载阿霉素的磷脂纳米粒与靶向肽修饰的磷脂纳米粒与 DNA 的相互作用。

Interaction of Doxorubicin Embedded into Phospholipid Nanoparticles and Targeted Peptide-Modified Phospholipid Nanoparticles with DNA.

机构信息

Institute of Biomedical Chemistry, Pogodinskaya Street, 10, Build 8, 119121 Moscow, Russia.

Faculty of Biochemistry, Pirogov Russian National Research Medical University, Ostrovitianov Street, 1, 117997 Moscow, Russia.

出版信息

Molecules. 2023 Jul 10;28(14):5317. doi: 10.3390/molecules28145317.

DOI:10.3390/molecules28145317

PMID:37513191

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10385298/

Abstract

The interactions of dsDNA with new targeted drug delivery derivatives of doxorubicin (DOX), such as DOX embedded into phospholipid nanoparticles (NPhs) and DOX with the NGR targeted peptide-modified NPhs were studied electrochemically by differential pulse voltammetry technique. Screen-printed electrodes (SPEs), modified with stable fine dispersions of carbon nanotubes (CNTs), were used for quantitative electrochemical investigations of direct electrochemical oxidation of guanine, adenine, and thymine heterocyclic bases of dsDNA, and their changes in the presence of DOX nanoderivatives. Analysing the shifts of peak potentials of nucleobases in the presence of drug, we have shown that the doxorubicin with NGR targeted peptide changed the mode of interaction in DNA-drug complexes from intercalative to electrostatic. Binding constants () of DNA-drug complexes were calculated in accordance with adenine, guanine, and thymine oxidation signals. Based on our experiments, we have proven that the surface modification of a drug delivery system with NGR targeted peptide dramatically changed the mechanism of interaction of drug with genetic material. DNA-mediated drug toxicity was calculated based on the concentration-dependent "response" of heterocyclic nucleobases on drug influence. DOX, DOX-loaded phospholipid nanoparticles (NPhs), and DOX with NGR addressed peptide-modified NPhs were moderately toxic in the concentration range of 0.5-290 µM.

摘要

通过差分脉冲伏安技术研究了阿霉素（DOX）的新型靶向药物传递衍生物（如嵌入磷脂纳米颗粒（NPhs）中的 DOX 和具有 NGR 靶向肽修饰的 NPhs 的 DOX）与双链 DNA 的相互作用。使用修饰有稳定的碳纳米管（CNT）细分散体的丝网印刷电极（SPE），对双链 DNA 的鸟嘌呤、腺嘌呤和胸腺嘧啶杂环碱基的直接电化学氧化及其在 DOX 纳米衍生物存在下的变化进行了定量电化学研究。通过分析药物存在时核碱基峰电位的偏移，我们表明，具有 NGR 靶向肽的阿霉素改变了 DNA-药物复合物的相互作用模式，从嵌入型变为静电型。根据腺嘌呤、鸟嘌呤和胸腺嘧啶氧化信号，计算了 DNA-药物复合物的结合常数（Kb）。基于我们的实验，我们已经证明，用 NGR 靶向肽对药物传递系统的表面修饰极大地改变了药物与遗传物质的相互作用机制。基于杂环核碱基对药物影响的浓度依赖性“反应”，计算了 DNA 介导的药物毒性。在 0.5-290 μM 的浓度范围内，DOX、载 DOX 的磷脂纳米颗粒（NPhs）和具有 NGR 靶向肽修饰的 NPhs 的 DOX 具有中度毒性。