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Ruthenium-containing supramolecular nanoparticles based on bipyridine-modified cyclodextrin and adamantyl PEI with DNA condensation properties.

ABSTRACT: Exploring safe and highly efficient gene carriers made from biocompatible constituents has great prospects for clinical gene therapy. Here, a supramolecular gene delivery system was readily constructed by assembling adamantyl-modified polyethylenimine (PEI-Ada) units with a versatile ruthenium bipyridine-modified cyclodextrin (Ru-CD) through host-guest interactions. The photophysical and morphological features of the PEI-Ada@Ru-CD nanoparticles were systematically characterized by techniques including UV-vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy, dynamic light scattering, and zeta potential experiments. The small size and suitably positive zeta potential of the nanoparticles facilitated their cellular uptake and gene transfection. As expected, DNA interaction studies, which were performed using agarose gel electrophoresis and atomic force microscopy, showed that the ability of the nanoparticles to condense DNA was higher than that of the gold standard, i.e., PEI, at low N/P ratios. The design of these ruthenium-containing supramolecular nanoparticles based on bipyridine-modified cyclodextrin and adamantyl PEI has great prospects in the development of gene delivery vehicles.

SUBMITTER: Yan F

PROVIDER: S-EPMC6300456 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Ruthenium-containing supramolecular nanoparticles based on bipyridine-modified cyclodextrin and adamantyl PEI with DNA condensation properties.

Yan Fang F Wu Jian-Shuang JS Liu Zhi-Li ZL Yu Hong-Li HL Wang Yong-Hong YH Zhang Wei-Fen WF Ding De-Jun DJ

Nanoscale research letters 20181219 1

Exploring safe and highly efficient gene carriers made from biocompatible constituents has great prospects for clinical gene therapy. Here, a supramolecular gene delivery system was readily constructed by assembling adamantyl-modified polyethylenimine (PEI-Ada) units with a versatile ruthenium bipyridine-modified cyclodextrin (Ru-CD) through host-guest interactions. The photophysical and morphological features of the PEI-Ada@Ru-CD nanoparticles were systematically characterized by techniques inc ...[more]

PMID: 30569227

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Project description:Localized aerosol delivery of gene therapies is a promising treatment of severe pulmonary diseases including lung cancer, cystic fibrosis, COPD and asthma. The administration of drugs by inhalation features multiple benefits including an enhanced patient acceptability and compliance. The application of a spray dried powder formulation has advantages over solutions due to their increased stability and shelf life. Furthermore, optimal sizes of the powder can be obtained by spray drying to allow a deep lung deposition. The present study optimized the parameters involved with spray drying polyplexes formed by polyethylenimine (PEI) and nucleic acids in inert excipients to generate a nano-embedded microparticle (NEM) powder with appropriate aerodynamic diameter. Furthermore, the effects of the excipient matrix used to generate the NEM powder on the biological activity of the nucleic acid and the ability to recover the embedded nanoparticles was investigated. The study showed that bioactivity and nucleic acid integrity was preserved after spray drying, and that polyplexes could be reconstituted from the dry powders made with trehalose but not mannitol as a stabilizer. Scanning electron microscopy (SEM) showed trehalose formulations that formed fused, lightly corrugated spherical particles in the range between 1 and 5 µm, while mannitol formulations had smooth surfaces and consisted of more defined particles. After redispersion of the microparticles in water, polyplex dispersions are obtained that are comparable to the initial formulations before spray drying. Cellular uptake and transfection studies conducted in lung adenocarcinoma cells show that redispersed trehalose particles performed similar to or better than polyplexes that were not spray dried. A method for quantifying polymer and nucleic acid loss following spray drying was developed in order to ensure that equal nucleic acid amounts were used in all in vitro experiments. The results confirm that spray dried NEM formulations containing nucleic acids can be prepared with characteristics known to be optimal for inhalation therapy.

Project description:UnlabelledBackgroundRecently, various metallocenes were synthesized and analyzed by biological activity point of view (such as antiproliferative properties): ruthenocenes, cobaltoceniums, titanocenes, zirconocenes, vanadocenes, niobocenes, molibdocenes etc. Two main disadvantages of metallocenes are the poor hydrosolubility and the hydrolytic instability. These problems could be resolved in two ways: synthetically modifying the structure or finding new formulations with enhanced properties. The aqueous solubility of metallocenes with cytostatic activities could be enhanced by molecular encapsulation in cyclodextrins, as well as the hydrolytic instability of these compounds could be reduced.ResultsThis study presents a theoretical approach on the nanoencapsulation of a series of titanocenes with cytotoxic activity in ?-, ?-, and ?-cyclodextrin. The HyperChem 5.11 package was used for building and molecular modelling of titanocene and cyclodextrin structures, as well as for titanocene/cyclodextrin complex optimization. For titanocene/cyclodextrin complex optimization experiments, the titanocene and cyclodextrin structures in minimal energy conformations were set up at various distances and positions between molecules (molecular mechanics functionality, MM+). The best interaction between titanocene structures and cyclodextrins was obtained in the case of ?- and ?-cyclodextrin, having the hydrophobic moieties oriented to the secondary face of cyclodextrin. The hydrophobicity of titanocenes (logP) correlate with the titanocene-cyclodextrin interaction parameters, especially with the titanocene-cyclodextrin interaction energy; the compatible geometry and the interaction energy denote that the titanocene/?- and ?-cyclodextrin complex can be achieved. Valuable quantitative structure-activity relationships (QSARs) were also obtained in the titanocene class by using the same logP as the main parameter for the in vitro cytotoxic activity against HeLa, K562, and Fem-x cell lines.ConclusionsAccording to our theoretical study, the titanocene/cyclodextrin inclusion compounds can be obtained (high interaction energy; the encapsulation is energetically favourable). Further, the most hydrophobic compounds are better encapsulated in ?- and ?-cyclodextrin molecules and are more stable (from energetically point of view) in comparison with ?-cyclodextrin case. This study suggests that the titanocene / ?- and ?-cyclodextrin complexes (or synthetically modified cyclodextrins with higher water solubility) could be experimentally synthesized and could have enhanced cytotoxic activity and even lower toxicity.

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Ruthenium-containing supramolecular nanoparticles based on bipyridine-modified cyclodextrin and adamantyl PEI with DNA condensation properties.

Publications

Ruthenium-containing supramolecular nanoparticles based on bipyridine-modified cyclodextrin and adamantyl PEI with DNA condensation properties.

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