For combinatorial monitoring and chemotherapy of hepatocellular carcinoma, the macromolecular prodrug based on hyaluronic acid and doxorubicin hydrochloride was prepared by an acid-labile hydrazone linkage, and then conjugated with amine-modified iron oxide nanoparticles by a carbodiimide mediated coupling reaction. The resultant hybrid nanoparticles have the characteristics of good water dispersibility, superparamagnetic property and high magnetic relaxivity for magnetic resonance imaging. In particular, they demonstrated significant cellular uptake and specific accumulation in human hepatocellular liver carcinoma HepG2 cells due to specific biological recognition of hyaluronic acid. In addition, in vitro cumulative release of doxorubicin hydrochloride from the resultant hybrid nanoparticles was significantly accelerated at a mildly acidic pH of 5.0–6.0 when compared to its release at the physiological pH of 7.4, suggesting the pH-responsive feature of this conjugated prodrug for effective chemotherapy of hepatocellular carcinoma. In vivo antitumor efficacy of the mice further confirmed the effect.
The diselenide bond has attracted intense interest for drug delivery systems (DDSs) for tumor chemotherapy, owing to it possessing higher redox sensitivity than the disulfide one. Various redox-responsive diselenide-containing carriers have been developed for chemotherapeutics delivery. However, the premature drug leakage from these DDSs was significant enough to cause toxic side effects on normal cells. Here, a pH/redox co-triggered degradable polyprodrug was designed as a drug self-delivery system (DSDS) by incorporating drug molecules as structural units in the polymer main chains, using a facile one-pot two-step approach. The proposed PDOX could only degrade and release drugs by breaking both the neighboring acid-labile acylhydrazone and the redox-cleavable diselenide conjugations in the drug’s structural units, triggered by the higher acidity and glutathione (GSH) or reactive oxygen species (ROS) levels in the tumor cells. Therefore, a slow solubility-controlled drug release was achieved for tumor-specific chemotherapy, indicating promising potential as a safe and efficient long-acting DSDS for future tumor treatment.
Ultrasound has been recognized as an exciting tool to enhance the therapeutic efficacy in tumor chemotherapy owing to the triggered drug release, facilitated intracellular drug delivery, and improved spatial precision. Aiming for a precise localized drug delivery, novel dendritic polyurethane-based prodrug (DOX-DPU-PEG) was fabricated with a drug content of 18.9% here by conjugating DOX onto the end groups of the functionalized dendritic polyurethane via acid-labile imine bonds. It could easily form unimolecular micelles around 38 nm. Compared with the non-covalently drug-loaded unimolecular micelles (DOX@Ph-DPU-PEG), they showed excellent pH/ultrasound dual-triggered drug release performance, with drug leakage of only 4% at pH 7.4, but cumulative release of 14% and 88% at pH 5.0 without and with ultrasound, respectively. The ultrasound responsiveness was attributed to the unique strawberry-shaped topological structure of the DOX-DPU-PEG, in which DOX was embedded in the skin layer of the hydrophobic DPU cores. With ultrasound, the DOX-DPU-PEG unimolecular micelles possessed enhanced tumor growth inhibition than free DOX but showed no obvious cytotoxicity on the tumor cells without ultrasound. Such feature makes them promising potential for precise localized drug delivery.
Han Hu,Ying Tian,Zhengyang Kong,Wu Bin Ying,Chao Chen,Fenglong Li,Ruoyu Zhang,Jin Zhu
The gradual degradation of polyester in daily use causes unpredictable failure and restricts its reliable applications. The realization of excellent stability in use and controlled degradation in a specific environment is highly appreciated but still remains challengeable. Here, we demonstrate a new solution via introducing acetal units into poly(butylene succinate): “locking” the biodegradation of copolyesters by rigid spiro diacetal, which could be “unlocked” in strong acidic circumstances. In detail, a series of poly(butylene succinate-co-spirocyclic succinate) (PBSS) copolyesters containing different contents of spiroglycol (SPG) were prepared and characterized. Among them PBSS65 behaved as an excellent candidate for future application, which possessed a high elastic modulus (1.87 GPa) and tensile strength (46 MPa) and moderate elongation at break (252%). It kept stable after melt processing and pH 0–14 soaking, showing solid reliability in daily use. Its biodegradation was locked by the steric hindrance effect of SPG units. Only after treatment in acetone/H2O mixed acidic solution could the biodegradation be triggered. Moreover, it was found that the prolongation of the acid treatment time could accelerate the biodegradation process. The controlled degradation mechanism was proposed to be consisted of acid cleavage of SPG unit and enzymatic degradation of ester group.
危险品化学品经营许可证（带存储）