Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

Chu, Liuxiang; Wang, Aiping; Ni, Ling; Yan, Xiuju; Song, Yina; Zhao, Mingyu; Sun, Kaoxiang; Mu, Hongjie; Li, Sha; Wu, Zimei; Zhang, Chunyan

doi:10.1080/10717544.2018.1494226

Cited by 103 publications

(50 citation statements)

References 34 publications

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“…Many strategies are taken to increase the temozolomide concentration in the CNS, overcoming the boundaries of BBB [64][65][66][67][68]. What was shown earlier, simple implementation of radiotherapy, which is the damaging factor of BBB [69], improves the efficacy of TMZ [70].…”

Section: Discussionmentioning

confidence: 99%

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

2020

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Temozolomide (TMZ) is a drug of choice in glioblastoma treatment. Its therapeutic applications expand also beyond high grade gliomas. However, a significant number of recurrences and resistance to the drug is observed. The key factor in each chemotherapy is to achieve the therapeutic doses of a drug at the pathologic site. Nonetheless, the rate of temozolomide penetration from blood to cerebrospinal fluid is only 20-30%, and even smaller into brain intestinum. That makes a challenge for the therapeutic regimens to obtain effective drug concentrations with minimal toxicity and minor side effects. The aim of our research was to explore a novel epigenetic mechanism of temozolomide action in therapeutic conditions. We analyzed the epigenetic effects of TMZ influence on different glioblastoma cell lines in therapeutically achieved TMZ concentrations through total changes of the level of 5-methylcytosine in DNA, the main epigenetic marker. That was done with classical approach of radioactive nucleotide post-labelling and separation on thin-layer chromatography. In the range of therapeutically achieved temozolomide concentrations we observed total DNA hypomethylation. The significant hypermethylating effect was visible after reaching TMZ concentrations of 10-50 μM (depending on the cell line). Longer exposure time promoted DNA hypomethylation. The demethylated state of the glioblastoma cell lines was overcome by repeated TMZ applications, where dosedependent increase in DNA 5-methylcytosine contents was observed. Those effects were not seen in non-cancerous cell line. The increase of DNA methylation resulting in global gene silencing and consecutive down regulation of gene expression after TMZ treatment may explain better glioblastoma patients' survival.questions about its efficacy, patient selection, outcome, and prognosis still remain, and therapy failures are observed in the vast majority of glioblastoma patients. The changing of dosing regimens didn't fulfill the expectations to increase the treatment effectivity [9].Temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene-9-carboxamide) is a small prodrug, with a molecular weight of 194.15, that undergoes chemical conversion at physiological pH to the active species 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), and generates an active methyl group, that reacts with DNA bases [10]. The cytotoxic activity of TMZ manifests mainly through methylation at the O 6 position of guanine. Although that methyl adduct comprises less than 5% of the total temozolomide induced DNA modifications [11][12][13], O 6 -methylguanine leads to DNA mismatch repair, which results in preservation of the lesion and double-strand breaks, what leads to cell apoptosis [14,15]. Other alkyl adducts, like N 7 -methylguanine and N 3 -methyladenine, comprising ca. 80% of the total TMZ methylation products, are generally not cytotoxic, while they are easily repaired by the base excision repair system [12,13] (Fig 1). Therefore it is believed that generation of O 6 -meth...

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Section: Discussionmentioning

confidence: 99%

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

2020

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“…The nanocarrier was functionalized with a tyrosine kinase antibody, EPHA3 (ephrin type-A receptor 3) which effectively target the drug-loaded nanocarrier to the glioblastoma in the brain, The results show 1.3 fold prolonged release and significantly higher brain concentration. 128 However, all the studies are performed on the animal models, ie, still in the preclinical stage, which suggested the need of a lot of further clinical studies on human volunteers to establish its applicability in real patients.…”

Section: Quantum Dotsmentioning

confidence: 99%

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

Alexander¹,

Agrawal²,

Uddin³

et al. 2019

IJN

122

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The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood–brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.

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“…Anti-EPHA3 functionalized nanoparticles increased the median animal survival by 1.37-fold compared to non-targeted nanoparticles. Overall, the author concluded that anti-EPHA3 modified PLGA nanoparticles might potentially serve as a nose-to-brain drug carrier for the treatment of GBM [120].…”

Section: Drug Delivery Systems For Nose-to-brain Delivery In Glioblasmentioning

confidence: 99%

“…Ephrin type-A receptor 3 (EPHA3) is a membrane-associated receptor overexpressed in the stroma and vasculature of gliomas[153]. Chu and co-authors developed PLGA nanoparticles functionalized with anti-EPHA3 antibodies for direct nose-to-brain delivery of temozolomide butyl ester (TBE)[120]. Nanoparticles loaded with TMZ were prepared by emulsion-solvent evaporation method and subsequently coated with N-trimethylated chitosan (TMC) and their surface functionalized with anti-EPHA3 antibodies.The drug release studies showed a sustained release of TMZ from the nanoparticles up to 48 h. The results of a cytotoxicity assay on C6 cells and of nanoparticles cellular uptake demonstrated that the anti-EPHA3 functionalization could enhance GBM targeting increasing the cytotoxic effect of the drug.…”

mentioning

confidence: 99%

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials

Bruinsmann¹,

Vaz²,

Alves³

et al. 2019

Preprint

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Glioblastoma (GBM) is the most lethal form of brain tumor, characterized by rapid growth and surrounding tissue invasion. The current standard treatment is surgery followed by radiotherapy, and concurrent chemotherapy, typically with temozolomide. Although extensive research has been performed over the past years to develop an effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in the overall survival of patients with GBM. Thus, new therapeutic approaches are urgently needed. A major challenge in the development of therapies for central nervous system (CNS) disorders is overcoming the blood–brain barrier (BBB). In this context, the intranasal (IN) route of drug administration has been proposed as a non-invasive alternative route to directly targeting the CNS. In fact, this route of drug administration may bypass the blood-brain barrier and reduce systemic side effects. Recently, formulations have been developed to further enhance nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review will be on the strategies developed to deliver a number of anticancer compounds for the treatment of GBM using the nasal administration. In particular, the specific properties of nanomedicines proposed for the nose-to-brain delivery will be critically evaluated. The number of preclinical and clinical data reviewed support the idea that nasal delivery of anticancer drugs might represent a breakthrough advancement in the fight against GBM.

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Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

Cited by 103 publications

References 34 publications

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

<p>Recent expansions of novel strategies towards the drug targeting into the brain</p>

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials

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