在新药物的开发中，典型的聚合物或大分子基的纳米载体因制造过程的复杂性、不必要的系统毒性和低负载能力而备受困扰。然而，无载体的纳米医药在药物传递和药代动力学方面取得了卓越的进展，在靶向抗癌疗法中展示了纳米粒子的大部分优点。为了克服纳米载体和传统细胞毒药物的问题，我们开发了一种新型的无载体自组装前药，包括亲水性基团（或组）和羟基脂肪酸（16碳链正十六烷链，palmitic）成分以及包含半胱氨酸蛋白酶3特定可裂解肽（Asp-Glu-Val-Asp，DEVD）和细胞毒药物（多柔比星，DOX）的肿瘤细胞前药。这种两性共聚物，羟基脂肪酸-palmitic-DEVD-DOX，具有在盐水中自组装成纳米粒子的能力，无需任何载体或纳米配方。此外，多柔比星的包含是以前药形式进行的，而凋亡特异性DEVD肽可以导致多柔比星在正常组织中副作用减少。此外，由于增强的渗透和滞留效应，无载体的羟基脂肪酸-palmitic-DEVD-DOX纳米粒子可以被动地积累在荷瘤小鼠的肿瘤组织中。因此，与未经修改的DEVD-DOX共轭物相比，羟基脂肪酸-palmitic-DEVD-DOX共轭物显示出了增强的治疗效果。因此，这种无载体的羟基脂肪酸-palmitic-DEVD-DOX前药在治疗实体肿瘤方面具有巨大的治疗潜力，可以克服传统化疗和纳米粒子的问题。

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 n-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.