SsDNA nanotubes for selective targeting of glioblastoma and delivery of doxorubicin for enhanced survival.
Ontology highlight
ABSTRACT:
SUBMITTER: Harris MA
PROVIDER: S-EPMC8635432 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
Publications
ssDNA nanotubes for selective targeting of glioblastoma and delivery of doxorubicin for enhanced survival.
Harris Michael A MA Kuang Huihui H Schneiderman Zachary Z Shiao Maple L ML Crane Andrew T AT Chrostek Matthew R MR Tăbăran Alexandru-Flaviu AF Pengo Thomas T Liaw Kevin K Xu Beibei B Lin Lucy L Chen Clark C CC O'Sullivan M Gerard MG Kannan Rangaramanujam M RM Low Walter C WC Kokkoli Efrosini E
Science advances 20211201 49
Effective treatment of glioblastoma remains a daunting challenge. One of the major hurdles in the development of therapeutics is their inability to cross the blood-brain tumor barrier (BBTB). Local delivery is an alternative approach that can still suffer from toxicity in the absence of target selectivity. Here, we show that nanotubes formed from self-assembly of ssDNA-amphiphiles are stable in serum and nucleases. After bilateral brain injections, nanotubes show preferential retention by tumors ...[more]
Similar Datasets
Project description:In cancer imaging, nanoparticle biodistribution is typically visualized in living subjects using 'bulk' imaging modalities such as magnetic resonance imaging, computerized tomography and whole-body fluorescence. Accordingly, nanoparticle influx is observed only macroscopically, and the mechanisms by which they target cancer remain elusive. Nanoparticles are assumed to accumulate via several targeting mechanisms, particularly extravasation (leakage into tumour). Here, we show that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6C(hi) monocytes (almost 100% uptake in Ly-6C(hi) monocytes, below 3% in all other circulating cells), and delivered to the tumour in mice. We also demonstrate that a targeting ligand (RGD) conjugated to nanotubes significantly enhances the number of single-walled carbon nanotube-loaded monocytes reaching the tumour (P < 0.001, day 7 post-injection). The remarkable selectivity of this tumour-targeting mechanism demonstrates an advanced immune-based delivery strategy for enhancing specific tumour delivery with substantial penetration.
| S-EPMC4236538 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, characterized by rapid progression, resistance to treatments, and low survival rates; the development of a targeted treatment for this disease is still today an unattained objective. Among the different strategies developed in the latest few years for the targeted delivery of nanotherapeutics, homotypic membrane-membrane recognition is one of the most promising and efficient. In this work, we present an innovative drug-loaded nanocarrier with improved targeting properties based on the homotypic recognition of GBM cells. The developed nanoplatform consists of boron nitride nanotubes (BNNTs) loaded with doxorubicin (Dox) and coated with cell membranes (CM) extracted from GBM cells (Dox-CM-BNNTs). We demonstrated as Dox-CM-BNNTs are able to specifically target and kill GBM cells in vitro, leaving unaffected healthy brain cells, upon successful crossing an in vitro blood-brain barrier model. The excellent targeting performances of the nanoplatform can be ascribed to the protein component of the membrane coating, and proteomic analysis of differently expressed membrane proteins present on the CM of GBM cells and of healthy astrocytes allowed the identification of potential candidates involved in the process of homotypic cancer cell recognition.
| S-EPMC7212088 | biostudies-literature
Project description: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 brain-derived 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.
| S-EPMC7347880 | biostudies-literature
Project description:Glioblastoma is the most common primary brain tumor in adults and carries a dismal prognosis despite advancements in treatment. Diffuse tumor infiltration precludes curative surgical resection and necessitates advancements in drug delivery mechanisms. Convection-enhanced delivery (CED) enables continuous local drug delivery for a diverse population of antitumor agents. Importantly, CED circumvents therapeutic challenges posed by the blood-brain barrier by facilitating concentrated local therapeutic drug delivery with limited systemic effects. Here, we present a concise review of properties essential for safe and efficient convection-enhanced drug delivery, as well as a focused review of clinical studies evaluating CED in the treatment of glioblastoma.
| S-EPMC6088338 | biostudies-literature
Project description:Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency. The aim of this work was to develop a nanoscale drug carrier, which could be loaded with an anti-cancer drug and be directed by an external magnetic field. Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template. These polymer nanotubes (PNT) could be functionalized with iron oxide nanoparticles for magnetic manipulation, without affecting the large internal pore, or inherent low toxicity. Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes. Lastly, doxorubicin could be loaded to the PNTs, causing increased toxicity towards neuroblastoma cells, rendering a platform technology now ready for adaptation with different nanoparticles, degradable pre-polymers, and various therapeutics.
| S-EPMC4664922 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumour, which is associated with a poor two-year survival rate and a high rate of fatal recurrence near the original tumour. Focal/local drug delivery devices hold promise for improving therapeutic outcomes for GBM by increasing drug concentrations locally at the tumour site, or by facilitating the use of potent anti-cancer drugs that are poorly permeable across the blood brain barrier (BBB). For inoperable tumours, stereotactic delivery to the tumour necessitates the development of nanoscale/microscale injectable drug delivery devices. Herein we assess the ability of a novel class of polymer nanotube (based on poly(ethylene glycol) (PEG)) to load doxorubicin (a mainstay breast cancer therapeutic with poor BBB permeability) and release it slowly. The drug loading properties of the PEG nanotubes could be tuned by varying the degree of carboxylic acid functionalisation and hence the capacity of the nanotubes to electrostatically bind and load doxorubicin. 70% of the drug was released over the first seven days followed by sustained drug release for the remaining two weeks tested. Unloaded PEG nanotubes showed no toxicity to any of the cell types analysed, whereas doxorubicin loaded nanotubes decreased GBM cell viability (C6, U-87 and U-251) in a dose dependent manner in 2D in vitro culture. Finally, doxorubicin loaded PEG nanotubes significantly reduced the viability of in vitro 3D GBM models whilst unloaded nanotubes showed no cytotoxicity. Taken together, these findings show that polymer nanotubes could be used to deliver alternative anti-cancer drugs for local therapeutic strategies against brain cancers.
| S-EPMC9418774 | biostudies-literature
Project description:Effective treatment of glioblastoma (GBM) remains a formidable challenge. Survival rates remain poor despite decades of clinical trials of conventional and novel, biologically targeted therapeutics. There is considerable evidence that most of these therapeutics do not reach their targets in the brain when administered via conventional routes (intravenous or oral). Hence, direct delivery of therapeutics to the brain and to brain tumors is an active area of investigation. One of these techniques, convection-enhanced delivery (CED), involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered using continuous, low-positive-pressure bulk flow. Investigation in preclinical and clinical settings has demonstrated that CED can produce effective delivery of therapeutics to substantial volumes of brain and brain tumor. However, limitations in catheter technology and imaging of delivery have prevented this technique from being reliable and reproducible, and the only completed phase III study in GBM did not show a survival benefit for patients treated with an investigational therapeutic delivered via CED. Further development of CED is ongoing, with novel catheter designs and imaging approaches that may allow CED to become a more effective therapeutic delivery technique.
| S-EPMC4483037 | biostudies-literature
Project description:IntroductionConvection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied-combined with the additional costs of performing a trial evaluating CED-has limited the field's ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess.Materials and methodsWe searched PubMed using the phrase "convection-enhanced delivery and glioblastoma". The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances.ResultsWe review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM.ConclusionWhile the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.
| S-EPMC8034832 | biostudies-literature
Project description:Nanoscale micelles as an effective drug delivery system have attracted increasing interest in malignancy therapy. The present study reported the construction of the cholesterol-enhanced doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (CDM/DOX), poly(L-lactide)-based micelle (CLM/DOX), and stereocomplex micelle (CSCM/DOX) from the equimolar enantiomeric 4-armed poly(ethylene glycol)-polylactide copolymers in aqueous condition. Compared with CDM/DOX and CLM/DOX, CSCM/DOX showed the smallest hydrodynamic size of 96 ± 4.8 nm and the slowest DOX release. The DOX-loaded micelles exhibited a weaker DOX fluorescence inside mouse renal carcinoma cells (i.e., RenCa cells) compared to free DOX·HCl, probably because of a slower DOX release. More importantly, all the DOX-loaded micelles, especially CSCM/DOX, exhibited the excellent antiproliferative efficacy that was equal to or even better than free DOX·HCl toward RenCa cells attributed to their successful internalization. Furthermore, all of the DOX-loaded micelles exhibited the satisfactory hemocompatibility compared to free DOX·HCl, indicating the great potential for systemic chemotherapy through intravenous injection.
| S-EPMC5455236 | biostudies-other
Project description:PurposeTo formulate f-MWNTs-cationic liposome hybrids for the simultaneous delivery of siPLK1 and doxorubicin to cancer cells.Methodf-MWNTs-cationic liposome hybrids were prepared by the thin film hydration method where the lipid film was hydrated with 100 μg/ml or 1 mg/ml of ox-MWNTs-NH3 (+) or MWNTs-NH3 (+) in 5% dextrose. siRNA complexation and protection ability was determined by agarose gel electrophoresis. f-MWNTs and liposome interaction was evaluated using Nile Red (NR) fluorescence spectroscopy. Cellular uptake in A549 cells was assessed by flow cytometry. Silencing of target proteins was determined by Luciferase and MTT assays. Sub-G1 analysis was performed to evaluate apoptosis following co-delivery of siPLK1 and Doxorubicin (Dox).ResultsZeta potential and siRNA complexation profile obtained for all hybrids were comparable to those achieved with cationic liposomes. ox-MWNTs-NH3 (+) showed greater extent of interaction with cationic liposomes compared to MWNTs-NH3 (+). ox-MWNTs-NH3 (+) was able to protect siRNA from nuclease-mediated degradation. Enhanced cellular uptake of both the carrier and loaded siRNA in A549 cell, were observed for this hybrid compared to the liposomal carrier. A synergistic pro-apoptotic effect was obtained when siPLK1 silencing was combined with doxorubicin treatment for the hybrid:siRNA complexes compared to the lipoplexes, in A549 cells in vitro.Conclusionsf-MWNTs-cationic liposome hybrid designed in this study can serve as a potential vehicle for the co-delivery of siRNA and cytotoxic drugs to cancer cells in vitro.
| S-EPMC4577551 | biostudies-literature