EpCAM靶向白桦脂酸类似物纳米疗法可提高疗效并诱导结直肠癌肿瘤微环境中的抗肿瘤免疫反应。

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-08-20 DOI:10.1186/s12929-024-01069-8
Debasmita Dutta, Ashique Al Hoque, Brahamacharry Paul, Jun Hyoung Park, Chinmay Chowdhury, Mohiuddin Quadir, Soumyabrata Banerjee, Arghadip Choudhury, Soumik Laha, Nayim Sepay, Priyanka Boro, Benny Abraham Kaipparettu, Biswajit Mukherjee
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引用次数: 0

摘要

背景:白桦脂酸(BA)因其抗增殖和线粒体途径介导的凋亡诱导作用而被广泛研究。然而,其溶解性差和脱靶活性限制了其在临床试验中的应用。此外,白桦脂酸类似物在肿瘤微环境(TME)中的免疫调节作用在很大程度上也是未知的。在此,我们设计了一种潜在的纳米疗法来治疗结直肠癌(CRC),该疗法使用的白桦脂酸类似物被命名为 2c,它带有一个 1,2,3-三唑分子,通过连接体与 BA 相连。上皮细胞粘附分子(EpCAM)在 CRC 细胞膜上高度过表达。可折叠成三维结构的单链短寡核苷酸序列--aptamer(Apt)可用作靶向配体,与靶蛋白特异性结合。我们设计了EpCAM靶向aptamer,用于将aptamer-conjugated-2c-loaded nanoparticles(Apt-2cNP)在CRC肿瘤部位特异性归位,以提高治疗潜力并减少对正常细胞的脱靶毒性。我们研究了aptamer共轭纳米疗法在CRC-TME中的体内外疗效和抗肿瘤免疫反应:在表征了纳米工程化的aptamer共轭白桦脂酸纳米疗法后,我们使用基于细胞的实验和小鼠、大鼠模型评估了其疗效、肿瘤靶向效率和抗肿瘤免疫反应:结果:我们发现 Apt-2cNP 改善了药物的生物利用度,延长了生物半衰期,提高了抗增殖活性,并最大限度地减少了脱靶细胞毒性。重要的是,在体内TME中,Apt-2cNP显示出抗肿瘤免疫反应的良好迹象(mDC/pDC比率增加、M1巨噬细胞群和CD8 T细胞增加)。此外,体内促凋亡基因的上调和抗凋亡基因的下调以及对癌症组织病理学的显著疗效表明,Apt-2cNP 比非aptamer-conjugated 纳米粒子和游离药物具有更大的治疗潜力。此外,在 CRC 大鼠模型中,我们通过活体成像观察到放射性标记的 Apt-2cNP 有更大的肿瘤蓄积:结论:Apt-2cNP 在 CRC-TME 中增强的疗效和强大的抗肿瘤免疫反应是其有望成为治疗 CRC 的潜在药物的指标。不过,还需要进一步研究。
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EpCAM-targeted betulinic acid analogue nanotherapy improves therapeutic efficacy and induces anti-tumorigenic immune response in colorectal cancer tumor microenvironment.

Background: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME.

Methods: After the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models.

Results: We found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model.

Conclusions: Enhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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