Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal; Institute for Research and Innovation in Health (i3s), University of Porto, 4200-135 Porto, Portugal; Institute for Biomedical Engineering (INEB), 4200-135 Porto, Portugal; Digestive Cancer Research Group, 1495-161 Algés, Portugal.
Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; Digestive Cancer Research Group, 1495-161 Algés, Portugal.
Int J Pharm. 2019 Oct 30;570:118646. doi: 10.1016/j.ijpharm.2019.118646. Epub 2019 Aug 26.
Gastric cancer is the third leading cause of cancer-related death worldwide, with half of patients developing metastasis within 5 years after curative treatment. Moreover, many patients cannot tolerate or complete systemic treatment due severe side-effects, reducing their effectiveness. Thus, targeted therapeutics are warranted to improve treatment outcomes and reduce toxicity. Herein, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with 5-fluorouracil (5-FU) and paclitaxel were surface-functionalized with a monoclonal antibody targeting sialyl-Lewis A (sLeA), a known glycan mediating hematogenous metastasis. Nanoparticles, ranging from 137 to 330 nm, enabled the controlled release of cytotoxic drugs at neutral and acid pH, supporting potential for intravenous and oral administration. Nanoencapsulation also reduced the initial toxicity of the drugs against gastric cells, suggesting it may constitute a safer administration vehicle. Furthermore, nanoparticle functionalization significantly enhanced targeting to sLeA cells in vitro and ex vivo (over 40% in comparison to non-targeted nanoparticles). In summary, a glycoengineered nano-vehicle was successfully developed to deliver 5-FU and paclitaxel therapeutic agents to metastatic gastric cancer cells. We anticipate that this may constitute an important milestone to establish improved targeted therapeutics against gastric cancer. Given the pancarcinomic nature of the sLeA antigen, the translation of this solution to other models may be also envisaged.
胃癌是全球第三大癌症相关死亡原因，半数患者在根治性治疗后 5 年内发生转移。此外，由于严重的副作用，许多患者无法耐受或完成全身治疗，降低了其疗效。因此，有必要开发靶向治疗药物来改善治疗效果并降低毒性。在此，载有 5-氟尿嘧啶（5-FU）和紫杉醇的聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒被靶向唾液酸化-Lewis A（sLeA）的单克隆抗体表面功能化，sLeA 是一种已知的介导血源性转移的聚糖。纳米颗粒的粒径范围为 137 至 330nm，可在中性和酸性 pH 值下控制释放细胞毒性药物，支持静脉内和口服给药的潜力。纳米封装还降低了药物对胃细胞的初始毒性，表明它可能构成更安全的给药载体。此外，纳米颗粒的功能化显著增强了对 sLeA 细胞的体外和离体靶向作用（与非靶向纳米颗粒相比，超过 40%）。总之，成功开发了一种糖基工程纳米载体，用于将 5-FU 和紫杉醇治疗剂递送至转移性胃癌细胞。我们预计，这可能是建立针对胃癌的改进靶向治疗的重要里程碑。鉴于 sLeA 抗原的泛癌特性，也可以设想将该解决方案转化为其他模型。
