癌症的耐药性对寻找癌症患者的有效治疗方法提出了严峻的挑战，因为影响这一复杂现象的因素有很多。解决这个问题的一种方法是使用更有针对性和剂量限制的药物输送方法，而不是依赖具有多种有害副作用的传统疗法。传统上，稳定性和特异性一直是基于肽的递送载体的核心问题。在这项研究中，我们采用结构回归建模方法来设计、合成和表征一系列肽，这些肽属于大致相同的拓扑簇，但由于给定氨基酸中氨基酸的不同定位而编码了不同的静电特征。顺序。标记有荧光团 5(6)-羧基荧光素的肽在癌细胞中表现出较高的摄取量，其中一些肽共定位于溶酶体中。标有抗癌药物甲氨蝶呤的肽在三阴性乳腺癌细胞中表现出增强的细胞毒性并诱导细胞凋亡。他们还显示出对具有干细胞样特性的肺癌侧群细胞的类似吸收。在体内研究中，与未经治疗的小鼠相比，最优化的肽显示出在肿瘤中的积累，导致肿瘤大小显着减小。我们的结果指向以下方向； (i) 肽可以设计用于靶向递送 (ii) 肽主链的立体化学工程可以抵抗蛋白水解酶，以及 (iii) 可以通过改变其静电特征来调节肽进入癌细胞的细胞渗透。© 2024。控释协会。

Drug resistance in cancer poses a serious challenge in finding an effective remedy for cancer patients, because of the multitude of contributing factors influencing this complex phenomenon. One way to counter this problem is using a more targeted and dose-limiting approach for drug delivery, rather than relying on conventional therapies that exhibit multiple pernicious side-effects. Stability and specificity have traditionally been the core issues of peptide-based delivery vectors. In this study, we employed a structural regression modelling approach in the design, synthesis and characterization of a series of peptides that belong to approximately same topological cluster, yet with different electrostatic signatures encoded as a result of their differential positioning of amino acids in a given sequence. The peptides tagged with the fluorophore 5(6)-carboxyfluorescein, showed higher uptake in cancer cells with some of them colocalizing in the lysosomes. The peptides tagged with the anti-cancer drug methotrexate have displayed enhanced cytotoxicity and inducing apoptosis in triple-negative breast cancer cells. They also showed comparable uptake in side-population cells of lung cancer with stem-cell like properties. The most-optimized peptide showed accumulation in the tumor resulting in significant reduction of tumor size, compared to the untreated mice in in-vivo studies. Our results point to the following directives; (i) peptides can be design engineered for targeted delivery (ii) stereochemical engineering of peptide main chain can resist proteolytic enzymes and (iii) cellular penetration of peptides into cancer cells can be modulated by varying their electrostatic signatures.© 2024. Controlled Release Society.