Photodynamic therapy (PDT) is a promising treatment modality for tumor suppression. However, the hypoxic state of most solid tumors might largely hinder the efficacy of PDT. Here, a functional covalent organic framework (COF) is fabricated to enhance PDT efficacy by remodeling the tumor extracellular matrix (ECM). Anti-fibrotic drug pirfenidone (PFD) is loaded in an imine-based COF (COFTTA-DHTA) and followed by the decoration of poly(lactic-co-glycolic-acid)-poly(ethylene glycol) (PLGA-PEG) to fabricate PFD@COFTTA-DHTA@PLGA-PEG, or PCPP. After injected intravenously, PCPP can accumulate and release PFD in tumor sites, leading to down-regulation of ECM compenents such as hyaluronic acid (HA) and collagen I. Such depletion of tumor ECM reduces the intratumoral solid stress, a compressive force exerted by the ECM and cells, decompresses tumor blood vessels, and increases the density of effective vascular areas, resulting in significantly improved oxygen supply in tumor. Furthermore, PCPP-mediated tumor ECM depletion also enhances the tumor uptake of subsequently injected Protoporphyrinl IX (PPIX)-conjugated peptide formed nanomicelles (NM-PPIX) due to the improved enhanced permeability and retention (EPR) effect. Both the alleviated tumor hypoxia and improved tumor homing of photosensitizer (PS) molecules after PCPP treatment significantly increase the reactive oxygen species (ROS) generation in tumor and therefore realize greatly enhanced PDT effect of tumor in vivo.

中文翻译：

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基于功能性共价有机框架重塑细胞外基质，以增强肿瘤的光动力治疗。

光动力疗法（PDT）是一种有前途的肿瘤抑制治疗方法。但是，大多数实体瘤的低氧状态可能会大大阻碍PDT的疗效。在这里，通过重塑肿瘤细胞外基质（ECM）来制造功能性共价有机骨架（COF），以增强PDT功效。将抗纤维化药物吡非尼酮（PFD）装入基于亚胺的COF（COFTTA-DHTA）中，然后修饰聚乳酸-乙醇酸-聚乙二醇（PLGA-PEG）以制造PFD @ COFTTA-DHTA @ PLGA-PEG或PCPP。静脉注射后，PCPP可以在肿瘤部位积聚和释放PFD，从而导致ECM成分（如透明质酸（HA）和胶原I）下调。这种肿瘤ECM的消耗减少了肿瘤内的固体应力，即由肿瘤形成的压力。 ECM和细胞，减压肿瘤血管，并增加有效血管区域的密度，从而显着改善肿瘤中的氧气供应。此外，由于改善的通透性和保留（EPR）效果提高，PCPP介导的肿瘤ECM耗竭还增强了随后注射的原卟啉IX（PPIX）结合肽形成的纳米胶束（NM-PPIX）的肿瘤吸收。PCPP处理后缓解的肿瘤缺氧和光敏剂（PS）分子改善的肿瘤归巢性均显着增加了肿瘤中的活性氧（ROS）生成，因此在体内实现了大大增强的PDT效应。PCPP介导的肿瘤ECM耗竭还改善了随后注射的原卟啉IX（PPIX）偶联肽形成的纳米胶束（NM-PPIX）的肿瘤吸收，这是因为其增强的通透性和保留（EPR）效果得到改善。PCPP处理后缓解的肿瘤缺氧和光敏剂（PS）分子改善的肿瘤归巢性均显着增加了肿瘤中的活性氧（ROS）生成，因此在体内实现了大大增强的PDT效应。PCPP介导的肿瘤ECM耗竭还改善了随后注射的原卟啉IX（PPIX）偶联肽形成的纳米胶束（NM-PPIX）的肿瘤吸收，这是因为其增强的通透性和保留（EPR）效果得到改善。PCPP处理后缓解的肿瘤缺氧和光敏剂（PS）分子改善的肿瘤归巢性均显着增加了肿瘤中的活性氧（ROS）生成，因此在体内实现了大大增强的PDT效应。