Polymer-Lipid Hybrid Nanoparticles for Enhanced Gentamicin Efficacy Against Drug-Resistant Bacteria

Alaa Eldeen Yassin,1,2 Faisal Alsuwayyid,1,3 Lama Alkhathran,1 Sabiha Alrouisan,1 Ghadah Alotaibi,1 Majd Alyaqub,1 Weam Alsalman,1 Raghad R Alzahrani,2,4 Ibrahim Farh,1,2 Majed Halwani,1,2 Shmeylan Al Harbi1,2,5 1Department of Pharmaceutical Sciences, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, 11481, Saudi Arabia; 2Nanomedicine Department, King Abdullah International Medical Research Center, Riyadh, 11481, Saudi Arabia; 3Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN, 47907, USA; 4Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia; 5Pharmaceutical Care Department, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, 11426, Saudi ArabiaCorrespondence: Alaa Eldeen Yassin, College of Pharmacy, King Saud bin Abdulaziz University for Health Science, P.O. Box 3660, Riyadh, 11481, Saudi Arabia, Tel +966114295038, Email [email protected]: Antibiotic resistance is a critical global health concern, exacerbated by biofilm formation and the declining effectiveness of conventional therapies. This study investigates polymer-lipid hybrid nanoparticles (PLNs) as an innovative nanocarrier system to enhance the antibacterial efficacy of gentamicin (Gen) while overcoming its inherent hydrophilicity and poor encapsulation efficiency.Methods: Using an optimized double-emulsification/solvent-evaporation technique, PLNs were designed to improve drug encapsulation efficiency (EE%) and loading capacity (DL%). The resulting formulations (F0, f1, F2, F3, F4) were characterized for particle size, polydispersity index (PDI), zeta potential, and EE%. Transmitted electron microscopy (TEM) provided insights into particle morphology, while antibacterial activity was tested against multiple bacterial strains, including resistant isolates.Results: The optimized formulation (F4) demonstrated favorable characteristics (p≤ 0.05) including, EE% of 42.1± 3.8%, a DL% of 8.0± 0.7%, and uniform small average particle size (143.4± 3.69 nm) and zeta potential − 37.9± 3.1 mV. TEM analysis confirmed Gen encapsulation within the lipid-polymer matrix. In vitro antibacterial assays demonstrated that F4 significantly enhanced antibacterial activity (p ≤ 0.05), achieving up to a 160-fold reduction in minimum inhibitory and bactericidal concentrations (MIC/MBC) against Methicillin-resistant Staphylococcus aureus (MRSA-59) and Pseudomonas aeruginosa (PA-78) compared with free Gen.Conclusion: These findings underscore the potential of PLNs as a robust platform for targeted drug delivery, offering a promising strategy to combat antimicrobial resistance.Keywords: polymer-lipid hybrid nanoparticles, gentamicin, double-emulsification/solvent-evaporation, entrapment efficiency