Development of poly-L-lysine multi-functionalized muco-penetrating self- emulsifying drug delivery system (SEDDS) for improved solubilization and targeted delivery of ciprofloxacin against intracellular Salmonella typhi

Salmonella typhi infections are difficult to treat due to poor penetration of current antibiotic ciprofloxacin (CIP)modalities into the intracellular compartments of macrophages owing to poor solubilization and oral bioavailability. Poor penetration and dissolution of CIP lead to development of intracellular pathogens induced multi-drug resistance and resistant biofilms formation. Here, we developed a novel strategy for the design and development of mucopenetrating self-emulsifying drug delivery system (SEDDS) of CIP to target intracellular Salmonella typhi bacterium with high specificity and selectivity. Oleic oil, Tween 80, and PEG 200 were selected as oil, surfactant and co-surfactant based on solubilizing capacity and pseudo ternary diagram emulsification capability.

Highlights

Muco-penetrating amphiphilic conjugate for the first time incorporated into SEDDS.

Multi-functionalized SEDDS shows non-toxic behavior on Macrophages RAW 264.7.

SEDDS are involved in intracellular targeted killing of S. typhi.

SEDDS overcome S. typhi resistance via bypassing non-specific drug delivery.

SEDDS proved to be promising vehicle for enhancing solubilization of CIP.

Mucopenetration feature of the SEDDS was enhanced by inclusion of poly-L-lysine functionalized carbohydrates (mannose, preactivated hyaluronic acid) co-block pluronic F127 (PLL-M-PTHA-F127) polymeric excipient. PLL-M-PTHA-F127 was developed as an amphiphilic muco-penetrating targeted anti-bacterial biological entity for intracellular targeting of Salmonella typhi infection reservoirs. Characterization of these self-nanoemulsifying carriers was carried out via dynamic light scattering (DLS), transmission electron microscopy (TEM) and fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), x-ray diffraction (XRD) and thermogravimetric analysis (TGA) The observed hydrodynamic diameter of PLL-M-PTHA-F 127 self- nano emulsifying drug delivery system (SEDDS) was 247 nm with low PDI and negatively charged zeta potential showing the stabilization of as-prepared formulation.

In vitro drug release kinetics of nanocarriers exhibited 85% sustained release within 72 h under sink conditions. PLL-M-PTHA-F127 SEDDS of CIP showed very strong killing capability against Salmonella typhi strains even at lowest concentrations as compared to CIP and were found to be hemocompatible and biocompatible. The intracellular Salmonella typhi survival rate has been minimized with PLL-M-PTHA-F127 SEDDS as compared to CIP alone. Fluorescence microscopy images confirmed the proficient cellular uptake within the intracellular compartment of macrophages and rapid gallstone biofilm dispersion/clearance activity as compared to other formulations and CIP. In summary, PLL-M-PTHA-F₁₂₇-SEDDS of CIP seemed to be an ideal candidate for eradication of Salmonella typhi intracellularly.

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Article information: Rabia Arshad, Tanveer A. Tabish, Abbas Ali Naseem, Muhammad Rauf ul Hassan, Irshad Hussain, Shahzad Shaikh Hussain, Gul Shahnaz. Journal of Molecular Liquids, 2021. https://doi.org/10.1016/j.molliq.2021.115972.