# Impact of chain-length of sulfhydryl-modified surface-decorated surfactants on mucoadhesive nanostructured lipid carriers

## TL;DR

This study shows that short-chain sulfhydryl-modified surfactants improve the performance of drug-carrying nanoparticles for better drug absorption.

## Contribution

The study reveals how surfactant chain-length affects mucoadhesion, permeation, and bioavailability in nanostructured lipid carriers.

## Key findings

- Short-chain surfactants showed 11.6-fold enhanced mucoadhesion compared to long-chain surfactants.
- Short-chain surfactants achieved 5.38-fold higher Cmax and 34.8% relative bioavailability.
- Short-chain surfactants improved cellular permeation and deeper mucus penetration.

## Abstract

Nanostructured lipid carriers (NLCs) decorated with sulfhydryl-modified surfactants have recently gained attention for delivering BCS Class IV drugs. However, the impact of the chain-length of these surfactants on the permeation and bioavailability properties of NLCs is still unknown. Therefore, this study investigates the effect of surfactant chain-length on the mucoadhesive, permeation, and bioavailability properties of NLCs. For this purpose, short- and long-chain sulfhydryl-modified polyethoxylated surfactants were generated to develop mucoadhesive NLCs and loaded with the model drug aprepitant (APT). NLCs were characterized and assessed for comprehensive physicochemical and biological evaluations. Moreover, in-vivo studies were performed for proof-of-concept to show enhanced oral drug bioavailability. NLCs showed particle size under 200 nm with 6.9 and 6.7% drug loading and 85 and 84% drug entrapment for short- and long-chain surfactants, respectively. The drug-loaded NLCs were safe and stable, and short- and long-chain surfactants containing NLCs exhibited 11.6- and 9.6-fold enhanced mucoadhesion, respectively. Moreover, in comparison to long-chain sulfhydryl-modified surfactant, short-chain surfactant is transported into deeper segments of mucus due to less interaction with the mucus. Similarly, short-chain sulfhydryl-modified surfactants showed significantly enhanced cellular permeation across Caco-2 cell lines. Furthermore, the long-chain sulfhydryl-modified surfactants showed 4.38-fold enhanced Cmax, whereas due to better diffusion and mucoadhesion properties, the short-chain surfactants exhibited 5.38-fold enhanced Cmax. Similarly, 34.8% relative bioavailability was attained for short-chain surfactants and 24.8% for long-chain surfactants. These results suggest short-chain sulfhydryl surfactants are promising candidates for improving the oral delivery of poorly soluble drugs and warrant further investigation for clinical translation.

The online version contains supplementary material available at 10.1007/s13346-025-01905-w.