Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Republic of Korea.
Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungju 27478, Republic of Korea.
Bioconjug Chem. 2023 Feb 15;34(2):333-344. doi: 10.1021/acs.bioconjchem.2c00490. Epub 2023 Feb 3.
In the development of new drugs, typical polymer- or macromolecule-based nanocarriers suffer from manufacturing process complexity, unwanted systematic toxicity, and low loading capacity. However, carrier-free nanomedicines have made outstanding progress in drug delivery and pharmacokinetics, demonstrating most of the advantages associated with nanoparticles when applied in targeted anticancer therapy. Here, to overcome the problems of nanocarriers and conventional cytotoxic drugs, we developed a novel, carrier-free, self-assembled prodrug consisting of a hydrophobic palmitic (16-carbon chain -hexadecane chain) moiety and hydrophilic group (or moiety) which is included in a caspase-3-specific cleavable peptide (Asp-Glu-Val-Asp, DEVD) and a cytotoxic drug (doxorubicin, DOX). The amphiphilic conjugate, the palmitic-DEVD-DOX, has the ability to self-assemble into nanoparticles in saline without the need for any carriers or nanoformulations. Additionally, the inclusion of doxorubicin is in its prodrug form and the apoptosis-specific DEVD peptide lead to the reduced side effects of doxorubicin in normal tissue. Furthermore, the carrier-free palmitic-DEVD-DOX nanoparticles could passively accumulate in the tumor tissues of tumor-bearing mice due to an enhanced permeation and retention (EPR) effect. As a result, the palmitic-DEVD-DOX conjugate showed an enhanced therapeutic effect compared with the unmodified DEVD-DOX conjugate. Therefore, this carrier-free palmitic-DEVD-DOX prodrug has great therapeutic potential to treat solid tumors, overcoming the problems of conventional chemotherapy and nanoparticles.
在新药的开发中，典型的聚合物或大分子纳米载体存在制造工艺复杂、系统毒性不可控和载药量低等问题。然而，无载体纳米药物在药物输送和药代动力学方面取得了显著进展，当应用于靶向抗癌治疗时，表现出与纳米颗粒相关的大多数优势。在这里，为了克服纳米载体和传统细胞毒性药物的问题，我们开发了一种新型的无载体自组装前药，由疏水性棕榈酸（16 个碳链-十六烷链）部分和亲水基团（或部分）组成，其中包含半胱天冬酶-3 特异性切割肽（Asp-Glu-Val-Asp，DEVD）和细胞毒性药物（多柔比星，DOX）。两亲性缀合物，棕榈酸-DEVD-DOX，具有在生理盐水中自组装成纳米颗粒的能力，而无需任何载体或纳米制剂。此外，多柔比星以其前药形式存在，凋亡特异性 DEVD 肽导致多柔比星在正常组织中的副作用降低。此外，由于增强的渗透和保留（EPR）效应，无载体棕榈酸-DEVD-DOX 纳米颗粒可以被动地在荷瘤小鼠的肿瘤组织中积累。因此，与未修饰的 DEVD-DOX 缀合物相比，棕榈酸-DEVD-DOX 缀合物表现出增强的治疗效果。因此，这种无载体棕榈酸-DEVD-DOX 前药具有治疗实体瘤的巨大治疗潜力，克服了传统化疗和纳米颗粒的问题。
