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通过连接环状 RGD 肽增强甲基化β-环糊精穿线聚轮烷的肿瘤靶向性和抗肿瘤活性。

Enhanced Tumor Targeting and Antitumor Activity of Methylated β-Cyclodextrin-Threaded Polyrotaxanes by Conjugating Cyclic RGD Peptides.

机构信息

Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.

出版信息

Biomolecules. 2024 Feb 15;14(2):223. doi: 10.3390/biom14020223.

DOI:10.3390/biom14020223
PMID:38397461
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10886891/
Abstract

We previously reported that acid-degradable methylated β-cyclodextrins (Me-β-CDs)-threaded polyrotaxanes (Me-PRXs) can induce autophagic cell death through endoplasmic reticulum (ER) stress-related autophagy, even in apoptosis-resistant cells. Hence, Me-PRXs show great potential as anticancer therapeutics. In this study, peptide-supermolecule conjugates were designed to achieve the targeted delivery of Me-PRX to malignant tumors. Arg-Gly-Asp peptides are well-known binding motifs of integrin αβ, which is overexpressed on angiogenic sites and many malignant tumors. The tumor-targeted cyclic Arg-Gly-Asp (cRGD) peptide was orthogonally post-modified to Me-PRX via click chemistry. Surface plasmon resonance (SPR) results indicated that cRGD-Me-PRX strongly binds to integrin αβ, whereas non-targeted cyclic Arg-Ala-Glu (cRGE) peptide conjugated to Me-PRX (cRGE-Me-PRX) failed to interact with integrins αβ. In vitro, cRGD-Me-PRX demonstrated enhanced cellular internalization and antitumor activity in 4T1 cells than that of unmodified Me-PRX and non-targeted cRGE-Me-PRX, due to its ability to recognize integrin αβ. Furthermore, cRGD-Me-PRX accumulated effectively in tumors, leading to antitumor effects, and exhibited excellent biocompatibility and safety in vivo. Therefore, cRGD conjugation to enhance selectivity for integrin αβ-positive cancer cells is a promising design strategy for Me-PRXs in antitumor therapy.

摘要

我们之前曾报道过，可酸降解的甲基化β-环糊精（Me-β-CDs）-穿的聚轮烷（Me-PRXs）可通过内质网（ER）应激相关自噬诱导自噬性细胞死亡，甚至在凋亡抵抗细胞中也是如此。因此，Me-PRX 具有作为抗癌治疗剂的巨大潜力。在这项研究中，设计了肽超分子缀合物以实现 Me-PRX 对恶性肿瘤的靶向递送。精氨酸-甘氨酸-天冬氨酸肽是整合素 αβ的已知结合基序，整合素 αβ在血管生成部位和许多恶性肿瘤中过度表达。通过点击化学将肿瘤靶向的环精氨酸-甘氨酸-天冬氨酸（cRGD）肽正交后修饰到 Me-PRX 上。表面等离子体共振（SPR）结果表明，cRGD-Me-PRX 与整合素 αβ强烈结合，而未靶向的环精氨酸-丙氨酸-谷氨酸（cRGE）肽连接到 Me-PRX（cRGE-Me-PRX）则无法与整合素 αβ相互作用。在体外，cRGD-Me-PRX 在 4T1 细胞中显示出比未修饰的 Me-PRX 和未靶向的 cRGE-Me-PRX 更强的细胞内化和抗肿瘤活性，这是由于其识别整合素 αβ 的能力。此外，cRGD-Me-PRX 可有效积聚在肿瘤中，从而发挥抗肿瘤作用，并在体内表现出优异的生物相容性和安全性。因此，cRGD 缀合可增强对整合素 αβ 阳性癌细胞的选择性，是 Me-PRX 在抗肿瘤治疗中的一种有前途的设计策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/abc553e82a0f/biomolecules-14-00223-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/82100481f421/biomolecules-14-00223-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/25f6fb37e014/biomolecules-14-00223-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/e27d6e97e9c3/biomolecules-14-00223-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/0bc161c7fc33/biomolecules-14-00223-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/ccc47fdd49bb/biomolecules-14-00223-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/9dbb93127a8e/biomolecules-14-00223-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/342486baa1a3/biomolecules-14-00223-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/78a8a1b05d41/biomolecules-14-00223-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/084e0f6fd835/biomolecules-14-00223-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/abc553e82a0f/biomolecules-14-00223-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/82100481f421/biomolecules-14-00223-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/25f6fb37e014/biomolecules-14-00223-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/e27d6e97e9c3/biomolecules-14-00223-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/0bc161c7fc33/biomolecules-14-00223-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/ccc47fdd49bb/biomolecules-14-00223-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/9dbb93127a8e/biomolecules-14-00223-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/342486baa1a3/biomolecules-14-00223-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/78a8a1b05d41/biomolecules-14-00223-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/084e0f6fd835/biomolecules-14-00223-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c41/10886891/abc553e82a0f/biomolecules-14-00223-g010.jpg

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