelivery systems of TMZ analogue (N3Propargyl) including an apoferritin (AFt) nanocage, a sulfobutyl ether β-cyclodextrin (SBE-β-CD) nanocomplex, and SBE-β-CD in nanoliposomes and tested on 2D-spheroids and 3D obtained from DIPG cell lines resistant to TMZ.…”