Brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles for brain cancers

Geldenhuys, Werner J.; Wehrung, Daniel; Groshev, Anastasia; Hirani, Anjali; Sutariya, Vijaykumar

doi:10.3109/10837450.2014.892130

Cited by 52 publications

(30 citation statements)

References 41 publications

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“…GSH receptors at the BBB interface offer an option in targeting these receptors by GSH-coated nanoparticles to escalate the active or passive transcytosis of therapeutic agents to the brain [12,13]. GSH-PEGylated liposomes have been effectively applied as a brain drug delivery platform for the improvement of numerous treatments.…”

Section: Discussionmentioning

confidence: 99%

“…GSH, an endogenous tripeptide, possesses a central nervous system (CNS) concentration up to 3 mM [12]. It has antioxidant-like characteristics and is readily transported across the BBB [13]. Recent reports have demonstrated that GSH can be used as a targeting ligand linked to PEGylated nanoparticles to improve delivery of therapeutics to CNS [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80

Lin¹,

Hong²,

Wang³

et al. 2016

IJMS

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been demonstrated to effectively treat the patients of extracranial non-small cell lung cancer (NSCLC). However, these patients often develop brain metastasis (BM) during their disease course. The major obstacle to treat BM is the limited penetration of anticancer drugs across the blood–brain barrier (BBB). In the present study, we utilized gefitinib-loaded liposomes with different modifications to improve gefitinib delivery across the in vitro BBB model of bEnd.3 cells. Gefitinib was encapsulated in small unilamellar liposomes modified with glutathione (GSH) and Tween 80 (SUV-G+T; one ligand plus one surfactant) or RF (SUV-RF; one α-helical cell-penetrating peptide). GSH, Tween 80, and RF were tested by the sulforhodamine B (SRB) assay to find their non-cytotoxic concentrations on bEnd.3 cells. The enhancement on gefitinib across the BBB was evaluated by cytotoxicity assay on human lung adenocarcinoma PC9 cells under the bEnd.3 cells grown on the transwell inserts. Our findings showed that gefitinib incorporated in SUV-G+T or SUV-RF across the bEnd.3 cells significantly reduced the viability of PC9 cells more than that of free gefitinib. Furthermore, SUV-RF showed no cytotoxicity on bEnd.3 cells and did not affect the transendothelial electrical resistance (TEER) and transendothelial permeability of sodium fluorescein across the BBB model. Moreover, flow cytometry and confocal laser scanning microscopy were employed to evaluate the endocytosis pathways of SUV-RF. The results indicated that the uptake into bEnd.3 cells was mainly through adsorptive-mediated mechanism via electrostatic interaction and partially through clathrin-mediated endocytosis. In conclusion, cell penetrating peptide-conjugated SUV-RF shed light on improving drug transport across the BBB via modulating the transcytosis pathway(s).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80

Lin¹,

Hong²,

Wang³

et al. 2016

IJMS

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“…Several previous studies have underlined the importance of both astrocytes and endothelial cells to reproduce in vitro structural and functional characteristics of the BBB in vivo [ 16 , 31 – 36 ]. Since glial factors are well conserved among species, many heterologous models have been described so far [ 37 – 40 ].…”

Section: Discussionmentioning

confidence: 99%

Melanoma Cells Homing to the Brain: AnIn VitroModel

Rizzo

Vasco

Girgenti

et al. 2015

BioMed Research International

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We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 μm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, αvβ3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion.

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“… 5 Many receptors are overexpressed on the brain cells such as the cloned μ opioid receptor, 6 the low-density lipoprotein receptor, 7 N -methyl- d -aspartate receptor, insulin receptor, 8 kinin-B2 receptors (BK-B2R), 9 angiotensin II AT1 and AT2 receptors, 10 and glutathione. 11 – 13 …”

Section: Introductionmentioning

confidence: 99%

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

Salem¹,

Ahmed²,

Hassaballah³

et al. 2015

DDDT

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BackgroundThe blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain.MethodsGlutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency.ResultsThe size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than −65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824.ConclusionOverall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new therapeutic option for the treatment of the brain infections.

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Brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles for brain cancers

Abstract: We conclude that the initial in vitro characterization of the NPs demonstrates potential in delivering doxorubicin to cancer cells with possible future application in targeting brain cancers in vivo.

Cited by 52 publications

References 41 publications

Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80

Enhancing Anticancer Effect of Gefitinib across the Blood–Brain Barrier Model Using Liposomes Modified with One α-Helical Cell-Penetrating Peptide or Glutathione and Tween 80

Melanoma Cells Homing to the Brain: AnIn VitroModel

Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

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