Nanoparticle-Stabilized Liposomes for pH-Responsive Gastric Drug Delivery

Abstract

We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~ 10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~ 75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However when the stabilized liposomes are present in an environment with neutral pH, the gold stabilizers detach from the liposomes resulting in free liposomes that can actively fuse with bacterial membranes. Using Helicobacter pylori as a model bacterium and doxycycline as a model antibiotic, we demonstrate such pH-responsive fusion activity and drug release profile of the nanoparticle-stabilized liposomes. Particularly, at neutral pH the gold nanoparticles detach and thus the doxycycline-loaded liposomes rapidly fuse with bacteria and cause superior bactericidal efficacy as compared to the free doxycycline counterpart. Our results suggest that the reported liposome system holds a substantial potential for gastric drug delivery; it remains inactive (stable) in the stomach lumen but actively interact with bacteria once reaches the mucus layer of the stomach where the bacteria may reside.

Phospholipase A2-responsive antibiotic delivery via nanoparticle-stabilized liposomes for the treatment of bacterial infection

“…First, AuChi were synthesized by an ex-situ stabilization technique as previously described, where gold nanoparticles were made with a sodium borohydride reduction method and then stabilized by adding calculated amount of chitosan under ambient condition 14, 17 . Dynamic light scattering (DLS) measurements of AuChi showed a diameter of approximately 10 nm with a narrow size distribution and a strong positive surface charge of 35.5 ± 0.9 mV, indicating the presence of cationic amine groups of chitosan on gold surfaces.…”

“…For instance, cationic liposomes bound with negatively charged gold nanoparticles only fused with bacteria at acidic pH, which made them suitable for treating various skin pathogens that thrive in acidic infection sites such as the case with Propionibacterium acnes 13 . Conversely, anionic liposomes stabilized by positively charged gold nanoparticles were highly stable in gastric acid, but capable of fusing with bacteria at physiological pH, making them suitable to treat gastric pathogens such as Helicobacter pylori ( H. pylori ) 14 . Even in the absence of such stimulus-induced detachment of the nanoparticle stabilizers, these liposomes still had a substantial fraction of their surface areas exposed and highly accessible to membrane-targeting biochemical molecules such as bacterial toxins and enzymes.…”

Nanoparticle approaches against bacterial infections

“…For instance, cationic liposomes bound with negatively charged gold nanoparticles only fused with bacteria at acidic pH, which made them suitable for treating various skin pathogens that thrive in acidic infection sites such as the case with Propionibacterium acnes ( P. acnes ) 64 . Conversely, anionic liposomes stabilized by positively charged gold nanoparticles were highly stable in gastric acid, but capable of fusing with bacteria at physiological pH, making them suitable to treat gastric pathogens such as H. pylori 65 . Even in the absence of such stimulus-induced detachment of the nanoparticle stabilizers, these liposomes still had a substantial fraction of their surface areas exposed and highly accessible to bacterial toxins.…”

Co-assembly in chitosan–surfactant mixtures: thermodynamics, structures, interfacial properties and applications

“…In particular, their potential as topical delivery system was demonstrated by several studies [162,[232][233][234][235], in particular dealing with ocular, nasal, and pulmonary delivery arising from the high adherence of chitosan towards these tissues [205,236]. A different approach for the use of chitosan and phospholipids for drug delivery purposes consists in the adsorption of chitosan-modified gold nanoparticles the outer surface of loaded liposomes [237]. Such liposomes were shown to be stable in acidic medium, while they exhibit a pronounced tendency to fuse with bacterial membrane upon increase of pH, therefore effectively releasing their content.…”