Hyaluronic Acid–Zein Core-Shell Nanoparticles Improve the Anticancer Effect of Curcumin Alone or in Combination with Oxaliplatin against Colorectal Cancer via CD44-Mediated Cellular Uptake

Abstract

Curcumin (CUR) has been reported to enhance the chemotherapeutic efficacy of oxaliplatin (OXA) in colorectal cancer (CRC) and inhibit OXA-induced side effects. However, shortcomings, including poor solubility and sensitivity to metabolic transformation, have greatly undermined its value in clinical applications. In this study, the potential of CUR-encapsulated hyaluronic acid (HA)–zein composite nanoparticles (HZ-CUR) as an oral adjuvant for OXA-based chemotherapy was assessed in representative CRC models in mice. Cell viability and colony formation assays in three human CRC cell lines showed that HZ-CUR had a stronger anti-CRC effect than free CUR when given alone and a stronger synergistic effect when combined with OXA, especially in HCT116 and HT29 cell lines. Western blotting, cellular uptake, and RNA interference assays revealed that OXA-induced upregulation of CD44 likely contributed to enhanced cellular uptake of HZ-CUR and thus the enhanced anticancer effect. The significantly improved anti-CRC effects and potential underlying mechanism of HZ-CUR alone and in combination with OXA were further validated in a subcutaneous xenograft and an in situ CRC model in mice. These findings support that HZ-CUR may be an effective oral adjuvant for OXA-based CRC chemotherapy that would not only improve its efficacy but also help reduce the associated side effects.

Protein and Peptide-based Nanoparticles as an emerging strategy to tackle cancer drug resistance

“…This mechanism was verified through the assay of the curcumin intracellular content after the inhibition of the expression of CD44, where the results showed significant reduction in the curcumin intracellular content in the HCT116 and HT29 cells. This showed that the endocytosis mechanism is important for the HZ-CUR nanoparticles uptake [66].…”

Current Advances of Nanomaterial-Based Oral Drug Delivery for Colorectal Cancer Treatment

“…The oHA can compete for the binding of endogenous HA to CD44 by inhibiting the MDR and other ABC transporter protein expression, breaking the "HA-CD44" barrier in vivo, reversing the chemotherapy resistance of tumors, and penetrating the colonic mucosa more potently to play a role. Liu et al [85] assessed the potential of CUR-encapsulated HA-zein composite nanoparticles (HZ-CUR) as an oral adjuvant for OXA-based chemotherapy in representative CRC models in mice. The specific recognition/interaction between HA and CD44 contributes to the tumor-targeting property of HA-coated nanocarriers.…”

Synthesis of a smart pH sensitive micelle containing hyaluronic acid-curcumin bioconjugate against colorectal cancer

“…This nding veri ed active targeting of CD44 receptor in C26 cells via HA as a ligand. Other studies have also reported the uptake of HA-decorated NPs by CD44-mediated endocytosis [24,37,38]. For instance, Shahriari et al indicated that the HA-coated platform is able to enhance the cellular internalization and cytotoxicity against CD44 overexpressing 4T1 cells [26].…”