State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
Biomaterials. 2010 May;31(15):4426-33. doi: 10.1016/j.biomaterials.2010.02.007. Epub 2010 Feb 25.
Chitosan and its derivatives have shown great potential as non-viral vectors for gene delivery therapy. Folic acid receptor (FR) is an important anti-cancer therapy target that is applicable to many cancer types. In this study, we developed an efficient and targeted delivery of antisense oligodeoxynucleotides asODNs, using folic acid (FA) conjugated hydroxypropyl-chitosan (HPCS). These nanoparticles were designed to reduce production of P-gp, in order to overcome tumor drug resistance. Nanoparticles prepared were found to be 181 nm in diameter. Spectrofluorimetry was utilized to evaluate the effect of charge ratio of the nanoparticles on loading efficiency. In PBS buffer, 40% of asODNs were released from the nanoparticles at first 24 h. However, just another 15% was released between 24 and 48 h. The antitumor effect of the nanoparticles was evaluated in KB-A-1 cells implanted in Balb/c-nu/nu mice. They inhibited the growth of tumor by 35% compared to the bare asODNs. The FA-HPCS-asODNs nanoparticles demonstrated significantly inhibition of the multi drug resistance (MDR) 1 gene levels and P-gp levels in vitro and in vivo, respectively, related with bare asODNs and HPCS-asODNs ones. During in vivo studies, FA-HPCS-asODNs nanoparticles were also found to bind specifically and efficiently to FR high-expressing cancer cells. These results suggested that the use of targeted, antisense agent nanoparticles would be potential approach to overcome tumor drug resistance.
壳聚糖及其衍生物在基因治疗中作为非病毒载体显示出巨大的潜力。叶酸受体（FR）是一种重要的抗癌治疗靶点，适用于多种癌症类型。在这项研究中，我们使用叶酸（FA）修饰的羟丙基壳聚糖（HPCS）开发了一种高效靶向传递反义寡核苷酸（asODNs）的方法。这些纳米粒子旨在减少 P-糖蛋白（P-gp）的产生，以克服肿瘤耐药性。所制备的纳米粒子的直径为 181nm。荧光分光光度法用于评估纳米粒子的电荷比对载药效率的影响。在 PBS 缓冲液中，40%的 asODNs 在最初的 24 小时内从纳米粒子中释放出来。然而，在 24 到 48 小时之间，只有另外 15%的 asODNs 被释放出来。纳米粒子的抗肿瘤效果在 Balb/c-nu/nu 小鼠中植入的 KB-A-1 细胞中进行了评估。与裸 asODNs 相比，它们抑制肿瘤生长了 35%。FA-HPCS-asODNs 纳米粒子在体外和体内分别显著抑制了多药耐药（MDR）1 基因水平和 P-糖蛋白水平，与裸 asODNs 和 HPCS-asODNs 相比。在体内研究中，还发现 FA-HPCS-asODNs 纳米粒子能够特异性和有效地结合 FR 高表达癌细胞。这些结果表明，使用靶向、反义药物纳米粒子可能是克服肿瘤耐药性的一种潜在方法。
