Glycoengineered nanoparticles enhance the delivery of 5-fluoroucil and paclitaxel to gastric cancer cells of high metastatic potential

Abstract

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.