Cheewatanakornkool Kamonrak, Niratisai Sathit, Manchun Somkamol, Dass Crispin R, Sriamornsak Pornsak
Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand.
Pharmaceutical Biopolymer Group (PBiG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand.
Asian J Pharm Sci. 2017 Nov;12(6):509-520. doi: 10.1016/j.ajps.2017.07.005. Epub 2017 Jul 12.
Novel oral microbeads were developed based on a biopolymer-drug conjugate of doxorubicin (DOX) conjugated with thiolated pectin via reducible disulfide bonds. The microbeads were fabricated by ionotropic gelation with cations such as Al, Ca and Zn. The results showed that using zinc acetate can produce the strongest microbeads with spherical shape. However, the microbeads prepared from thiolated pectin-DOX conjugate were very soft and irregular in shape. To produce more spherical microbeads with suitable strength, the native pectin was then added to the formulations. The particle size of the microbeads ranged from 0.87 to 1.14 mm. The morphology of the microbeads was characterized by optical and scanning electron microscopy. DOX was still in crystalline form when used in preparing the microbeads, as confirmed by powder X-ray diffractometry. Drug release profiles showed that the microbeads containing thiolated pectin-DOX conjugate exhibited reduction-responsive character; in reducing environments, the thiolated pectin-DOX conjugate could uncouple resulting from a cleavage of the disulfide linkers and consequently release the DOX. The best-fit release kinetics of the microbeads containing thiolated pectin-DOX conjugate, in the medium without reducing agent, fit the Korsmeyer-Peppas model while those in the medium with reducing agent fit a zero-order release model. These results suggested that the microbeads containing thiolated pectin-DOX conjugate may be a promising platform for cancer-targeted delivery of DOX, exploiting the reducing environment typically found in tumors.
新型口服微球是基于阿霉素（DOX）的生物聚合物-药物共轭物开发的，该共轭物通过可还原的二硫键与硫醇化果胶结合。微球通过与铝、钙和锌等阳离子进行离子凝胶化制备。结果表明，使用醋酸锌可以制备出形状为球形且强度最强的微球。然而，由硫醇化果胶-DOX共轭物制备的微球非常柔软且形状不规则。为了制备出形状更规则且强度合适的球形微球，随后将天然果胶添加到配方中。微球的粒径范围为0.87至1.14毫米。通过光学显微镜和扫描电子显微镜对微球的形态进行了表征。粉末X射线衍射法证实，制备微球时使用的DOX仍为结晶形式。药物释放曲线表明，含有硫醇化果胶-DOX共轭物的微球具有还原响应特性；在还原环境中，硫醇化果胶-DOX共轭物可因二硫键连接子的断裂而解偶联，从而释放出DOX。在不含还原剂的介质中，含有硫醇化果胶-DOX共轭物的微球的最佳拟合释放动力学符合Korsmeyer-Peppas模型，而在含有还原剂的介质中则符合零级释放模型。这些结果表明，含有硫醇化果胶-DOX共轭物的微球可能是一种有前景的阿霉素癌症靶向递送平台，利用了肿瘤中典型的还原环境。
