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用于通过增强铁死亡和缓解缺氧微环境有效克服结直肠癌耐药性的激光激活氧自供应纳米平台。

Laser-activatable oxygen self-supplying nanoplatform for efficiently overcoming colorectal cancer resistance by enhanced ferroptosis and alleviated hypoxic microenvironment.

作者信息

Jiang Hao, Tian Hailong, Wang Zhihan, Li Bowen, Chen Rui, Luo Kangjia, Lu Shuaijun, Nice Edouard C, Zhang Wei, Huang Canhua, Zhou Yuping, Zheng Shaojiang, Gao Feng

机构信息

The First Hospital of Ningbo University, Ningbo, 315020, China.

State Key Laboratory of Biotherapy and Cancer Center, West China School of Basic Medical Sciences & Forensic Medicine, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.

出版信息

Biomater Res. 2023 Sep 23;27(1):92. doi: 10.1186/s40824-023-00427-1.

DOI:10.1186/s40824-023-00427-1
PMID:37742011
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10518107/
Abstract

BACKGROUND

Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC.

METHODS

Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis.

RESULTS

This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models.

CONCLUSIONS

Taken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance.

摘要

背景

结直肠癌（CRC）是全球第二大致命性癌症，化疗耐药性仍然是CRC治疗中的主要障碍。值得注意的是，氧化还原稳态介导的铁死亡失衡和缺氧肿瘤微环境的调节被视为克服CRC化疗耐药性的新切入点。

方法

受此启发，我们通过共组装顺铂（CDDP）和经亚油酸（LA）修饰的IR820，合理设计了一种光激活氧自供应化疗光热纳米平台，以增强铁死亡来对抗结直肠癌化疗耐药性。在这个纳米平台中，CDDP可以通过一系列酶促反应在CRC细胞中产生过氧化氢，随后在激光触发的光热作用下释放氧气以缓解缺氧。此外，引入的LA可以向CRC细胞中添加外源性不饱和脂肪酸，通过与氧化应激相关的过氧化脂质积累触发铁死亡。同时，光热可以有效提高酶促反应速率和局部血流量，从而增加氧气供应并氧化LA以增强铁死亡。

结果

该纳米平台在化疗耐药细胞系中表现出优异的抗肿瘤疗效，并在裸鼠异种移植模型中显示出强大的抑制能力。

结论

综上所述，该纳米平台通过增强铁死亡和缓解缺氧肿瘤微环境，为克服CRC化疗耐药性提供了一种有前景的范例。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/19cd2225610b/40824_2023_427_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/d07e48b56d85/40824_2023_427_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/b0026506abf1/40824_2023_427_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/9d7fa6c8180b/40824_2023_427_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/b220be6e340d/40824_2023_427_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/f04c8837b479/40824_2023_427_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/b61c5fbac626/40824_2023_427_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/19cd2225610b/40824_2023_427_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/d07e48b56d85/40824_2023_427_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/b0026506abf1/40824_2023_427_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/9d7fa6c8180b/40824_2023_427_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/b220be6e340d/40824_2023_427_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/f04c8837b479/40824_2023_427_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/b61c5fbac626/40824_2023_427_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70ea/10518107/19cd2225610b/40824_2023_427_Fig6_HTML.jpg

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