ß-cyclodextrin dendritic derivatives as permeation mediators to enhance the in vitro albendazole cysticidal activity by the improvement of the diffusion component.

The improvement of permeation of drugs across parasites' membranes to promote their diffusion component represents a challenge to achieve better therapeutic effects, including the avoidance of drug resistance. In the context of medicinal chemistry, suitable structural modifications can be made, either on a drug or a nanocarrier, to trigger different mechanisms that promote the influx across membranes. This study aimed to demonstrate the potential of a set of dendritic derivatives of ß-cyclodextrin (m2G, h2G, and m3G) as nanocarriers, based on their physicochemical and biological behavior in terms of (i) stability, monitored by 1H NMR at pH 7 for seven days, (ii) ability to complex, and subsequently release around 50-80% of the cargo molecule (albendazole) in a biphasic medium and (iii) the absence of in vitro cysticidal effect in cysticercus cultures. The albendazole/nanocarrier inclusion complexes (ICs) were proved in the T. crassiceps model. According to the EC50 values related to the cysticidal activity of albendazole, either free or complexed, the potency of this drug in the ICs experienced a significant increase, which may be attributed to the enhancement of its solubility but also to a better permeation mediated by the amphiphilic dendritic moieties, which ultimately positively impacts the diffusion of this drug through the tegument of the cysticerci. Additional considerations akin to synthetic ease of the dendritic nanocarriers, and production cost, along with the obtained outcomes, allowed us to place m2G followed by m3G as the best options to be considered for further in vivo assays.

Mono-Dendronized ß-Cyclodextrin Derivatives as Multitasking Containers for Curcumin. Impacting Its Solubility, Loading, and Tautomeric Form.

In this study, three mono-dendronized ß-cyclodextrin (ßCD) derivatives (ßCD-1G, ßCD-2G, and ßCD-3G) were used as multitasking containers of curcumin (CUR) to influence its aqueous solubility and tautomerism, both of which are related to its biological activity. We evaluated the relevant physicochemical properties of these containers associated with their potential hosting capacity. All mono-dendronized derivatives exhibited enhanced solubility in different solvents, including water, in comparison with native ßCD. Gas-phase geometry optimizations by density functional theory (DFT) confirmed that none of the dendrons blocked the passage of CUR into the ßCD cavity, and depending on the generation, different preorganization scenarios were promoted before complexation. Phase solubility diagrams showed that all the dendronized containers have superior performance for solubilizing CUR compared to native ßCD. We proved that coprecipitation is most efficient than lyophilization for forming inclusion complexes (ICs) with dendronized containers. Even though ßCD-3G with the largest 3G dendron exhibited the highest CUR loading, the complexation of CUR with ßCD-2G provided the supramolecular system that contains CUR preferentially in its diketo tautomer, which is known for its antioxidant activity.

Convergent click synthesis of macromolecular dendritic ß-cyclodextrin derivatives as non-conventional drug carriers: Albendazole as guest model.

From a materials science perspective, herein we present the design and synthesis of six macromolecular carbohydrate derivatives, obtained by combining the native cyclic oligosaccharide ßCD and dendritic poly(ester) moieties, coupled by CuAAc click reactions, in a convergent fashion. We envisioned two structural variables to promote the formation of inclusion complexes (ICs) with the anti-parasitic drug Albendazole, the degree of substitution on the ßCD (mono or hepta-substitution) and the dendritic generation (from first to third). In terms of synthetic effort and cost, the mono-substituted ßCD derivatives were obtained in more approachable experimental conditions in comparison to the ßCD dendrimers (hepta-substituted macrocycle). The six dendritic derivatives were more soluble in water and showed better complexation capacity than native ßCD. For both, mono and hepta-substituted ßCD, we observed that the amount of encapsulated ABZ increases when the dendron generation increases. Interestingly, different degrees of substitution (mono and hepta) lead comparable results of ABZ complexation. In conclusion, the encapsulation performance and the consequent solubility enhancement, make these molecular containers excellent materials to positively impact the therapeutic desirability of ABZ.