Doxorubicin-loaded iron oxide nanoparticles for glioblastoma therapy: a combinational approach for enhanced delivery of nanoparticles

Abstract

Although doxorubicin (DOX) is an effective anti-cancer drug with cytotoxicity in a variety of different tumors, its effectiveness in treating glioblastoma multiforme (GBM) is constrained by insufficient penetration across the blood-brain barrier (BBB). In this study, biocompatible magnetic iron oxide nanoparticles (IONPs) stabilized with trimethoxysilylpropyl-ethylenediamine triacetic acid (EDT) were developed as a carrier of DOX for GBM chemotherapy. The DOX-loaded EDT-IONPs (DOX-EDT-IONPs) released DOX within 4 days with the capability of an accelerated release in acidic microenvironments. The DOX-loaded EDT-IONPs (DOX-EDT-IONPs) demonstrated an efficient uptake in mouse brainderived microvessel endothelial, bEnd.3, Madin-Darby canine kidney transfected with multi-drug resistant protein 1 (MDCK-MDR1), and human U251 GBM cells. The DOX-EDT-IONPs could augment DOX's uptake in U251 cells by 2.8-fold and significantly inhibited U251 cell proliferation. Moreover, the DOX-EDT-IONPs were found to be effective in apoptotic-induced GBM cell death (over 90%) within 48 h of treatment. Gene expression studies revealed a significant downregulation of TOP II and Ku70, crucial enzymes for DNA repair and replication, as well as MiR-155 oncogene, concomitant with an upregulation of caspase 3 and tumor suppressors i.e., p53, MEG3 and GAS5, in U251 cells upon treatment with DOX-EDT-IONPs. An in vitro MDCK-MDR1-GBM co-culture model was used to assess the BBB permeability and anti-tumor activity of the DOX-EDT-IONPs and DOX treatments. While DOX-EDT-IONP showed improved permeability of DOX across MDCK-MDR1 monolayers compared to DOX alone, cytotoxicity in U251 cells was similar in both treatment groups. Using a cadherin binding peptide (ADTC5) to transiently open tight junctions, in combination with an external magnetic field, significantly enhanced both DOX-EDT-IONP permeability and cytotoxicity in the MDCK-MDR1-GBM co-culture model. Therefore, the combination of magnetic enhanced convective diffusion and the cadherin binding peptide for transiently opening the BBB tight junctions are expected to enhance the efficacy of GBM chemotherapy using the DOX-EDT-IONPs. In general, the developed approach enables the chemotherapeutic to overcome both BBB and multidrug resistance (MDR) glioma cells while providing site-specific magnetic targeting. Glioblastoma multiforme (GBM) is the most common and aggressive form of malignant gliomas whose current standard of care involves surgical recession followed by chemotherapy and radiotherapy 1,2. Nevertheless, the median survival of GBM patients who receive the current standard of care is 14.6 months post-diagnosis, and 5-year survival rate is only 9.8% 3 .

Circumventing drug treatment? Polyethylenimine functionalized nanoparticles inherently and selectively kill patient-derived glioblastoma stem cells

“…Therefore, our data confirm this finding and strengthens the theory of the lysosomal vulnerability of GSCs. Our results further suggest that PEI modification imparts a new, inherent property to nanoparticles in selective killing of GSCs without any additional anti-cancer drug treatment, which is contrary to recently reported drug based nanomedicinal approaches to eradicate GB [64][65][66][67]. We also demonstrated the potential of the PEI-MSNs to be directly delivered to GSCs via intranasal or intravenous administration for the successful eradication of GSCs in vivo.…”

Nanoparticles Based on Quaternary Ammonium Chitosan-methyl-β-cyclodextrin Conjugate for the Neuropeptide Dalargin Delivery to the Central Nervous System: An In Vitro Study

“…Furthermore, according to a recent study [ 26 ], bEnd.3 was found to have a higher lysosomal degradation activity than primary cells, therefore making it particularly suitable for studies involving biological permeation mechanisms such as transcytosis. For this reason, this model has recently been widely used to study the permeability of nanosystems through the BBB [ 27 , 28 , 29 ]. The paracellular pathway permeability to fluorescein ( Figure S4 ), the monolayer integrity, and adequate cell differentiation by the hematoxylin/eosin coloring and the fluorescence analysis (scanning laser confocal microscopy) ( Figure S5 ) were verified.…”

Delivery of Nanoconstructs in Cancer Therapy: Challenges and Therapeutic Opportunities

“…[245] Recent studies have also shown that CED treatments under the guidance of MRI or single photon emission computed tomography provide useful real-time feedback to the clinicians in monitoring the drug delivery process and to confirm adequacy of the drugs delivered to the tumor. [245][246][247][248][249] With recent advances in image-guided drug delivery, locoregional targeted chemotherapy will continue to grow and improve the mortality and morbidity of cancer patients. This method may be coupled with active and passive targeting strategies to reduce the influence of blood flow direction and diffusion gradients from the intravascular to the interstitial space.…”

“…Locoregional chemotherapy. [244][245][246][247][248][249] active targeting moieties. [253] This phenomenon could prolong the circulation time of the drug and enables the delivery of anticancer agents to different tumor compartments, hence resulting in better therapeutic outcomes.…”