Development of a Highly Biocompatible Antituberculosis Nanodelivery Formulation Based on Para-Aminosalicylic Acid—Zinc Layered Hydroxide Nanocomposites

Abstract

Tuberculosis is a lethal epidemic, difficult to control disease, claiming thousands of lives every year. We have developed a nanodelivery formulation based on para-aminosalicylic acid (PAS) and zinc layered hydroxide using zinc nitrate salt as a precursor. The developed formulation has a fourfold higher efficacy of PAS against mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) found to be at 1.40 μg/mL compared to the free drug PAS with a MIC of 5.0 μg/mL. The newly developed formulation was also found active against Gram-positive bacteria, Gram-negative bacteria, and Candida albicans. The formulation was also found to be biocompatible with human normal lung cells MRC-5 and mouse fibroblast cells-3T3. The in vitro release of PAS from the formulation was found to be sustained in a human body simulated phosphate buffer saline (PBS) solution at pH values of 7.4 and 4.8. Most importantly the nanocomposite prepared using zinc nitrate salt was advantageous in terms of yield and free from toxic zinc oxide contamination and had higher biocompatibility compared to one prepared using a zinc oxide precursor. In summary, these promising in vitro results are highly encouraging for the continued investigation of para-aminosalicylic acid and zinc layered hydroxide nanocomposites in vivo and eventual preclinical studies.

Inorganic nanolayers: structure, preparation, and biomedical applications

“…37 They have also designed a similar sustainedrelease PAS ZnLH nanocomposite with higher drug loading by using zinc nitrate as a precursor. 152 Both of these nanocomposite formulations were found to be highly biocompatible with normal human lung fibroblast cells (MRC-5) and 3T3 fibroblast cells. In addition, the nanocomposites showed higher efficacy against bacteria MTB compared to the free drug PAS.…”

“…[37][38][39] In the first method, salt is used as the starting material, which is dissolved in aqueous solution and its pH is increased by the slow addition of basic solutions, such as sodium hydroxides, aqueous solution of ammonia, or aqueous carbonate, until precipitation occurs. 40 This method is very much similar to the coprecipitation method used in LDH preparation, where aqueous salt solutions are coprecipitated with counteranions of interest.…”

Enhanced anti-inflammatory potential of cinnamate-zinc layered hydroxide in lipopolysaccharide-stimulated RAW 264.7 macrophages

“…ZLH was synthesized by a conventional coprecipitation method using aqueous solutions of zinc nitrate hexahydrate. 40 ZnO was used as the parent material in the synthesis of ZCA through a newly developed direct method. 39 Hydrolysis of ZnO formed a layer of Zn(OH) 2 , while the reaction of Zn ion species, hydroxyls, water, and cinnamate anions in the solution generated ZCA.…”

A Novel Para-Amino Salicylic Acid Magnesium Layered Hydroxide Nanocomposite Anti-Tuberculosis Drug Delivery System with Enhanced in vitro Therapeutic and Anti-Inflammatory Properties

“…16,[22][23][24][25] PAS has been loaded with zinc layered hydroxides (ZLH) and Zn/Al-LDHs. 26,27 Compared to these, MgLH is more suitable as it does not require trivalent ions like LDHs and more importantly, magnesium is more biocompatible than Zn 2+ , as we consume more magnesium in green vegetables on a regular basis. 28 Magnesium layered hydroxide (MgLH) is a non-toxic material that has a wide range of applications such as in cosmetic products, serving as a catalyst in flame-retardants and has been used as inorganic absorbents, etc.…”