Ortiz Raúl, Cabeza Laura, Arias José L, Melguizo Consolación, Álvarez Pablo J, Vélez Celia, Clares Beatriz, Áranega Antonia, Prados Jose
Department of Health Science, University of Jaén, 23071, Jaén, Spain.
AAPS J. 2015 Jul;17(4):918-29. doi: 10.1208/s12248-015-9761-5. Epub 2015 Apr 17.
The clinical use of 5-fluorouracil, one of the drugs of choice in colon cancer therapy, is limited by a nonuniform oral absorption, a short plasma half-life, and by the development of drug resistances by malignant cells. We hypothesized that the formulation of biodegradable nanocarriers for the efficient delivery of this antitumor drug may improve its therapeutic effect against advanced or recurrent colon cancer. Hence, we have engineered two 5-fluorouracil-loaded nanoparticulate systems based on the biodegradable polymers poly(butylcyanoacrylate) and poly(ε-caprolactone). Drug incorporation to the nanosystems was accomplished by entrapment (encapsulation/dispersion) within the polymeric network during nanoparticle synthesis, i.e., by anionic polymerization of the monomer and interfacial polymer disposition, respectively. Main factors determining 5-fluorouracil incorporation within the polymeric nanomatrices were investigated. These nanocarriers were characterized by high drug entrapment efficiencies and sustained drug-release profiles. In vitro studies using human and murine colon cancer cell lines demonstrated that both types of nanocarriers significantly increased the antiproliferative effect of the encapsulated drug. In addition, both nanoformulations produced in vivo an intense tumor growth inhibition and increased the mice survival rate, being the greater tumor volume reduction obtained when using the poly(ε-caprolactone)-based formulation. These results suggest that these nanocarriers may improve the antitumor activity of 5-fluorouracil and could be used against advanced or recurrent colon cancer.
5-氟尿嘧啶是结肠癌治疗的首选药物之一，其临床应用受到口服吸收不均一、血浆半衰期短以及恶性细胞产生耐药性的限制。我们推测，制备可生物降解的纳米载体以有效递送这种抗肿瘤药物，可能会提高其对晚期或复发性结肠癌的治疗效果。因此，我们基于可生物降解聚合物聚氰基丙烯酸丁酯和聚己内酯设计了两种负载5-氟尿嘧啶的纳米颗粒系统。药物掺入纳米系统是通过在纳米颗粒合成过程中包埋（封装/分散）在聚合物网络内实现的，即分别通过单体的阴离子聚合和界面聚合物沉积来实现。研究了决定5-氟尿嘧啶掺入聚合物纳米基质的主要因素。这些纳米载体具有高药物包封率和持续的药物释放曲线。使用人和小鼠结肠癌细胞系的体外研究表明，两种类型的纳米载体均显著增强了包封药物的抗增殖作用。此外，两种纳米制剂在体内均产生了强烈的肿瘤生长抑制作用，并提高了小鼠的存活率，使用基于聚己内酯的制剂时肿瘤体积减小得更大。这些结果表明，这些纳米载体可能会提高5-氟尿嘧啶的抗肿瘤活性，并可用于治疗晚期或复发性结肠癌。
