Nanoscale coordination polymers (NCPs) are promising nanomedicine platforms featured with biodegradability and versatile functionalities. However, multi-step post-synthesis surface modification is usually required to functionalize as-made NCPs before their biomedical applications. Moreover, efforts are still required to design therapeutic NCPs responsive to the unique tumor microenvironment to achieve more specific and effective therapy. Herein, we uncover a simple yet general strategy to synthesize a series of polyethylene glycol (PEG) modified NCPs via a one-step method by adding poly-histidine-PEG co-polymer into the mixture of metal ions and organic ligands during NCPs formation. With NCPs consisting Ca²⁺/dicarboxylic cisplatin (IV) prodrug as the example, we show that such Ca/Pt(IV)@pHis-PEG NCPs are highly sensitive to pH changes. With slightly negative charges and compact structure under pH 7.4 during blood circulation, those NCPs exhibit efficient passive accumulation in the tumor, in which the reduced pH (c.a. 6.5) would trigger charge conversion and size expansion to enhance their tumor retention and cell internationalization. After cellular uptake, NCPs within cell endo-/lysosomes with further reduced pH would then lead to decomposition of those NCPs and thus drug release. Chemotherapy with Ca/Pt(IV)@pHis-PEG NCPs in our animal tumor model demonstrates great efficacy under low drug doses, and is found to be particularly effective towards solid tumors with reduced pH.

纳米级配位聚合物（NCP）是具有生物降解性和多功能功能的有前途的纳米医学平台。但是，通常需要进行多步合成后表面修饰，才能在生物医学应用之前功能化已制成的NCP。而且，仍然需要努力设计对独特的肿瘤微环境有反应的治疗性NCP，以实现更具体和有效的治疗。本文中，我们揭示了一种简单而通用的策略，可通过一步法在NCP形成过程中将聚组氨酸-PEG共聚物添加到金属离子和有机配体的混合物中，从而一步一步合成一系列聚乙二醇（PEG）改性的NCP。使用包含Ca ^2+的NCP以二羧酸顺铂（IV）前药为例，我们表明此类Ca / Pt（IV）@ pHis-PEG NCP对pH变化高度敏感。这些NCP在血液循环过程中在pH 7.4下具有轻微的负电荷和紧凑的结构，在肿瘤中表现出有效的被动积累，其中降低的pH（ca 6.5）将触发电荷转换和大小扩展，从而增强其肿瘤保留和细胞国际化。细胞摄取后，pH进一步降低的细胞内/溶酶体内的NCP将导致这些NCP分解，从而释放药物。在我们的动物肿瘤模型中，用Ca / Pt（IV）@ pHis-PEG NCP进行的化学疗法在低药物剂量下显示出了巨大的功效，并且被发现对降低pH的实体瘤特别有效。