Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, 100081, P.R. China.
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, P.R. China.
Nat Commun. 2023 Mar 25;14(1):1660. doi: 10.1038/s41467-023-37315-0.
Nanomedicine holds great promise to enhance cancer therapy. However, low active pharmaceutical ingredient (API) loading content, unpredictable drug release, and potential toxicity from excipients limit their translational capability. We herein report a full-API nanodrug composed of FDA-approved 5-aminolevulinic acid (ALA), human essential element Fe, and natural bioactive compound curcumin with an ideal API content and pH-responsive release profile for continuous spatiotemporal cancer therapy achieved by multi-step tandem endogenous biosynthesis. First, ALA enzymatically converts into photosensitizer protoporphyrin IX (PpIX). Afterward, multiple downstream products including carbon monoxide (CO), Fe, biliverdin (BV), and bilirubin (BR) are individually biosynthesized through the PpIX-heme-CO/Fe/BV-BR metabolic pathway, further cooperating with released Fe and curcumin, ultimately eliciting mitochondria damage, membrane disruption, and intracytoplasmic injury. This work not only provides a paradigm for exploiting diversified metabolites for tumor suppression, but also presents a safe and efficient full-API nanodrug, facilitating the practical translation of nanodrugs.
纳米医学在增强癌症治疗方面具有巨大的潜力。然而，低活性药物成分 (API) 负载含量、不可预测的药物释放以及赋形剂的潜在毒性限制了它们的转化能力。我们在此报告了一种全 API 纳米药物，由 FDA 批准的 5-氨基酮戊酸 (ALA)、人体必需元素 Fe 和天然生物活性化合物姜黄素组成，具有理想的 API 含量和 pH 响应释放特性，可通过多步串联内源性生物合成实现连续时空癌症治疗。首先，ALA 酶促转化为光敏剂原卟啉 IX (PpIX)。随后，通过 PpIX-血红素-CO/Fe/BV-BR 代谢途径，分别生物合成包括一氧化碳 (CO)、Fe、胆绿素 (BV) 和胆红素 (BR) 在内的多种下游产物，这些产物与释放的 Fe 和姜黄素协同作用，最终导致线粒体损伤、膜破裂和细胞内损伤。这项工作不仅为利用多样化代谢物抑制肿瘤提供了范例，还提出了一种安全有效的全 API 纳米药物，促进了纳米药物的实际转化。
