Design and synthesis of multifunctional polymeric micelles for targeted delivery in Helicobacter pylori infection

• Published in: Journal of molecular liquids 2022-10, Vol.363, p.119802, Article 119802
• Main Authors: Qaiser, Aimen, Kiani, Maria Hassan, Parveen, Rashida, Sarfraz, Muhammad, Shahnaz, Gul, Rahdar, Abbas, Taboada, Pablo
• Format: Article
• Language: English
• Subjects: H. pylori infection; Mucoadhesion; Mucopenetration; Nanomicelles; Targeted delivery
• ISSN: 0167-7322; 1873-3166
• DOI: 10.1016/j.molliq.2022.119802

•Hyaluronic acid-based block copolymer micelles for H. pylori infection were obtained.•HA-based nanomicelles showed important mucoadhesive and mucopenetrating properties.•The polymeric micelles are largely retained in gastric conditions, releasing the bioactive cargo.•The micelles were shown to highly penetrate in the mucus gasstric layer.•The present nanoformulation showed a high bioactivity both in vitro and in vivo against H. pylori infection. This study aimed to design a hyaluronic acid-based targeted, mucoadhesive and mucopenetrating drug delivery system encapsulating clarithromycin that would improve the drug residence time at H. pylori infection site. Clarithromycin-loaded thiolated hyaluronic acid-co-oleic acid (CLR-thHA-co-OA), clarithromycin-loaded ureido-conjugated thiolated hyaluronic acid-co-oleic acid (CLR-Ur-thHA-co-OA), and clarithromycin-loaded papain-modified ureido-conjugated thiolated hyaluronic acid-co- oleic acid (CLR-PAP-Ur-thHA-co-OA) nanomicelles were prepared by an ultra-sonication method. FTIR data confirmed the successful grafting of the different ligands to polymer backbone. XRD analysis revealed the amorphous nature of the polymer conjugate and drug inside nanomicelles. The critical micelle concentration of PAP-Ur-thHA-co-OA nanomicelles was found to be 15.85 µg/ml. Also, the sizes of nanomicelles were in the range of 210–258 nm. TEM analysis of CLR-PAP-Ur-thHA-co-OA nanomicelles confirmed their small size and spherical shape. Zeta potential and entrapment efficiency of CLR-PAP-Ur-thHA-co-OA nanomicelles were –24 mV and 80 ± 7.2% respectively. A sustained drug release pattern was observed for all types of prepared nanomicelles, whereas CLR-PAP-Ur-thHA-co-OA ones also displayed improved stability at acidic pH. Due to the presence of thiol groups in the polymer backbone, thiolated nanomicelles displayed important mucoadhesive properties. In this regard, FDA loaded PAP-Ur-thHA-co-OA nanomicelles showed the deepest penetration distance into the mucus by cleavage of mucoglycoproteins when compared to papain-unmodified nanomicelles. Fluorescent images of gastric tissues revealed the greater gastric retention time of nanomicelles compared to the free drug. As consequence, an enhanced in vitro efficacy against H. pylori was observed by nanomicelles. The in vivo clearance study showed an improved eradication of H. pylori by CLR-PAP-Ur-thHA-co-OA nanomicelles in comparison to other nanoformulations. Thus, the newly synthesized CLR-PAP-U