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 tumortargeting 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.

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.

Background Studies have shown that pyruvate kinase M2 (PKM2) and Notch1 are highly expressed in colorectal cancer (CRC) tissues and have a certain relationship with disease occurrence and development. The expression levels of PKM2 and Notch1 are also related to the effect of chemotherapy and radiotherapy, which seriously influence the prognosis of CRC patients. Thus, both PKM2 and Notch1 have been identified as key targets of CRC treatment and research. However, correlations between PKM2 and Notch1 have not yet been established. Methods Immunohistochemical analysis was conducted to detect the expression of PKM2 and Notch1 in CRC tissues. The mRNA and protein expression levels of PKM2 and Notch1 in CRC cell lines were detected by quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Compound 3K and tangeretin (TGN) were used to inhibit the expression of PKM2 and Notch1, respectively. The proliferation and migration of cancer cells in each group were detected with the CCK-8 and wound healing assays. Results The Immunohistochemical analysis showed that PKM2 and Notch1 were highly expressed in CRC and related to tumor stage and lymph node metastasis. The qRTPCR and western blot results showed that PKM2 and Notch1 were notably upregulated in CRC cells both at the mRNA and protein levels. PKM2 and Notch1 form a positive feedback loop to promote the occurrence and development of CRC, and inhibition of PKM2 and Notch1 has a synergistic effect on the proliferative and invasive capabilities of CRC cells. Conclusion The combination of the PKM2 inhibitor compound 3K and the Notch1 inhibitor TGN presents a novel and effective strategy for treatment of CRC.