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. 2021 Dec;28(1):920-929.
doi: 10.1080/10717544.2021.1914777.

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

Wenlong Du  1 , Xiaoping Yang  1 , Shenfu He  2 , Jia Wang  1 , Yuanxian Guo  1 , Bangguo Kou  1 , Yongjie Jiang  1 , Pan Bian  1 , Bingtai Li  1 , Lanning Yin  1   2
Affiliations

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

Wenlong Du et al. Drug Deliv. 2021 Dec.

Abstract

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.

Keywords: CD44v6; Hyaluronic acid oligosaccharide; colorectal cancer; drug delivery system; oxaliplatin.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Interaction between HA and CD44v6 increased chemotherapy resistance in colorectal cancer cells. (A,B) Expression of CD44v6 in the indicated cells (***p < .001, compared with NCM460 cells). (C) Expression of HA in the indicated cells (***p < .001, compared with NCM460 cells). (D) Cytotoxicity of oxaliplatin in the indicated cells. RKO cells were more resistant to oxaliplatin than HT-29 cells. (E) RKO cells were treated with 0.05 mM 4MU or 0.05 mM 4MU + 10 μM Oxa for 72 h. DMSO was used as the vehicle control. The 4-MU can sensitize RKO cells to Oxa (**p < .01). All results are expressed as the mean ± SD of three independent experiments.
Figure 2.
Figure 2.
oHA competitively inhibited HA and increased the oxaliplatin sensitivity of RKO cells. (A,B) Competitive inhibition of HA by oHA in RKO cells. CD44v6 was cross-linked by BS3 treatment. When the HA synthase inhibitors 4-MU and hyaluronidase were added, the expression of CD44v6 at 170 kDa decreased, indicating that cross-linking of CD44v6 requires HA. Adding oHA, the expression of cross-linked protein is also reduced, indicating that oHA competitively inhibits HA. (C) RKO cell sensitivity to oxaliplatin in the presence versus absence of oHA treatment (*p < .05, oHA + Oxa vs. Oxa). (D-E) Flow cytometry analysis of the effect of oHA on oxaliplatin sensitivity. Oxaliplatin combined with oHA produced greater sensitivity than did oxaliplatin alone (*p < .001).
Figure 3.
Figure 3.
Molecular structures of DLPE and oHA-4.
Figure 4.
Figure 4.
Characterization of Lipid-Oxa and oHA-Lipid-Oxa. (A) Zeta potentials of Lipid-Oxa and oHA-Lipid-Oxa. (B) Size distributions of Lipid-Oxa and oHA-Lipid-Oxa. (C) Transmission electron microscopy images of Lipid-Oxa and oHA-Lipid-Oxa. (D) Stabilities of Lipid-Oxa and oHA-Lipid-Oxa.
Figure 5.
Figure 5.
Drug loading and encapsulation efficiency of oxaliplatin in oHA-Lipid-Oxa, and the mass of oHA-4 connected. (A,B) Oxaliplatin drug loading and encapsulation efficiency detected by HPLC. (C) The mass of oHA-4 detected by carbazole sulfate.
Figure 6.
Figure 6.
Flow cytometry analysis of the effect of oHA-Lipid-Oxa in vitro after 24 h. A. Representative flow cytometry plots. B. Ratios of apoptotic cells to total cancer cells. The anti-tumor activity in RKO cells was significantly greater for oHA-Lipid-Oxa than Lipid-Oxa or Oxa (***p < .001).
Figure 7.
Figure 7.
Comparison of general morphology after administration of different treatments.
Figure 8.
Figure 8.
Tumor suppressive effects of Lipid-Oxa and oHA-Lipid-Oxa treatments in vivo in an RKO-bearing nude mouse model. Variations in (A) tumor volume and (B) body weight.
Figure 9.
Figure 9.
Images of hematoxylin and eosin staining (×200). (A) PBS, (B) oHA, (C) Oxa, (D) Lipid-Oxa, and (E) oHA-Lipid-Oxa.
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