Hyaluronic acid oligosaccharide-modified zeolitic imidazolate framework-8 nanoparticles loaded with oxaliplatin as a targeted drug-delivery system for colorectal cancer therapy.

Aim: Exploring a nanoscale targeted drug-delivery system (DDS) for oxaliplatin (Oxa) to improve its therapeutic effect in colorectal cancer. Materials & methods: Nanoparticles were prepared using zeolitic imidazole framework-8 (ZIF-8) modified by hyaluronic acid oligosaccharide (oHA) as an Oxa carrier (oHA@ZIF-8@Oxa). After multiple characterizations, the therapeutic efficacy of the DDS was evaluated by cytotoxicity testing and a nude mouse tumor transplantation experiment in vivo. Results: The results of characterization showed the DDS was homogeneous in morphology and uniform in dispersion. The drug loading of Oxa was 11.82% and the encapsulation efficiency was 90.8%. The cytotoxicity test and in vivo experiments showed that oHA@ZIF-8@Oxa had a more significant anticolorectal cancer effect than free Oxa. Conclusion: This work offers a promising potential DDS for enhancing the anticolorectal cancer effect of Oxa.

Novel hyaluronic acid oligosaccharide-loaded and CD44v6-targeting oxaliplatin nanoparticles for the treatment of colorectal cancer.

Oxaliplatin resistance is one of the main causes of failed colorectal cancer treatment, followed by recurrence and metastasis. In this study, we found that colorectal cancer cells secrete a high level of hyaluronic acid (HA), which interacts with its receptor CD44v6 to mediate colorectal cancer resistance to chemotherapy. HA oligosaccharide (oHA) is a degradation product of HA. We found that it competitively binds to CD44v6, reversing the HA-CD44v6-mediated effect of HA on oxaliplatin resistance. In addition, oHA showed no toxicity or immunogenicity but exhibited good biocompatibility and tumor-targeting capability. Therefore, we synthesized oHA-loaded oxaliplatin liposome nanoparticles (oHA-Lipid-Oxa) using a thin-film hydration method. The cytotoxicity of oHA-Lipid-Oxa was assessed in vitro using flow cytometry, which revealed greater lethality than oxaliplatin alone. Finally, we established a tumor-bearing nude mouse model and separately injected oHA-Lipid-Oxa, Lipid-Oxa, Oxa, oHA, and phosphate-buffered saline (PBS) into the tail vein to observe the antitumor effects of nanoparticles in vivo. The oHA-Lipid-Oxa group exhibited the highest tumor suppression rate, but the weight loss was not obvious. Hematoxylin and eosin staining showed greatest lymphocyte and macrophage infiltration in the oHA-Lipid-Oxa group. Moreover, oHA-Lipid-Oxa induced tumor cell apoptosis and necrosis most robustly compared with the other groups. We showed that oHA-Lipid-Oxa has excellent histocompatibility and CD44v6-targeting capabilities, thus greatly increasing the sensitivity to oxaliplatin and reducing adverse reactions. Accordingly, oHA-Lipid-Oxa has a broad potential for therapeutic application.