PDF(Pubmed)
Abstract：
While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered self-repairing autophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel (NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundant NO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles (MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtain MNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability to perform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distribution and strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and this process is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over one month and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel at the tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NO effectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronously destroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26 colon tumors are completely eliminated without causing severe side-effects.
摘要：
虽然轻度热疗在实体瘤的治疗中具有巨大的潜力，热应激触发的自我修复自噬显著损害其功效.为了绕过这个障碍，开发了一种可注射水凝胶（NO-Gel），该凝胶由热敏聚（乙二醇）-多肽共聚物组成，该共聚物在其侧链上具有丰富的NO供体。同时,合成了具有高磁热转化效率的铁磁Zn0.5Fe2.5O4磁性纳米颗粒（MNPs），并将其负载到NO-Gel中，以获得MNPs@NO-Gel。MNPs@NO-Gel系统在加热时表现出溶胶-凝胶转变，由于MNPs在NO-Gel中的均匀分布和强固定，仅一次给药后就具有进行多次磁热治疗（MHT）的能力。NO可以从NO-凝胶中连续释放,并且MHT显著加速了该过程。此外,MNPs@NO-凝胶在体内维持其完整性超过一个月,释放的MNPs被脾脏代谢。在肿瘤部位单次施用MNPs@NO-Gel后，实现了三种具有相似效果的轻度MHT治疗，充足的NO通过阻断自噬体的形成和同步破坏溶酶体，有效抑制MHT诱导的自噬通量，从而显著提高轻度MHT的功效。因此,CT-26结肠肿瘤完全消除，不会引起严重的副作用。
