Hydrophobic Nanoprecipitates of β-Cyclodextrin/Avermectins Inclusion Compounds Reveal Insecticide Activity against Aedes aegypti Larvae and Low Toxicity against Fibroblasts

Abstract

In the present work, hydrophobic nanoprecipitates (HNPs) of inclusion complexes formed between β-cyclodextrin (βCD) and the avermectins (AVMs) named eprinomectin (EPRI) and ivermectin (IVER) were synthesized and characterized, and their larvicidal activity against Aedes aegypti and human safety against fibroblasts were evaluated. Initially, thermogravimetric analysis/differential thermal analysis data revealed that inclusion increased the thermal stability of AVMs in the presence of βCD. Nuclear magnetic resonance experiments and density functional theory calculations pointed out the inclusion of the benzofuran ring of the two AVMs in the βCD cavity. Isothermal titration calorimetry experiments allowed identification of different binding constants for EPRI/βCD ( K = 1060) and βCD/IVER ( K = 1700) systems, despite the structural similarity. Dynamic light scattering titrations of AVMs' dimethyl sulfoxide solution in βCD aqueous solution demonstrated that the formed HNPs have lower sizes in the presence of βCD. Finally, the inclusion of EPRI in βCD increased its larval toxicity and reduced its human cytotoxicity, while for IVER/βCD no beneficial effect was observed upon inclusion. These results were rationalized in terms of structural differences between the two molecules. Finally, the EPRI/βCD complex has great potential as an insecticide against A. aegypti larvae with high human safety.

Hydrophobic nanoprecipitates formed by benzoylphenylureas and β-cyclodextrin inclusion compounds: synthesis, characterization and toxicity against aedes aegypti larvae

“…Thus, it is justified the preparation of inclusion compounds with this molar ratio for biological experiments, using DMSO. In overall, the equilibrium constants determined for the systems were in the same magnitude as that found in literature for other inclusion compounds [21, 32, 33].…”

“…9 and 10 in supplementary material are shown the 1 H NMR spectra of NOV, DIF, βCD, NOV/βCD and DIF/βCD. The 1 H NMR spectra of NOV and DIF were similar to that provided by Sigma-Aldrich ® while the βCD spectrum was similar to others found in literature [21].

Fig. 9 1 H RMN spectra for NOV, βCD and inclusion compound (NOV/βCD) at 400 MHz, DMSO-d 6 and 27 °C.

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“…Considering that the insecticides described in the present work, even in presence of βCD, presented very low solubilities, it was proposed the strategy to use them in form of hydrophobic nanoprecipitates. Such kind of materials are formed when a low water soluble substance, previously dissolved in an organic solvent (such as DMSO), is added in water at low co-solvent concentration and volume [13, 21]. They can be stabilized in an aqueous environment by the appropriate concentration control of the solid phase and mixture ratio of solvent/cosolvent.…”

“…Thus, aiming the developing of new formulations to overcome the problems about A. aegypti resistance against conventional insecticides, in this work we have synthetized and characterized the inclusion compounds formed between βCD and the benzoylphenylureas DIF and NOV, aiming to improve their activity against Aedes aegypti larvaes. Concerning the low aqueous solubility of these BPUs, even in presence of βCD, additionally we have invoked the simple concept of hydrophobic nanoprecipitates (HNP) [13, 20, 21] by using an organic co-solvent (DMSO) to promote the initial solubilization of compounds and subsequent precipitation of nanostructured material by mixture with water.…”

Enhanced Solubility, Stability, and Herbicidal Activity of the Herbicide Diuron by Complex Formation with β-Cyclodextrin

“…Experiments showed that β -CD improved the thermal stability of avermectins. The EPRI– β -CD inclusion complex increased the larvicidal activity against Aedes aegypti and reduced the human cytotoxicity of EPRI, which brought better insecticidal effect [10]. Studies have shown that the complexation of butachlor with HP β CD reduced the adsorption capacity of soil and enhanced the mobility of butachlor in soil.…”