Deferasirox-TAT(47–57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine

Goswami, Dibakar; Vitorino, Hector Aguilar; Alta, Roxana Yesenia Pastrana; Silvestre, Daniel Menezes; Nomura, Cassiana Seimi; Miranda, Maria Terêsa Machini de; Espósito, Breno Pannia

doi:10.1007/s10534-015-9873-5

Cited by 7 publications

(12 citation statements)

References 24 publications

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“…Goswami et al were synthesized the deferasirox-TAT(47-57) peptide conjugate to obtain water soluble alternatives of deferasirox, and also better efficacy to chelate brain iron. It was reported that solubility of deferasirox was increased from <1 mg/mL to >10 mg/mL [27]. In our study, maximum solubility increase was obtained with 10% SLS at pH 1.2 (from 0.9 µg/mL to 333.7 µg/mL), and with 5% Pluronic F127 at pH 6.8 (from 46.8 µg/mL to 334.2 µg/mL).…”

Section: Solubility Studysupporting

confidence: 56%

Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox

Gülsün¹,

Akdag²,

Izat³

et al. 2019

jrp

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Deferasirox is an oral iron chelator used for the treatment of chronic iron overload in blood transfusions. Deferasirox is a BCS Class II drug with low solubility and high permeability. In the formulation development stage for BCS Class II compounds, one of the main approaches is solubility enhancement to achieve better dissolution profiles, increased bioavailability and in some cases, dose reduction. The aim of the study was to investigate the effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. Ball milling method was used to reduce the particle size of deferasirox. Pluronic F127 or sodium lauril sulfate (SLS) were selected as surfactants at different concentrations. The maximum increase in the solubility was obtained with 10% SLS at pH 1.2 (from 0.9 µg/mL to 333.7 µg/mL), and with 5% Pluronic F127 at pH 6.8 (from 46.8 µg/mL to 334.2 µg/mL). Dissolution studies revealed that time to dissolve 85% of deferasirox was decreased as a function of ball milling time and particle size. Permeability studies showed that, in 100 µM concentration, deferasirox permeability was significantly enhanced by all concentrations of SLS (p<0.05). With an increase in Pluronic F127 concentration, permeability of deferasirox was not altered (p>0.05). All these results clearly demonstrated that surfactant addition to the formulations was effective for solubility enhancement of deferasirox, and surfactant type in optimized concentrations was very crucial. Particle size reduction can be used as a promising approach to improve dissolution, and hence bioavailability of deferasirox.

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Section: Solubility Studysupporting

confidence: 56%

Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox

Gülsün¹,

Akdag²,

Izat³

et al. 2019

jrp

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“…Here we report that the selected MPPs were synthesized and linked to DFO by means of succinylation following the synthetic strategy established in our previous studies [ 10 , 15 ], although most steps were carried out at 60°C using conventional heating. After purification and characterization, the four mitochondria-targeted DFO conjugates (mtDFO, Fig 1 ) had their iron binding and antioxidant (against an iron-dependent oxidation model) properties studied.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron

et al. 2017

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Desferrioxamine (DFO) is a bacterial siderophore with a high affinity for iron, but low cell penetration. As part of our ongoing project focused on DFO-conjugates, we synthesized, purified, characterized and studied new mtDFOs (DFO conjugated to the Mitochondria Penetrating Peptides TAT49-57, 1A, SS02 and SS20) using a succinic linker. These new conjugates retained their strong iron binding ability and antioxidant capacity. They were relatively non toxic to A2780 cells (IC50 40–100 μM) and had good mitochondrial localization (Rr +0.45 –+0.68) as observed when labeled with carboxy-tetramethylrhodamine (TAMRA) In general, mtDFO caused only modest levels of mitochondrial DNA (mtDNA) damage. DFO-SS02 retained the antioxidant ability of the parent peptide, shown by the inhibition of mitochondrial superoxide formation. None of the compounds displayed cell cycle arrest or enhanced apoptosis. Taken together, these results indicate that mtDFO could be promising compounds for amelioration of the disease symptoms of iron overload in mitochondria.

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“…Cationic cell-penetrating peptides (CPPs) can facilitate the internalization of attached macromolecules and even nano-carriers (e.g., polymers, liposomes) by various cells via independent transporters and receptor-mediated endocytosis [ 21 , 22 ]. A number of CPPs including trans-activating transcriptional activator (TAT), angiopep, penetratin, rabies virus glycoprotein (RVG), prion peptide, and SynB have already been demonstrated the ability of improving drug delivery across the BBB [ 23 , 24 ]. Peptide Tat (YGRKKRRQRRR), derived from TAT protein, can increase the permeability of brain endothelial cells by inhibiting occludin expression and cleaving occludin via matrix metalloproteinase-9 [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Passage of Magnetic Tat-Conjugated Fe3O4@SiO2 Nanoparticles Across In Vitro Blood-Brain Barrier

et al. 2016

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Delivery of diagnostic or therapeutic agents across the blood-brain barrier (BBB) remains a major challenge of brain disease treatment. Magnetic nanoparticles are actively being developed as drug carriers due to magnetic targeting and subsequently reduced off-target effects. In this paper, we developed a magnetic SiO2@Fe3O4 nanoparticle-based carrier bound to cell-penetrating peptide Tat (SiO2@Fe3O4 -Tat) and studied its fates in accessing BBB. SiO2@Fe3O4-Tat nanoparticles (NPs) exhibited suitable magnetism and good biocompatibility. NPs adding to the apical chamber of in vitro BBB model were found in the U251 glioma cells co-cultured at the bottom of the Transwell, indicating that particles passed through the barrier and taken up by glioma cells. Moreover, the synergistic effects of Tat and magnetic field could promote the efficient cellular internalization and the permeability across the barrier. Besides, functionalization with Tat peptide allowed particles to locate into the nucleus of U251 cells than the non-conjugated NPs. These results suggest that SiO2@Fe3O4-Tat NPs could penetrate the BBB through the transcytosis of brain endothelial cells and magnetically mediated dragging. Therefore, SiO2@Fe3O4-Tat NPs could be exploited as a potential drug delivery system for chemotherapy and gene therapy of brain disease.

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Deferasirox-TAT(47–57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine

Cited by 7 publications

References 24 publications

Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox

Effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox

Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron

Passage of Magnetic Tat-Conjugated Fe3O4@SiO2 Nanoparticles Across In Vitro Blood-Brain Barrier

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