Raghul Nanjundan, Lye Anushree, Goswami Bhagwat Giri, Nayak Suman, Stewart Adele, Lo Rabindranath, Maity Biswanath, Das Priyadip
Department of Chemistry, SRM Institute of Science and Technology, SRM Nagar, Potheri, Kattankulathur, Tamil Nadu 603203, India.
Department of Biological Sciences, Bose Institute, Unified Academic Campus, EN80, Sector V, Bidhan Nagar, Kolkata 700091, West Bengal, India.
ACS Appl Bio Mater. 2025 Aug 18;8(8):7270-7283. doi: 10.1021/acsabm.5c00965. Epub 2025 Jul 30.
Design and development of functionalized and biocompatible drug delivery systems (DDS) for site-specific release of small molecules is emerging as a means to target disease sites while sparing healthy tissue. Cell penetrating short peptides capable of self-assembly and drug encapsulation represent one scaffold with which selective DDSs can be rationally designed due to their chemical diversity, biocompatibility, tunable bioactivity, ease of functionality, and high loading capacity. Herein, we designed and synthesized two tetra peptides, BOC-YWWD ( with Trp-Trp-Sequence) and BOC-WYWD ( without Trp-Trp sequence). Structural rigidification of these two peptides with Zn(II) in the self-assembled state were characterized by the density functional theory (DFT) method and demonstrated to shift self-assembly of their characteristic emission from the ultraviolet to visible range allowing for visualization of cellular entry. , unlike , exhibits cell penetrating capabilities and is photo and thermally stable and biocompatible. Self-assembled effectively encapsulated the chemotherapeutic drug Doxorubicin (Dox) and facilitated intracellular drug delivery. To test the utility of as a DDS, we chemically modified with folic acid to target folate receptor α (FLOR1), commonly overexpressed on the surface of cancer cells. In HeLa cervical cancer cells, this chemical conjugation with folic acid significantly improved the ability of Dox to activate the pro-apoptotic DNA damage response and trigger oxidative stress and mitochondrial dysfunction critical for the cancer cell killing actions of the drug. However, failed to facilitate Dox delivery into the lung cancer epithelial cell line, A549, which does not express high levels of FLOR1. Our results represent an important proof of concept describing the fabrication of fluorescent Zn(II) coordinated, self-assembled short peptides containing the sequential Trp-Trp unit that may be used to develop superior imaging reagents and site-specific DDSs.
设计和开发用于小分子药物定点释放的功能化且生物相容的药物递送系统（DDS），正成为一种在保护健康组织的同时靶向疾病部位的手段。能够自我组装和包封药物的细胞穿透短肽代表了一种支架，由于其化学多样性、生物相容性、可调节的生物活性、易于功能化和高负载能力，可以合理设计选择性DDS。在此，我们设计并合成了两种四肽，BOC - YWWD（具有Trp - Trp序列）和BOC - WYWD（没有Trp - Trp序列）。通过密度泛函理论（DFT）方法表征了这两种肽在自组装状态下与Zn(II)的结构刚性化，并证明其特征发射的自组装从紫外范围转移到可见范围，从而实现细胞内吞的可视化。与……不同，……具有细胞穿透能力，并且具有光稳定性、热稳定性和生物相容性。自组装的……有效地包封了化疗药物阿霉素（Dox）并促进了细胞内药物递送。为了测试……作为DDS的效用，我们用叶酸对……进行化学修饰，以靶向通常在癌细胞表面过度表达的叶酸受体α（FLOR1）。在HeLa宫颈癌细胞中，这种与叶酸的化学偶联显著提高了Dox激活促凋亡DNA损伤反应以及引发氧化应激和线粒体功能障碍的能力，而这些对于该药物的癌细胞杀伤作用至关重要。然而，……未能促进Dox递送至不高表达FLOR1的肺癌上皮细胞系A549中。我们的结果代表了一个重要的概念验证，描述了包含连续Trp - Trp单元的荧光Zn(II)配位自组装短肽的制备，该短肽可用于开发优质的成像试剂和定点DDS。
