Targeting CD30L in B-cell non-Hodgkin lymphoma: novel peptide conjugates and their therapeutic potential.

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chaowen Shi, Tianzheng Lan, Yufeng Gao, Zhiquan Liang, Yafei Zhang, Yanbei Tu, Hanqing Liu, Zhigang Tu
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引用次数: 0

Abstract

Background: B-cell non-Hodgkin lymphoma (B-NHL) constitutes the majority of NHL cases. Patients with B-NHL often experience multiple recurrences, necessitating several lines of antitumor therapy, and develop drug resistance. The recent success of therapeutic strategies targeting CD19 and CD20 highlights the therapeutic potential of identifying unique molecular markers in B-NHL for precision medicine, although challenges like immunogenicity and limited tumor penetration persist.

Methods: In this study, whole-cell phage display was employed to identify the specific binding peptide TG-1 towards B-NHL cells which was confirmed in vitro and in vivo, and its corresponding target CD30 ligand (CD30L) was identified by mass spectrometry and validated by functional assays, molecular docking, bioinformational analyses, knockdown, and rescue experiments. Additionally, the effects of TG-1 and functional roles of CD30L in B-NHL cells were investigated by exploring the molecular mechanisms of CD30/CD30L interactions. Furthermore, TG-1 peptide and doxorubicin co-functionalized gold nanoparticles (AuNPs) were characterized, and their effects on B-NHL cell proliferation were studied both in vitro and in vivo.

Results: Here, we identified and validated the CD30L as a novel target on B-NHL cells, along with its highly specific binding peptide TG-1, using whole-cell phage display. TG-1 binds CD30L, impairing lymphoma cell viability by disrupting the CD30-CD30L signaling axis, which is crucial for B-NHL cell survival. It demonstrates strong inhibitory effects on lymphoma cell proliferation both in vitro and in vivo. Additionally, the peptide and doxorubicin co-functionalized AuNPs demonstrated significant inhibitory effects on B-NHL cell proliferation, highlighting their potential as a promising therapeutic strategy.

Conclusions: In summary, our findings underscore the potential of CD30L as a novel target for B-NHL treatment and demonstrate the promise of CD30L-targeted peptides in advancing precision medicine for B-NHL, paving the way for future clinical developments.

靶向CD30L治疗b细胞非霍奇金淋巴瘤:新型肽偶联物及其治疗潜力
背景:b细胞非霍奇金淋巴瘤(B-NHL)占NHL病例的大多数。B-NHL患者经常出现多次复发,需要多种抗肿瘤治疗,并产生耐药性。最近针对CD19和CD20的治疗策略的成功突出了在B-NHL中识别独特分子标记物用于精准医疗的治疗潜力,尽管免疫原性和有限的肿瘤渗透等挑战仍然存在。方法:本研究采用全细胞噬菌体展示技术,对体外和体内已证实的靶向B-NHL细胞的特异性结合肽TG-1进行鉴定,并通过质谱法鉴定其对应的靶CD30配体(CD30L),并通过功能测定、分子对接、生物信息分析、敲低和拯救实验进行验证。此外,通过探索CD30/CD30L相互作用的分子机制,研究TG-1在B-NHL细胞中的作用和CD30L的功能作用。此外,我们还对TG-1肽和阿霉素共功能化金纳米粒子(AuNPs)进行了表征,并在体外和体内研究了它们对B-NHL细胞增殖的影响。结果:在这里,我们利用全细胞噬菌体展示技术,鉴定并验证了CD30L及其高度特异性结合肽TG-1作为B-NHL细胞的新靶点。TG-1结合CD30L,通过破坏CD30-CD30L信号轴来损害淋巴瘤细胞的活力,而CD30-CD30L信号轴对B-NHL细胞的存活至关重要。在体内和体外均显示出较强的抑制淋巴瘤细胞增殖的作用。此外,肽和阿霉素共功能化的AuNPs对B-NHL细胞增殖有显著的抑制作用,突出了它们作为一种有前景的治疗策略的潜力。总之,我们的研究结果强调了CD30L作为B-NHL治疗新靶点的潜力,并展示了CD30L靶向肽在推进B-NHL精准医疗方面的前景,为未来的临床发展铺平了道路。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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