用于抗癌靶向治疗的肽类给药载体的结构回归模型。

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Drug Delivery and Translational Research Pub Date : 2025-04-01 Epub Date: 2024-08-08 DOI:10.1007/s13346-024-01674-y
Yvonne Christian, Amay Sanjay Redkar, Naveen Kumar, Shine Varghese Jancy, Aneesh Chandrasekharan, Thankayyan Retnabai Santhoshkumar, Vibin Ramakrishnan
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引用次数: 0

摘要

癌症耐药性是为癌症患者寻找有效治疗方法的一项严峻挑战,因为影响这一复杂现象的因素众多。应对这一问题的方法之一是使用更具针对性和剂量限制的给药方法,而不是依赖会产生多种有害副作用的传统疗法。稳定性和特异性历来是基于多肽的给药载体的核心问题。在本研究中,我们采用了结构回归建模方法来设计、合成和表征一系列肽,这些肽大致属于同一拓扑群,但由于其氨基酸在特定序列中的位置不同而具有不同的静电特征。用荧光团 5(6)- 羧基荧光素标记的肽在癌细胞中的吸收率较高,其中一些肽在溶酶体中聚集。标记了抗癌药物甲氨蝶呤的多肽在三阴性乳腺癌细胞中显示出更强的细胞毒性并诱导细胞凋亡。它们还在具有类似干细胞特性的肺癌侧群细胞中显示出相当的吸收率。在体内研究中,与未经处理的小鼠相比,最优化的多肽在肿瘤内蓄积,使肿瘤体积显著缩小。我们的研究结果表明了以下几点:(i) 肽可以通过设计工程进行靶向递送;(ii) 肽主链的立体化学工程可以抵抗蛋白水解酶;(iii) 可以通过改变肽的静电特征来调节肽对癌细胞的细胞渗透。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural regression modelling of peptide based drug delivery vectors for targeted anti-cancer therapy.

Structural regression modelling of peptide based drug delivery vectors for targeted anti-cancer therapy.

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.

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来源期刊
Drug Delivery and Translational Research
Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY
CiteScore
11.70
自引率
1.90%
发文量
160
期刊介绍: The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.
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