2. Academic Validation
  3. Laser-responsive erastin-loaded chondroitin sulfate nanomedicine targeting CD44 and system xc- in liver cancer: A non-ferroptotic approach

Laser-responsive erastin-loaded chondroitin sulfate nanomedicine targeting CD44 and system xc- in liver cancer: A non-ferroptotic approach

  • J Control Release. 2024 Nov:375:574-588. doi: 10.1016/j.jconrel.2024.09.029.
So-Yeol Yoo 1,  Hyun Young Kim 2,  Dong Hyun Kim 3,  Wan Seob Shim 2,  Sang Min Lee 2,  Dong Hwan Lee 3,  Jang Mo Koo 3,  Ji Hoon Yoo 3,  Seokjin Koh 3,  Jong Chan Park 3,  Jieun Yu 3,  Jang Su Jeon 3,  Min-Jun Baek 2,  Dae-Duk Kim 4,  Ji-Yoon Lee 5,  Soo Jin Oh 6,  Sang Kyum Kim 7,  Jae-Young Lee 8,  Keon Wook Kang 9
Affiliations

Affiliations

  • 1 College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 3 College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • 4 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
  • 5 Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
  • 6 Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea; Department of Pharmacology, College of Medicine, University of Ulsan, Seoul, 05505, Republic of Korea.
  • 7 College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: sangkim@cnu.ac.kr.
  • 8 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: lee.jy@snu.ac.kr.
  • 9 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: kwkang@snu.ac.kr.
PMID: 39293529 DOI: 10.1016/j.jconrel.2024.09.029
Abstract

Erastin, a ferroptosis-inducing system xc- inhibitor, faces clinical challenges due to suboptimal physicochemical and pharmacokinetic properties, as well as relatively low potency and off-target toxicity. Addressing these, we developed ECINs, a novel laser-responsive erastin-loaded nanomedicine utilizing indocyanine green (ICG)-grafted chondroitin sulfate A (CSA) derivatives. Our aim was to improve erastin's tumor targeting via CSA-CD44 interactions and enhance its antitumor efficacy through ICG's photothermal and photodynamic effects in the laser-on state while minimizing off-target effects in the laser-off state. ECINs, with their nanoscale size of 186.7 ± 1.1 nm and high erastin encapsulation efficiency of 93.0 ± 0.8%, showed excellent colloidal stability and sustained drug release up to 120 h. In vitro, ECINs demonstrated a mechanism of Cancer cell inhibition via G1-phase cell cycle arrest, indicating a non-ferroptotic action. In vivo biodistribution studies in SK-HEP-1 xenograft mice revealed that ECINs significantly enhanced tumor distribution of erastin (1.9-fold greater than free erastin) while substantially reducing off-target accumulation in the lungs and spleen by 203-fold and 19.1-fold, respectively. Combined with laser irradiation, ECINs significantly decreased tumor size (2.6-fold, compared to free erastin; 2.4-fold, compared to ECINs without laser irradiation) with minimal systemic toxicity. This study highlights ECINs as a dual-modality approach for liver Cancer treatment, demonstrating significant efficacy against tumors overexpressing CD44 and system xc-.

Keywords

CD44–xCT axis; Cell cycle arrest; Chondroitin sulfate a nanomedicine; Erastin; Hepatocellular carcinoma; Photothermal and photodynamic therapy.

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