Chatterjee Atin, Sarkar Sandip, Bhattacharjee Sangheeta, Bhattacharyya Arpan, Barman Surajit, Pal Uttam, Pandey Raviranjan, Ethirajan Anitha, Jana Batakrishna, Das Benu Brata, Das Amitava
Department of Chemical Sciences and Center for Advanced Functional Materials, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur 741246, West Bengal, India.
Institute for Materials Research (Imo-imomec), Nanobiophysics and Soft Matter Interfaces (NSI) Group, Hasselt University, Martelarenlaan 42, B-3500 Hasselt, Belgium.
J Am Chem Soc. 2025 Jan 8;147(1):532-547. doi: 10.1021/jacs.4c11820. Epub 2024 Dec 26.
Triple-negative breast cancer (TNBC) poses significant treatment challenges due to its high metastasis, heterogeneity, and poor biomarker expression. The N-terminus of an octapeptide NAPVSIPQ () was covalently coupled to a carboxylic acid derivative of Ru(2,2'-bipy) () to synthesize an N-stapled short peptide-Rubpy conjugate (). This photosensitizer (PS) was utilized to treat TNBC through microtubule (MT) targeted chemotherapy and photodynamic therapy (PDT). formed more elaborate molecular aggregates with fibrillar morphology as compared to . A much higher binding affinity of over toward β-tubulin (: (6.8 ± 0.55) × 10 M; : (8.2 ± 1.1) × 10 M) was observed due to stronger electrostatic interactions between the MT with an average linear charge density of ∼85 e/nm and the cationic part of . This was also supported by docking, simulation, and appropriate imaging studies. promoted serum stability, specific binding of to the E-site of the β-tubulin followed by the disruption of the MT network, and effective singlet oxygen generation in TNBC cells (MDA-MB-231), causing cell cycle arrest in the G2/M phase and triggering apoptosis. Remarkably, MDA-MB-231 cells were more sensitive to compared to noncancerous human embryonic kidney (HEK293 cells) when exposed to light (IC[HEK293]: 17.2 ± 2.5 μM, compared to IC[MDA-MB-231]: 32.5 ± 7.8 nM, IC[HEK293]: > 80 μM, compared to IC[MDA-MB-231]: 2.9 ± 0.5 μM). also effectively inhibited tumor growth in MDA-MB-231 xenograft models in nude mice. Our findings provide strong evidence that has a potential therapeutic role in TNBC treatment.
三阴性乳腺癌（TNBC）因其高转移性、异质性和不良的生物标志物表达而带来重大的治疗挑战。将八肽NAPVSIPQ的N端与Ru(2,2'-联吡啶)的羧酸衍生物共价偶联，合成了一种N-钉合短肽-Rubpy共轭物。该光敏剂（PS）通过微管（MT）靶向化疗和光动力疗法（PDT）用于治疗TNBC。与[未提及的物质]相比，[共轭物名称未给出]形成了更精细的具有纤维形态的分子聚集体。由于平均线性电荷密度约为85 e/nm的MT与[共轭物名称未给出]的阳离子部分之间存在更强的静电相互作用，观察到[共轭物名称未给出]对β-微管蛋白的结合亲和力比[未提及的物质]高得多（[共轭物名称未给出]：(6.8 ± 0.55) × 10 M；[未提及的物质]：(8.2 ± 1.1) × 10 M）。对接、模拟和适当的成像研究也支持了这一点。[共轭物名称未给出]促进了血清稳定性，[共轭物名称未给出]与β-微管蛋白的E位点特异性结合，随后破坏MT网络，并在TNBC细胞（MDA-MB-231）中有效产生单线态氧，导致细胞周期停滞在G2/M期并引发凋亡。值得注意的是，当暴露于光时，MDA-MB-231细胞对[共轭物名称未给出]比非癌性人胚肾（HEK293细胞）更敏感（HEK293细胞的IC：17.2 ± 2.5 μM，而MDA-MB-231细胞的IC：32.5 ± 7.8 nM，HEK293细胞的IC：> 80 μM，而MDA-MB-231细胞的IC：2.9 ± 0.5 μM）。[共轭物名称未给出]在裸鼠的MDA-MB-231异种移植模型中也有效抑制了肿瘤生长。我们的研究结果提供了有力证据，表明[共轭物名称未给出]在TNBC治疗中具有潜在的治疗作用。
