Novel co-delivery nanomedicine for photodynamic enlarged immunotherapy by cascade immune activation and efficient Immunosuppression reversion.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-17 DOI:10.1016/j.bioorg.2024.107978
Yimei Zhang, Shiyi Xiang, Yayi Wu, Can Yang, Dianyong Tang, Zhongzhu Chen, Zheng Huang
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Abstract

Photodynamic therapy (PDT) combined with immunotherapy has become a promising antitumor strategy. However, precise regulation of the activation of antitumor immunity and effective reversion of immunosuppressive tumor microenvironment (TME) remains challenging. In this paper, a novel co-delivery nanomedicine is developed to solve these issues for photodynamic amplified immunotherapy. Specifically, the glycolysis inhibitor (Lon) is coupled with PD1/PDL1 blocker (BMS-1) by thioketal linkage to form smartly responsive prodrug LTB, which could further encapsulate photosensitizer chlorine e6 (Ce6) to construct a co-delivery nanoplatform (LTB-6 NPs) by self-assembly. Of note, LTB-6 NPs possess favorable stability, uniform morphology and improved cellular uptake. More importantly, LTB-6 NPs are capable of inhibiting glycolysis and blocking PD1/PDL1, which could greatly improve the immunosuppressive TME to promote immune activation. LTB-6 NPs-mediated PDT not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. In vivo experiments indicate that intravenously injected LTB-6 NPs remarkably suppresses the tumor growth while leads to a minimized side effect. This research provides a multi-synergized strategy for developing effective photodynamic nanoplatforms in tumor treatment.

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通过级联免疫激活和高效免疫抑制逆转,用于光动力扩大免疫疗法的新型联合给药纳米药物。
光动力疗法(PDT)与免疫疗法相结合已成为一种前景广阔的抗肿瘤策略。然而,精确调控抗肿瘤免疫的激活和有效逆转免疫抑制性肿瘤微环境(TME)仍具有挑战性。本文开发了一种新型联合给药纳米药物,以解决光动力放大免疫疗法中的这些问题。具体来说,糖酵解抑制剂(Lon)与PD1/PDL1阻断剂(BMS-1)通过硫酮连接形成智能响应原药LTB,LTB可进一步包裹光敏剂氯e6(Ce6),通过自组装构建协同给药纳米平台(LTB-6 NPs)。值得注意的是,LTB-6 NPs 具有良好的稳定性、均匀的形态和更高的细胞吸收率。更重要的是,LTB-6 NPs 能够抑制糖酵解和阻断 PD1/PDL1,从而大大改善免疫抑制 TME,促进免疫激活。LTB-6 NPs 介导的光动力疗法不仅能抑制肿瘤增殖,还能诱导 ICD 反应以激活免疫级联。体内实验表明,静脉注射 LTB-6 NPs 可显著抑制肿瘤生长,同时将副作用降至最低。这项研究为开发有效治疗肿瘤的光动力纳米平台提供了一种多重协同策略。
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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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