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Grouping of Poorly Soluble Low (Cyto)Toxic Particles: Example with 15 Selected Nanoparticles and A549 Human Lung Cells.

ABSTRACT: Poorly soluble, low (cyto)toxic particles (PSLTs) are often regarded as one group, but it is important that these particles can be further differentiated based on their bioactivity. Currently, there are no biological endpoint based groupings for inhaled nanoparticles (NPs) that would allow us to subgroup PSLTs based on their mode of action. The aim of this study was to group NPs based on their cytotoxicity and by using the in vitro response of the endo-lysosomal system as a biological endpoint. The endo-lysosomal system is a main cellular loading site for NPs. An impaired endo-lysosomal system in alveolar type II cells may have serious adverse effects on the maintenance of pulmonary surfactant homeostasis. The 15 different NPs were tested with human lung adenocarcinoma (A549) cells. The highly soluble NPs were most cytotoxic. With respect to PSLTs, only three NPs increased the cellular load of acid and phospholipid rich organelles indicating particle biopersistence. All the rest PSLTs could be regarded as low hazardous. The presented in vitro test system could serve as a fast screening tool to group particles according to their ability to interfere with lung surfactant metabolism. We discuss the applicability of the suggested test system for bringing together substances with similar modes-of-action on lung epithelium. In addition, we discuss this approach as a benchmark test for the comparative assessment of biopersistence of PSLTs.

SUBMITTER: Kononenko V

PROVIDER: S-EPMC6566622 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Grouping of Poorly Soluble Low (Cyto)Toxic Particles: Example with 15 Selected Nanoparticles and A549 Human Lung Cells.

Kononenko Veno V Warheit David B DB Drobne Damjana D

Nanomaterials (Basel, Switzerland) 20190506 5

Poorly soluble, low (cyto)toxic particles (PSLTs) are often regarded as one group, but it is important that these particles can be further differentiated based on their bioactivity. Currently, there are no biological endpoint based groupings for inhaled nanoparticles (NPs) that would allow us to subgroup PSLTs based on their mode of action. The aim of this study was to group NPs based on their cytotoxicity and by using the in vitro response of the endo-lysosomal system as a biological endpoint. ...[more]

PMID: 31064102

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Project description:Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

Dataset Information

Grouping of Poorly Soluble Low (Cyto)Toxic Particles: Example with 15 Selected Nanoparticles and A549 Human Lung Cells.

Publications

Grouping of Poorly Soluble Low (Cyto)Toxic Particles: Example with 15 Selected Nanoparticles and A549 Human Lung Cells.

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