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

Samia Kausar; Sofia O D Duarte; Ahmed Raza Hashmi; Farwa Zahra; Alia Erum; Shumaila Arshad; Ume Ruqia Tulain; Mulazim Hussain Asim; Pedro Fonte

doi:10.1007/s13346-025-01905-w

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

Drug Deliv Transl Res. 2025 Jun 24. doi: 10.1007/s13346-025-01905-w. Online ahead of print.

Authors

Samia Kausar^{1

2}, Sofia O D Duarte^{3

4}, Ahmed Raza Hashmi⁵, Farwa Zahra⁶, Alia Erum⁷, Shumaila Arshad⁸, Ume Ruqia Tulain¹, Mulazim Hussain Asim⁹, Pedro Fonte^{10

11

12

13}

Affiliations

¹ College of Pharmacy, University of Sargodha, Sargodha, Punjab, 40100, Pakistan.
² Lahore College of Pharmaceutical Sciences, Raiwind road, Lahore, 54000, Pakistan.
³ iBB- Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisboa, 1049-001, Portugal.
⁴ Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisboa, 1049-001, Portugal.
⁵ School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya, Selangor, Malaysia.
⁶ Doctor's Institute of Health Sciences, Sargodha, 40100, Pakistan.
⁷ College of Pharmacy, University of Sargodha, Sargodha, Punjab, 40100, Pakistan. alia.erum@uos.edu.pk.
⁸ ILM College of Pharmaceutical Sciences & Sargodha College of Medical Sciences, Sargodha, 40100, Pakistan.
⁹ College of Pharmacy, University of Sargodha, Sargodha, Punjab, 40100, Pakistan. mulazim.hussain@uos.edu.pk.
¹⁰ iBB- Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, Lisboa, 1049-001, Portugal. prfonte@ualg.pt.
¹¹ Associate Laboratory i4HB-Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, Lisboa, 1049-001, Portugal. prfonte@ualg.pt.
¹² Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of Algarve, Gambelas Campus, Faro, 8005-139, Portugal. prfonte@ualg.pt.
¹³ Centro de Ciências do Mar do Algarve (CCMAR/CIMAR LA), Universidade do Algarve, Campus de Gambelas, Faro, 8005-139, Portugal. prfonte@ualg.pt.

PMID: 40553323
DOI: 10.1007/s13346-025-01905-w

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 C_max, whereas due to better diffusion and mucoadhesion properties, the short-chain surfactants exhibited 5.38-fold enhanced C_max. 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.

Keywords: Aprepitant; Controlled drug release; Enhanced oral bioavailability; Mucoadhesive NLCs; Mucosal permeability; Sulfhydryl-modified surfactants.