A novel graphene oxide nanoparticle (GON)-based drug delivery system containing GONs as carriers of anticancer drugs and chitosan/dimethylmaleic anhydride-modified chitosan (CS/CS-DMMA) as surface charge-reversible shells is fabricated via the classic self-assembly of the deprotonated carboxyl of GONs and the protonated amine of the CS backbone by electrostatic interaction, and CS-DMMA serves as the outmost layer. In this GON-based drug delivery system, the GON cores as desired carriers might adsorb doxorubicin hydrochloride (DOX) via the π-π stacking interaction between the large π conjugated structures of GO and the aromatic structure of DOX. Meanwhile, the chitosan-based polyelectrolyte shells served as a smart protection screen to evade the premature release of the as-loaded DOX in normal extracellular condition, and then, the release of DOX was accelerated because of the detachment of chitosan coating at low pH. Furthermore, the re-exposure of amino groups after hydrolysis of CS-DMMA endowed the drug delivery system with positive surface charge by taking advantage of the pH difference between physiological conditions and the tumor microenvironment to enhance the cellular uptake. Then, the pH-dependent site-specific drug release was realized. The in vitro investigations confirmed that these promising GON/CS/CS-DMMA hybrids with the charge-reversible character possessed various merits including excellent encapsulation efficiency, high stability under physiological conditions, enhanced cellular uptake by HepG2 cells, and tunable intracellular chemotherapeutic agent release profiles, proving its capability as an intelligent anticancer agent nanocarrier with enhanced therapeutic effects. This smart GON/CS/CS-DMMA vehicle with the surface charge-reversible character may be used as a significant drug delivery system for cancer treatment.
The TPE moiety with AIE is employed as functional hydrophobic chain to induce copolymer self-assembly and form polymeric micelle that can show enzyme-responsive drug delivery.
HIGHLIGHTS • The formation of manganese oxide induces self-assembly of block copolymers to form polymeric vesicles. • The polymeric vesicles possessed strong stability and high drug loading capacity. • The drug-loaded polymeric vesicles have been demonstrated, especially in in vivo studies, to exhibit a higher efficacy of tumor suppression without known cardiotoxicity.
The polymerization of dopamine and its coupling occur in succession, which synergistically induces the self-assembly of block copolymer to yield ordered structures, including micelles and vesicles.
Smart poly(methacrylic acid-co-N,N-bis(acryloyl)cystamine)/DOX/MnO 2 -2/polyethylene glycol theranostic nanohybrids (PMAA BACy /DOX/MnO 2 -2/PEG TNs) were rationally fabricated using in situ generation of amorphous MnO 2 by taking advantage of the spatial confinement effect of PMAA BACy nanohydrogels, and its PEGylation was accomplished through Mn−N coordinate bonding. The amorphous MnO 2 of PMAA BACy /DOX/MnO 2 -2/PEG TNs was synthesized through the chelation between Mn 2+ ions and carboxyl groups of PMAA chains, which served as a gatekeeper to prevent the premature leakage of DOX during blood circulation. In the presence of intracellular acidic glutathione (GSH), the release of Mn 2+ ions from amorphous MnO 2 as a dual T 1 /T 2 contrast agent endowed the nanohybrids with enhanced acid/GSH-activated magnetic resonance imaging (MRI). In addition, the site-specific release of a chemotherapeutic drug (DOX) was also realized because of the disintegration of both amorphous MnO 2 and PMAA BACy in response to biological endogenous stimulus, such as increased GSH level and slightly acidic pH in tumor cells. The newly as-synthesized nanohybrids presented some excellent characteristics: they prevented premature release; enhanced the stability under physiological conditions; and exhibited excellent T 1 /T 2 MRI performance, remarkable biodegradability, and efficient site-specific release of DOX. Our findings indicated that such polymer/amorphous manganese oxide-based biodegradable nanohybrids can facilitate the development of a drug delivery system with a capacity for low premature release for real-time MRI-guided cancer therapy.
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