Stimuli-triggered drug release and improved drug loading are two key prerequisites in the preparation of nano-drug delivery systems. Herein, we constructed the first pluronic P123-double (d)–hydrazone bond (hyd)–docetaxel (DTX)/DTX complex micelles (P123-d–hyd–DTX/DTX) which integrated the highly pH-sensitive strategy and the dual drug-loading pattern in one platform. We synthesized pluronic P123-double (d)–hydrazone bond (hyd)–docetaxel (DTX) conjugates (P123-d–hyd–DTX) by conjugating DTX to the PEO chains of P123 via two hydrazone linkages in the backbone for the first time. An increase in the number of hydrazone linkages within the unimolecular conjugate was conducive to improve the pH sensitivity of conjugated-based micelles. Besides, aiming at improving drug loading, the dual drug-loading strategy (chemical conjugation and physical encapsulation) was adopted. Namely, pH-sensitive P123-d–hyd–DTX was used as a vehicle to further encapsulate DTX for preparing P123-d–hyd–DTX/DTX complex micelles. The resulting P123-d–hyd–DTX/DTX micelles exhibited intact spherical shape, uniform particle size distribution (110.37 nm) and higher drug loading (12.64%). The release study in vitro confirmed that P123-d–hyd–DTX/DTX micelles and P123-d–hyd–DTX micelles (as a control) showed highly pH-responsive release properties. In particular at pH 6.5, almost 90.9% and 75% of DTX was released within 48 h, respectively. Compared to P123-d–hyd–DTX micelles, P123-d–hyd–DTX/DTX complex micelles exhibited higher proliferation inhibition effects on B16F10 cells (p < 0.01), while the cytotoxicity of P123-d–hyd–DTX/DTX complex micelles was slightly inferior to that of free DTX (p < 0.05). In the xenograft B16F10 melanoma model, P123-d–hyd–DTX/DTX complex micelles suppressed tumor growth more effectively than Duopafei® (p < 0.01) and P123-d–hyd–DTX micelles (p < 0.05), without causing obvious adverse effects. Overall, the novel polymeric complex micelle based on double-hydrazone bond and dual drug-loading strategies was a promising delivery platform to improve therapeutic efficiency and decrease side effects in cancer treatments.
A complex micelle as a hemoglobin functional model with the biaoactive function of reversible oxygen transfer has been constructed through the hierarchical assembly of the diblock copolymer poly(ethylene glycol)- block poly(4-vinylpyridine- co - N -heptyl-4-vinylpyridine) (PEG- b -P(4VP- co -4VPHep)), tetrakis(4-sulfonatophenyl)porphinato iron(II) (Fe(II)TPPS) and β-cyclodextrin (β-CD). The μ-oxo dimer of Fe(II)TPPS was successfully inhibited because the Fe(II)TPPS was included into the cavities of β-CDs through host-guest interaction. Fe(II)TPPS coordinated with pyridine groups functions as the active site to reversibly bind dioxygen. In adition, the host-guest inclusion (β-CD/Fe(II)TPPS) was encapsulated in the hydrophobic core of the complex micelle and tightly fixed by P4VP chains. The hydrophilic PEG blocks stretched in aqueous solution to constitute the shells which stabilize the structure of the complex micelle as well as endow the complex micelle with sufficient blood circulation time. Dioxygen can be bound to the Fe(II)TPPS located in the confined space and excellent reversibility of the binding-release process of dioxygen can be achieved. The quaternary amine N-heptyl-4-vinylpyridine can coerce abundant S 2 O 4
2− ions into the core of the complex micelle to facilitate the self-reduction process. Dioxygen adducts (Fe(II)TPPS(O 2 )) were effectively protected by the double hydrophobic barriers constructed by the cavity of the cyclodextrin and the core of the complex micelle which enhances the ability to resist nucleophilic molecules. Therefore, the rationally designed amphiphilic structure can work as a promising artificial O 2 carrier. Potentially, the complex micelle can be expected to improve the treatment of diseases linked with hypoxia.
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