Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer

IF 10.5 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Journal of Controlled Release Pub Date : 2024-11-08 DOI:10.1016/j.jconrel.2024.10.062
Jiahui Li , Jaden Arnold , Monika Sima , Hasan Al Faruque , Jacob Galang , Sophia Hu-Lieskovan , Jindřich Kopeček , Jiyuan Yang
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Abstract

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical applications of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering.
To address the limitation, we developed N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WDCLDNRIGRRQCVKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as PH-cDR5 (high valence), PM-cDR5 (medium valence) and PL-cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells PM-cDR5 exhibited an IC50 of 94 pM, while PH-cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC50 for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy.

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多价 DR5 受体集群激动剂与组蛋白去乙酰化酶抑制剂联合治疗结肠癌。
死亡受体5(DR5)靶向疗法在介导细胞凋亡的外在途径中发挥着关键作用,因此前景广阔。尽管DR5在各种恶性肿瘤中过度表达,而且肿瘤坏死因子(TNF)相关凋亡诱导配体(TRAIL)也具有潜力,但抗DR5单克隆抗体(mAbs)的临床应用却受到了阻碍,原因可能是缺乏受体集群,导致疗效不理想。为了解决这一局限性,我们开发了基于 N-(2-羟基丙基)甲基丙烯酰胺(HPMA)共聚物的共轭物,其中整合了多份 DR5 靶向肽(环 WDCLDNRIGRRQCVKL;cDR5),以增强受体集群和细胞凋亡。我们制备了三种具有不同数量 cDR5 的共轭物,分别称为 PH-cDR5(高价)、PM-cDR5(中价)和 PL-cDR5(低价)。我们在对 TRAIL 敏感和耐药的癌细胞系中进行的研究表明,HPMA 共聚物-多肽共轭物(P-cDR5)能显著改善 DR5 受体的聚集,并有效诱导细胞凋亡。在对 TRAIL 敏感的结肠癌细胞(COLO205、HCT-116)中,P-cDR5 的疗效与抗 DR5 mAb 屈珠单抗(DRO)相当,但在对 TRAIL 抗性的细胞(HT-29)中,P-cDR5 的疗效优于 DRO,这凸显了有效受体聚类的重要性。在 COLO205 细胞中,PM-cDR5 的 IC50 为 94 pM,而 PH-cDR5 的 IC50 甚至更低,仅为 15 pM(基于 cDR5 的等效浓度),这表明与 TRAIL 的 IC50 0.12 nM 相比,基于多价 HPMA 共聚物的柔性聚合物骨架系统的效力更强。将 P-cDR5 与组蛋白去乙酰化酶抑制剂丙戊酸结合使用,可进一步增强诱导细胞凋亡的功效,同时还能破坏线粒体膜的稳定性,并提高 TRAIL 抗性细胞的敏感性。这些研究结果表明,将多个 cDR5 肽连接到柔性水溶性聚合物载体上不仅克服了以往设计的局限性,还为治疗耐药性癌症提供了一条前景广阔的途径,这表明有必要对这一创新策略进行进一步的临床前探索和验证。
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来源期刊
Journal of Controlled Release
Journal of Controlled Release 医学-化学综合
CiteScore
18.50
自引率
5.60%
发文量
700
审稿时长
39 days
期刊介绍: The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.
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