Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation (original) (raw)
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Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma
Proceedings of the National Academy of Sciences, 2013
Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.
Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments
Pharmaceutics
Glioblastoma Multiforme (GBM) is a devastating disease with a low survival rate and few efficacious treatment options. The fast growth, late diagnostics, and off-target toxicity of currently used drugs represent major barriers that need to be overcome to provide a viable cure. Nanomedicines (NMeds) offer a way to overcome these pitfalls by protecting and loading drugs, increasing blood half-life, and being targetable with specific ligands on their surface. In this study, the FDA-approved polymer poly (lactic-co-glycolic) acid was used to optimise NMeds that were surface modified with a series of potential GBM-specific ligands. The NMeds were fully characterised for their physical and chemical properties, and then in vitro testing was performed to evaluate cell uptake and GBM cell specificity. While all targeted NMeds showed improved uptake, only those decorated with the-cell surface vimentin antibody M08 showed specificity for GBM over healthy cells. Finally, the most promising targ...
2020
Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to twenty months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs) to several anticancer drugs, for which a systemically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multidrug therapies have the potential to improve the survival time. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with TMZ. Nanotechnology is an emerging field that shows great promise in drug delive...
International Journal of Pharmaceutics, 2020
Even though substantial advances in understanding glioma pathogenesis have prompted a more rational design of potential therapeutic strategies, glioblastoma multiforme remains an incurable disease with the lowest median overall survival among all malignant brain tumours. Therefore, there is a dire need to find novel drug delivery strategies to improve the current dismal survival outcomes. In this context, nanomedicine offers an appealing alternative as it shows potential to improve brain drug delivery. Accordingly, we here review nanomedicinebased drug delivery strategies tested in orthotopic animal models of glioblastoma intended to improve the efficacy of the drug candidates that are currently used in the clinical setting or that have entered clinical trials for the treatment of glioblastoma multiforme. We also outline the future perspectives of nanotechnology to provide emerging glioblastoma treatment with broad translational clinical potential based on the nanocarriers that have already entered the clinical trials stage for the treatment of malignant glioma.
Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations
International Journal of Molecular Sciences
Glioblastoma (GBM) is the most aggressive tumor type whose resistance to conventional treatment is mediated, in part, by the angiogenic process. New treatments involving the application of nanoformulations composed of encapsulated drugs coupled to peptide motifs that direct drugs to specific targets triggered in angiogenesis have been developed to reach and modulate different phases of this process. We performed a systematic review with the search criterion (Glioblastoma OR Glioma) AND (Therapy OR Therapeutic) AND (Nanoparticle) AND (Antiangiogenic OR Angiogenesis OR Anti-angiogenic) in Pubmed, Scopus, and Cochrane databases, in which 312 articles were identified; of these, only 27 articles were included after selection and analysis of eligibility according to the inclusion and exclusion criteria. The data of the articles were analyzed in five contexts: the characteristics of the tumor cells; the animal models used to induce GBM for antiangiogenic treatment; the composition of nanof...
Drug Delivery Nanosystems for the Localized Treatment of Glioblastoma Multiforme
Materials (Basel, Switzerland), 2018
Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood⁻brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood⁻brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the at...
GO-PEG as a drug nanocarrier and its antiproliferative effect on human cervical cancer cell line
Artificial Cells, Nanomedicine, and Biotechnology, 2016
The graphene oxide nanosheets can act as a nanocarrier for the delivery of therapeutic agents. The PEGylated GO has high solubility, good stability, and more biocompatibility in physiological solutions. In this study, the anticancer effects of synthesized GO-PEG as a drug nanocarrier evaluated to estimate the synergistic cytotoxic effect of drugs loaded on this type of nanocarrier and to determine the actual effect of any drugs encapsulated on it. The cytotoxic effects of GO-PEG nanosheets were evaluated on HeLa cell line by MTT assay. The results exhibited cytotoxic property of PEGylated GO drug nanocarrier significantly is dose dependent and incubation time dependent.
ACS Biomaterials Science & Engineering, 2018
Nanotechnology has acquired an immense recognition in cancer theranostic plethora. Considerable progress has been made in the development of targeted drug delivery system for potent delivery of anti-cancer drugs to tumour specific site. Recently multifunctional nanomaterials are being explored and used as nanovehicles to carry drug molecules with enhanced therapeutic efficacy. In this present work, graphene oxide quantum dot (GOQD) was conjugated with folic acid functionalized chitosan (FA-CH) to develop a nanocargo (FA-CH-GOQD) for drug delivery in cancer therapy. The synthesized nanomaterials were characterized using Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). Photoluminescence spectroscopy (PL) was also employed to characterize the formation of GOQD. To validate the efficacy of FA-CH-GOQD as nanocarriers, doxorubicin (DOX) drug was chosen for encapsulation. The in-vitro release pattern of DOX was examined in various pH ranges. The drug release rate in a tumour cell microenvironment at pH 5.5 was found higher than that under a physiological range of pH 6.5 and 7.4. A MTT assay was performed to understand the cytotoxic behavior of GOQD and FA-CH-GOQD/DOX. Cytomorphological micrographs of the A549 cell exhibited the various morphological arrangements subject to apoptosis of the cell. Cellular uptake studies manifested that FA-CH-GOQD could specifically transport DOX within a cancerous cell. Further anti-cancer efficacy of this nanomaterial was corroborated in a breast cancer cell line and demonstrated through 4',6-diamidino-2phenylindole dihydrochloride (DAPI) staining micrographs.
Nanotechnology for treatment of glioblastoma multiforme
Journal of Translational Internal Medicine, 2018
Glioblastoma multiforme (GBM), a grade IV astrocytoma as defined by the World Health Organization (WHO) criteria, is the most common primary central nervous system tumor in adults. After treatment with the current standard of care consisting of surgical resection, concurrent temozolomide (TMZ), and radiation, the median survival is only 15 months. The limited and less-effective treatment options for these highly aggressive GBMs call for the development of new techniques and the improvement of existing technologies. Nanotechnology has shown promise in treating this disease, and some nanomaterials have demonstrated the ability to cross the blood-brain barrier (BBB) and remain in GBM tissues. Although the retention of nanoparticles (NPs) in GBM tissue is necessary to elicit an antitumor response, the delivery of the NP needs to be enhanced. Current research in nanotechnology is directed at increasing the active targeting of GBM tissue not only for the aid of chemotherapeutic drug delivery but also for imaging studies. This review is aimed at describing advancements in increasing nanotechnology specificity to GBM tissue.
Impact of graphene oxide nano sheets loaded with chemotherapeutic drug on tumor cells
Journal of Nanoparticle Research, 2020
Graphene oxide (GO) nanosheet is a drug delivery system due to its structural properties, which can be augmented in presence of folic acid (FA). This study aimed to compare the efficacy of GO as a passive (GO/DOX) and active (GO/FA/DOX) forms for delivering doxorubicin (DOX). These two forms of conjugates were characterized before and after loading of DOX to confirm the conjugation as well as their properties including size and thermal stability. Using Ehrlich ascites carcinoma (EAC) cell line, the antitumor effect was evaluated by MTT assay in vitro and cell count; tumor cell cycle and apoptosis were evaluated by flow cytometry in vivo. The results showed that the loading percentages of DOX onto GO (GO/DOX) and GO/FA/DOX were 91% and 83%, respectively. TEM, FT-IR, and TGA confirmed the nano size, physical conjugation by shifted groups, and thermal stability. In vitro, the conjugates induced similar decrease of EAC cell viability, but still lower than those of free DOX. Treatment of EACbearing mice with GO/DOX or GO/FA/DOX forms induced significant decreases of the total numbers of EAC cells by 79% and 97%, respectively, as compared with free DOX (97%). DOX, GO/DOX, and GO/FA/DOX induced cell cycle arrest at G0, G1, and S phase, respectively. These conjugates also induced significant apoptosis with different profiles on viable, early, and late apoptotic EAC cells. In conclusion, loading DOX on GO nanosheet activated with FA can induce antitumor effect similar to those of free DOX but with different mechanisms.