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  2. Tumor-targeted hyaluronic acid-based oxidative stress nanoamplifier with ROS generation and GSH depletion for antitumor therapy

Tumor-targeted hyaluronic acid-based oxidative stress nanoamplifier with ROS generation and GSH depletion for antitumor therapy

  • Int J Biol Macromol. 2022 May 15;207:771-783. doi: 10.1016/j.ijbiomac.2022.03.139.
Qiuxing Liu 1 Xin Ding 1 Xiaoyu Xu 2 Hualu Lai 1 Zishan Zeng 2 Ting Shan 2 Tao Zhang 2 Meixu Chen 2 Yanjuan Huang 2 Zeqian Huang 2 Xiuling Dai 2 Meng Xia 2 Shengmiao Cui 3
Affiliations

Affiliations

  • 1 School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
  • 3 School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China. Electronic address: Cuism_gdpu@163.com.
Abstract

Tumor cells with innate oxidative stress are more susceptible to exogenous ROS-mediated oxidative damage than normal cells. However, the generated ROS could be scavenged by the overexpressed GSH in Cancer cells, thus causing greatly restricted efficiency of ROS-mediated antitumor therapy. Herein, using cinnamaldehyde (CA) as a ROS generator while β-phenethyl isothiocyanate (PEITC) as a GSH scavenger, we designed a tumor-targeted oxidative stress nanoamplifier to elevate intracellular ROS level and synchronously suppress antioxidant systems, for thorough redox imbalance and effective tumor cells killing. First, an amphiphilic acid-sensitive cinnamaldehyde-modified hyaluronic acid conjugates (HA-CA) were synthesized, which could self-assemble into nano-assembly in aqueous media via strong hydrophobic interaction and π-π stacking. Then, aromatic PEITC was appropriately encapsulated into HA-CA nano-assembly to obtain HA-CA/PEITC nanoparticles. Through enhanced permeability retention (EPR) effect and specific CD44 receptor-mediated endocytosis, HA-CA/PEITC nanoparticles could accumulate in tumor tissues and successfully release CA and PEITC under acidic lysosomal environment. Both in vitro and in vivo results showed that the nanoparticles could efficiently boost oxidative stress of tumor cells via generating ROS and depleting GSH, and finally achieve superior antitumor efficacy. This nanoamplifier with good biosafety provides a potential strategy to augment ROS generation and suppress GSH for enhanced oxidation therapy.

Keywords

Cinnamaldehyde; GSH depletion; Oxidation therapy; Oxidative stress; β-Phenethyl isothiocyanate.

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