Abstract
Infectious diseases caused by intracellular microorganisms represent a significant challenge in medical care due to interactions among drugs during coinfections and the development of resistance in microorganisms, limiting existing therapies. This work reports on itraconazole (ITZ) encapsulated into functional polymeric nanoparticles for their targeted and controlled release into macrophages to fight intracellular infections. NPs are based on poly (lactic acid-co-glycolic acid) (PLGA) polymers of different compositions, molecular weights, and lactic acid–to–glycolic acid ratios. They were self-assembled using the high-energy nanoemulsion method and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and differential scanning calorimetry. It was studied how the polymer-to-drug ratio, changes in the aqueous phase pH, and type and concentration of surfactant affected nanocarriers’ formation, drug-loading capacity, and encapsulation efficiency. Results showed that drug-loading capacity and encapsulation efficiency reached 6.7 and 80%, respectively, by lowering the pH to 5.0 and using a mixture of surfactants. Optimized formulation showed an initial immediate ITZ release, followed by a prolonged release phase that fitted better with a Fickian diffusion kinetic model and high stability at 4 and 37°C. NPs functionalized by using the adsorption and carbodiimide methods had different efficiencies, the carbodiimide approach being more efficient, stable, and reproducible. Furthermore, linking F4/80 and mannose to the NPs was demonstrated to increase J774A.1 macrophages’ uptake. Overall, in vitro assays showed the nanosystem’s efficacy to eliminate the Histoplasma capsulatum fungus and pave the way to design highly efficient nanocarriers for drug delivery against intracellular infections.
Highlights
Limited effectiveness of conventional therapies to combat intracellular infectious agents is commonly related to phagocytic evasion mechanisms, low-specificity treatments, manipulation of intracellular machinery by the pathogen, and the appearance of coinfections and drug resistance (Abushaheen et al, 2020)
The current study develops a biocompatible formulation of ITZ encapsulated into PLGA NPs with optimal colloidal properties regarding size, moderate polydispersity, and surface charge and optimal DLC and EE for adequate ITZ release (Scheme 1B)
The optimal conditions were 15 mg/ml PLGA, 30 μM Nile red, 3% surfactant, 20% sonication amplitude, 30 s sonication time, and 1:2 organic-to-water phase ratio, in which the diameter of NPs from PLGA 50:50 (148.2 ± 23.3 nm) was larger than that of PLGA 75:25 NPs (119.9 ± 18.1) (Supplementary Figure S1A). This behavior is explained by the increase in the inherent viscosity of the PLGA 50:50 system (0.32–0.44 dl/g), with a higher molecular weight than that of PLGA 75:25 (0.14–0.22 dl/g)
Summary
Limited effectiveness of conventional therapies to combat intracellular infectious agents is commonly related to phagocytic evasion mechanisms, low-specificity treatments, manipulation of intracellular machinery by the pathogen, and the appearance of coinfections and drug resistance (Abushaheen et al, 2020). In this context, nanoencapsulation of therapeutic principles in NPs has been introduced as a powerful alternative to improve therapeutic efficacy and provide higher specificity, reducing doses and adverse effects (Begines et al, 2020; Eleraky et al, 2020; Sánchez et al, 2020). Functional nanocarriers have been demonstrated to have the potential for the management of intracellular infections caused by viruses, certain bacteria (e.g., Mycobacterium tuberculosis), some protozoa (e.g., Toxoplasma gondii and Leishmania spp.), and some fungi (e.g., Histoplasma capsulatum) (Eleraky et al, 2020; Sánchez et al, 2020)
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