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J. Control. Release, Sep 16 2024, S0168-3659(24)00639-4 | https://doi.org/10.1016/j.jconrel.2024.09.029 Laser-responsive erastin-loaded chondroitin sulfate nanomedicine targeting CD44 and system xc- in liver cancer: A non-ferroptotic approach

So-Yeol Yoo ^a,b,1, Hyun Young Kim ^b,1, Dong Hyun Kim ^a, Wan Seob Shim ^b, Sang Min Lee ^b, Dong Hwan Lee ^a, Jang Mo Koo^a, Ji Hoon Yoo ^a, Seokjin Koh ^a, Jong Chan Park ^a, Jieun Yu ^a, Jang Su Jeon ^a, Min-Jun Baek ^b, Dae-Duk Kim ^b,c, Ji-Yoon Lee ^d, Soo Jin Oh ^d,e, Sang Kyum Kim ^a, Jae-Young Lee ^b,c, Keon Wook Kang ^b

^aCollege of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea

^bCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea

^cNatural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea

^dAsan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea

^eDepartment of Pharmacology, College of Medicine, University of Ulsan, Seoul, 05505, Republic of Korea

¹These authors made equal contributions to this work.

Corresponding authors : Sang Kyum Kim, Jae-Young Lee, Keon Wook Kang

Abstract

Erastin, a ferroptosis-inducing system x_c^- 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 x_c^-.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-23)
연구진국내 연구진
분야 의약학 > 약학

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