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Abstract. A pH-triggered drug delivery system of degradable core cross-linked (CCL) prodrug micelles was prepared by click chemistry. Doxorubicin conjugated block copolymers of azido functional poly(ethylene oxide)-b-poly(glycidyl methacrylate) were synthesized by the combination of RAFT polymerization, epoxide ring-opening reaction, and acid-cleavable hydrazone linkages. The CCL prodrug micelles were produced by the reaction of dipropargyl 3,3′-dithiodipropionate and dipropargyl adipate cross-linking agents with the azido groups of the micellar core via alkyne-azide click reaction, which were denoted as CCL/SS and CCL/noSS, respectively. The TEM images of CCL/SS prodrug micelles showed a spherical shape with the average diameter of 61.0 nm from water, and the shape was maintained with an increased diameter upon dilution with 5-fold DMF. The high DOX conjugation efficiency was 88.4%. In contrast to a very slow DOX release from CCL/SS prodrug micelles under the physiological condition (pH 7.4), the drug release is much faster (90%) at pH 5.0 and 10 mM of GSH after 96 h. The cytotoxicity test and confocal laser scanning microscopy analysis revealed that CCL/SS prodrug micelles had much enhanced intracellular drug release capability in HepG2 cells than CCL/noSS prodrug micelles.
Keywords: smart polymers, cross-linking, prodrug, doxorubicin, HepG2
1.Introduction
Polymeric core-shell architectures have attracted great attention due to potential applications in drug delivery [1-4]. In aqueous media, amphiphilic block copolymers can self-assemble into micelles which consist of hydrophilic corona and hydrophobic core. Drugs can be loaded into these micelles which not only avoid the metabolization and rapid clearance from the body but also reduce toxicity of drug towards healthy tissues [5-8]. The drug of interest is either dissolved, entrapped, attached or encapsulated into the polymeric micelles depending on the method of preparation [9-11]. However, the in vivo stability of polymeric micelles, following intravenous administration still leaves a challenge due to dissociation into unimers under certain factors such as low concentration, high shearing force in the blood circulation [12]. To stabilize polymeric micelles for in vivo applications, hydrophobic blocks can be cross-linked by various strategies including dimethylmaleide photo-crosslinking [13], phototriggered disulfide cross-link [14], and metal-coordination complexes [9, 15], resulting in core cross-linked micelles. Nevertheless, conventional antitumor drugs are quickly distributed at administration in the body leading to fast renal clearance, short durations of action, and significant dissipation, with only a fraction...