Self-assembling prodrugs represents a robust and effective nanotherapeutic approach for delivering poorly soluble anticancer drugs. With numerous intrinsic advantages, self-assembling prodrugs possess the maximum drug loading capacity, controlled drug release kinetics, prolonged blood circulation, and preferential tumor accumulation based on the enhanced permeability and retention (EPR) effect. These prodrug conjugates allow for efficient self-assembly into nanodrugs with the potential of encapsulating other therapeutic agents that have different molecular targets, enabling simultaneous temporal-spatial release of drugs for synergistic antitumor efficacy with reduced systemic side effects. The aim of this review is to summarize the recent progress of self-assembling prodrug cancer nanotherapeutics that are made through conjugating therapeutically active agents to Polyethylene glycol, Vitamin E, or drugs with different physicochemical properties via rational design, for synergistic tumor targeted drug delivery.

Statement of Significance

All current FDA-approved nanomedicines use inert biomaterials as drug delivery carriers. These biomaterials lack any therapeutic potential, contributing not only to the cost, but may also elicit severe unfavorable adverse effects. Despite the reduction in toxicity associated with the payload, these nanotherapeutics have been met with limited clinical success, likely due to the monotherapy regimen. The self-assembling prodrug (SAP) has been emerging as a powerful platform for enhancing efficacy through co-delivering other therapeutic modalities with distinct molecular targets. Herein, we opportunely present a comprehensive review article summarizing three unique approaches of making SAP for synergistic drug delivery: pegylation, vitamin E-derivatization, and drug-drug conjugation. These SAPs may inevitably pave the way for developing more efficacious, clinically translatable, combination cancer nanotherapies.

中文翻译：

---

自组装前药纳米治疗剂用于协同靶向肿瘤的药物递送。

自组装前药代表了用于递送难溶性抗癌药物的强大而有效的纳米治疗方法。自组装前药具有许多固有的优势，它们具有最大的载药量，受控的药物释放动力学，延长的血液循环以及基于增强的通透性和保留（EPR）效果的优先肿瘤蓄积。这些前药结合物可以有效地自我组装成纳米药物，并具有包封具有不同分子靶标的其他治疗剂的潜力，从而可以同时时空释放药物以发挥协同抗肿瘤功效，同时减少全身性副作用。

重要声明

当前所有FDA批准的纳米药物都使用惰性生物材料作为药物输送载体。这些生物材料缺乏任何治疗潜力，不仅增加了成本，而且还可能引起严重的不利影响。尽管降低了与有效载荷有关的毒性，但由于单药疗法，这些纳米疗法的临床成功率有限。自组装前药（SAP）已经成为通过共同提供具有独特分子靶标的其他治疗方式来增强疗效的强大平台。在此，我们适当地介绍了一篇全面的综述文章，概述了制备SAP协同药物递送的三种独特方法：聚乙二醇化，维生素E衍生化和药物-药物结合。