Liposomes‐Camouflaged Redox‐Responsive Nanogels to Resolve the Dilemma between Extracellular Stability and Intracellular Drug Release

Abstract

Liposomes have shown great promises for pharmaceutical applications, but still suffer from the poor storage stability, undesirable drug leakage, and uncontrolled drug release. Herein, liposomes-camouflaged redox-responsive nanogels platform (denoted as "R-lipogels") is prepared to integrate the desirable features of sensitive nanogels into liposomes to circumvent their intrinsic issues. The results indicate that drug-loaded R-lipogels with controlled size and high stability not only can achieve a very high doxorubicin (DOX)-loading capacity (12.9%) and encapsulation efficiency (97.3%) by ammonium sulfate gradient method and very low premature leakage at physiological condition, but also can quickly release DOX in the reducing microenvironment of tumor cells, resulting in effective growth inhibition of tumor cells. In summary, the strategy given here provides a facile approach to develop liposomes-nanogels hybrid system with combined beneficial features of stealthy liposomes and responsive nanogels, which potentially resolves the dilemma between systemic stability and intracellular rapid drug release.

Hybrid Nanogels: Stealth and Biocompatible Structures for Drug Delivery Applications

“…In 2018, Zhang et al prepared various liposome-camouflaged nanogels [82,108,109], adopting for all systems the PEGylation strategy with chains of 2000 Da grafted on the lipidic shell. Their most distinguished work [82] reports the drug delivery combined with the photothermal effect.…”

“…In a slight variation proposed by the same authors [109], the nanogel was prepared by adopting cysteine dimethacrylate as redox responsive disulfide crosslinker. Thus, the nanohybrid release is triggered by the presence of glutathione inside the cells.…”

Stimulus-responsive liposomes for biomedical applications

“…Another disulfide-based strategy entailed the formation of hydrogel cores with cross-linked 3D structures, which significantly improve mechanical stability, determine a unique rheological behavior and rapid stimuli-responsiveness to the resulting liposomal formulations [56]. LP-camouflaged, redox-responsive nanogels ("R-lipogels") were designed and prepared by LP-templated in situ polymerization process of acrylamide (AM) in presence of water-soluble cystine dimethacrylate (CDA).…”

A Comprehensive Outlook of Synthetic Strategies and Applications of Redox‐Responsive Nanogels in Drug Delivery

“…Many redox‐responsive cross‐linkers being utilized for nanogel synthesis contain cysteine and cystamine as redox‐responsive constituents, terminal acrylates to take part in radical polymerization, and PEG as a functional skeletal unit of the nanogel, owing to its advantageous properties as discussed in the preceding section . Some of the cross‐linkers mainly being used are l ‐cystine N ‐carboxyanhydride ( l ‐Cys NCA), dithiopropionyl poly(ethylene glycol)dimethacrylate (ssDMA), cystine dimethacrylate (CDA), 2‐(pyridin‐2‐yldisulfanyl)ethyl acrylate (PDSA), N,N′ ‐bis(acryloyl)cystamine (BAC), pendent disulfide‐functionalized methacrylate (HMssEt), 11,11′‐diselanediylbis(undecan‐1‐ol) (DSeOH), 11,11′‐ditellurediylbis(undecan‐1‐ol) (DTeOH), N,N′ ‐bis (methacryloyl)selenocystamine (BMASC), and dithio‐bis‐maleimidoethane (DTME) ( Figure 2 and Table 2 ). Disulfide (SS), ditellurium (TeTe), and diselenide (SeSe) bonds are the main reported building blocks and important structural units of redox‐responsive materials and are described to possess excellent activity in the presence of reductants/oxidants .…”