Highly Stable Tetra-Phenolato Titanium(IV) Agent Formulated into Nanoparticles Demonstrates Anti-Tumoral Activity and Selectivity.

Titanium(IV) complexes exhibit high potential as anti-tumor agents, particularly due to their low intrinsic toxicity and cytotoxicity toward cisplatin resistant cells. Nevertheless, Ti(IV) complexes generally undergo rapid hydrolysis that previously hampered their utilization as anticancer drugs. We recently overcame this difficulty by developing a highly stable Ti(IV) complex that is based on tetra-phenolato, hexadentate ligand, formulated into organic nanoparticles. Herein we investigated the activity of this complex in vitro and in vivo. Although inactive when tested directly due to poor solubility, when formulated, this complex displayed (a) high cytotoxicity toward cisplatin resistant human ovarian cells, A2780-cp, with resistance factor of 1.1; (b) additive behavior in combination with cisplatin toward ovarian and colon cancer cells; (c) selectivity toward cancer cells as implied by its mild activity toward non-cancerous, fibroblast lung cells, MRC-5; (d) high stability and durability as manifested by the ability to maintain cytotoxicity, even following one week of incubation in 100% aquatic medium solution; and (e) in vivo efficacy toward solid tumors of human colon cancer cells, HT-29, in nude mice without any clinical signs of toxicity. These features support the formulated phenolato Ti(IV) complex being an effective and selective anti-tumoral agent.

Low pressure mediated enhancement of nanoparticle and macromolecule loading into porous silicon structures.

Ensuring drug loading efficiency and consistency is one of the most critical stages in engineering drug delivery vectors based on porous materials. Here we propose a technique to significantly enhance the efficiency of loading by employing simple and widely available methods: applying low pressure with and without centrifugation. Our results point toward the advantages the proposed method over the passive loading, especially where the size difference of loaded materials and the pore size of the porous silicon particles is smaller, an increase up to 20-fold can be observed. The technique described in the study can be used for efficient and reproducible loading of porous materials with therapeutic molecules, nanoparticles and contrast imaging agents for biomedical application.

Anti-proliferative activity of nano-formulated phenolato titanium(IV) complexes against cancer cells.

Nanoparticles of titanium(IV) complexes of phenolato ligands were formed and evaluated for cytotoxicity toward human HT-29 colon cancer, murine T-25 lymphoma, and murine HU-2 multidrug-resistant (MDR) cells. The nano-formulation, besides increasing the complexes' shelf lives, is particularly efficient in overcoming limitations in solubility and cell-penetration, thus enhancing biological accessibility; large complexes that were inactive when measured in a non-formulated form showed marked activity when nano-formulated. For active and accessible small complexes, the effect of the formulation was negligible. Most complexes showed similar activity toward MDR cells and their drug-sensitive analogues, further increasing their therapeutic potential. An exception is a particularly hydrophobic complex, which is presumably more accessible to interaction with the membrane ABCB1 (MDR1) transporter active in the multidrug resistance of HU-2 cells. The most efficient compound is a mononuclear complex of a single hexadentate ligand, combining particularly high activity and hydrolytic stability with accessibility aided by the nano-formulation.

Drug-loaded nanoparticles and supramolecular nanotubes formed from a volatile microemulsion with bile salt derivatives.

The main objective of this study was to form nanoparticles of a model hydrophobic drug, celecoxib, from a volatile microemulsion stabilized by a bile salt derivative. Nanoparticles were obtained by conversion of the microemulsion nanodroplets with the dissolved drug into solid nanometric particles. The use of bile salt derivatives as the surfactants for the formation of a microemulsion enabled significantly higher loading of the drug in both the microemulsion and nanoparticles, compared with the native bile salt. In addition, superior stability of the particles was achieved with the bile salt derivatives, and drug crystallization was inhibited. Interestingly, differences in particle stability and crystallization inhibition were observed between two bile salt derivatives differing only by one hydroxyl group on the bile salt backbone, indicating the delicate balance of interactions in the system. For one of the derivatives, upon dispersion of the nanoparticles in water, they spontaneously arranged into well-defined elongated nanometric tubules as detected and attested by cryo-TEM. It was found that the drug present in nanoparticles induces formation of the nanotubes.

High antitumor activity of highly resistant salan-titanium(IV) complexes in nanoparticles: an identified active species.

A nanoformulated trinuclear hydrolysis product of a bis(alkoxo) salan-Ti(IV) complex shows high antitumor activity, which identifies it as an active species in cells. Additional highly stable mononuclear derivatives also show high activity, when formulated into nanoparticles, thus evincing that biologically friendly Ti(IV) can provide high cytotoxicity with controlled biological function.

Inhibition of crystallization and growth of celecoxib nanoparticles formed from volatile microemulsions.

The inhibitory effect of ammonium glycyrrhizinate (AG) on crystallization of celecoxib (CXB) nanoparticles in aqueous medium was studied. CXB nanoparticles in powder form were prepared by rapid evaporation of all solvents from a volatile oil-in-water microemulsion. A powder containing 13 wt % CXB was obtained by immediate conversion of microemulsion droplets into nanoparticles by spray drying. CXB was amorphous in this powder, which could be easily dispersed 1 wt % in water as nanoparticles. However, these particles crystallized rapidly upon dispersion, and a significant particle growth was observed. The natural surfactant, AG, which is US Food and Drug Administration approved for oral administration, inhibited crystallization of CXB, enabling a stable dispersion of nanoparticles with average size of 14 nm. Molecular dynamics simulations revealed rapid attachment of glycyrrhizinate to the growing CXB crystal and suggested that crystallization inhibition is due to interactions between the hydrophobic part of glycyrrhizinate and the phenyl moieties of CXB.

Formulation of water-dispersible nanopermethrin for larvicidal applications.

The formulation of water dispersible nanopermethrin was investigated for its larvicidal property. Nanopermethrin was prepared using solvent evaporation of oil in water microemulsion, which was obtained by mixing an organic and aqueous phase. The mean particle size of nanodispersion in water was 151 ± 27 nm. X-ray diffraction (XRD) of nanopermethrin showed it was amorphous. Larvicidal studies were carried out against Culex quinquefasciatus and the results were compared with bulk permethrin. The LC(50) of nanopermethrin to Cx. quinquefasciatus was 0.117 mg/L. The LC(50) of bulk permethrin to Cx. quinquefasciatus was 0.715 mg/L. Nanopermethrin may be a good choice as a potent and selective larvicide for Cx. quinquefasciatus.

Formation of celecoxib nanoparticles from volatile microemulsions.

A new composition of a fully water-dilutable microemulsion system stabilized by natural surfactants is presented as a template for preparation of celecoxib nanoparticles. Nanoparticles are obtained as a dry powder upon rapid conversion of microemulsion droplets with dissolved celecoxib into nanoparticles, followed by evaporation of all the liquid in a spray dryer. The resultant powder is easily re-dispersible in water to form a clear, transparent dispersion. The celecoxib nanoparticles are amorphous and their average size in the dispersion is 17 nm, in agreement with cryo-TEM results and concentration measurements after filtration. As a result of the nanometric size and amorphous state, about 10-fold increase in dissolution of the powder was obtained, compared to that for particulate celecoxib in the presence of surfactants.

Polyelectrolyte stabilized drug nanoparticles via flash nanoprecipitation: a model study with beta-carotene.

Polyelectrolyte protected beta-carotene nanoparticles (nanosuspensions) with average diameter of <100 nm were achieved by turbulent mixing and flash nanoprecipitation (FNP). Three types of multi-amine functional polyelectrolytes, epsilon-polylysine (epsilon-PL), poly(ethylene imine) (PEI), and chitosan, were investigated to electrosterically protect the nanoparticles. Particle size and distribution were measured by dynamic light scattering (DLS); particles were imaged via scanning electron microscopy (SEM) and cryogenic transmission electron microscopy (cryo-TEM). Low pH and high polyelectrolyte molecular weight gave the smallest and most stable particles. High drug loading capacity, >80 wt%, was achieved by using either PEI or chitosan. X-ray diffraction (XRD) patterns showed that beta-carotene nanoparticles were amorphous. These findings open the way for utilization of FNP for preparation of nanoparticles with enhanced bioavailability for highly water insoluble drugs.

Formation of organic nanoparticles from volatile microemulsions.

A method for preparation of nanoparticles of poorly water-soluble organic materials is presented. By this method, an oil-in-water microemulsion containing a volatile solvent with dissolved model material, propylparaben, undergoes solvent evaporation and conversion into nanoparticles by spray drying. The resulting powder can be easily dispersed in water to give a clear, stable dispersion of nanoparticles with a high loading of propylparaben. By filtration of this dispersion it was found that more than 95wt.% of the dispersed propylparaben is in particles of less than 450nm. X-ray diffraction revealed that propylparaben is present as nanocrystals of 40-70nm. After dispersion of the powder in water, formation of large crystals rapidly occurs. Addition of polyvinylpyrrolidone (PVP) prevented crystal growth during dispersion of the powder in water. The inhibition of propylparaben crystal growth by PVP was studied by molecular dynamic simulations that addressed the binding of PVP to the propylparaben crystal. A comparison was made between PVP and polyvinylalcohol, which did not display crystal inhibition properties.