Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China.
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China; National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
Acta Biomater. 2019 Jan 15;84:339-355. doi: 10.1016/j.actbio.2018.11.050. Epub 2018 Nov 29.
Polymer-drug conjugates has significantly improved the anti-tumor efficacy of chemotherapeutic drugs and alleviated their side effects. N-(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA) copolymer was synthesized via RAFT polymerization and polymer-doxorubicin (DOX) (diblock pDHPMA-DOX) were formed by conjugation, resulting in a self-aggregation-induced nanoprodrug with a favorable size of 21 nm and great stability. The nanoprodrug with a molecular weight (MW) of 95 kDa released drugs in response to tumor microenvironmental pH variations and they were enzymatically hydrolyzed into low MW segments (45 kDa). The nanoprodrug was transported through the endolysosomal pathway, released the drug into the cytoplasm and some was localized in the mitochondria, resulting in disruption of the cellular actin cytoskeleton. Cellular apoptosis was also associated with reduction in the mitochondrial potential caused by the nanoprodrug. Notably, the nanoprodrug had a significantly prolonged blood circulation time with an elimination half time of 9.8 h, displayed high accumulation within tumors, and improved the in vivo therapeutic efficacy against 4T1 xenograft tumors compared to free DOX. The tumor xenograft immunohistochemistry study clearly indicated tumor inhibition was through the inhibition of cell proliferation and antiangiogenic effects. Our studies demonstrated that the diblock pDHPMA-DOX nanoprodrug with a controlled molecular structure is promising to alleviate adverse effects of free DOX and have a great potential as an efficient anticancer agent. STATEMENT OF SIGNIFICANCE: In this work, we prepared a biodegradable diblock DHPMA polymer-doxorubicin conjugate via one-pot of RAFT polymerization and conjugate chemistry. The conjugate-based nanoprodrug was internalized by endocytosis to intracellularly release DOX and further induce disruption of mitochondrial functions, actin cytoskeleton alterations and cellular apoptosis. The nanoprodrug with a high molecular weight (MW) (95 kDa) showed a long blood circulation time and achieved high accumulation into tumors. The nanoprodrug was degraded into low MW (∼45 kDa) products below the renal threshold, which ensured its biosafety. Additionally, the multi-stimuli-responsive nanoprodrug demonstrated an enhanced antitumor efficacy against 4T1 breast tumors and alleviated side effects, showing a great potential as an efficient and safe anticancer agent.
聚合物-药物偶联物显著提高了化疗药物的抗肿瘤疗效，并减轻了其副作用。通过 RAFT 聚合合成了 N-(1,3-二羟基丙基)甲基丙烯酰胺(DHPMA)共聚物，并通过接枝形成了聚合物-阿霉素(DOX)(嵌段 pDHPMA-DOX)，形成了具有有利的 21nm 大小和良好稳定性的自聚集诱导纳米前药。分子量 (MW) 为 95kDa 的纳米前药响应肿瘤微环境 pH 值的变化释放药物，并被酶解成低 MW 片段(45kDa)。纳米前药通过内溶酶体途径转运，将药物释放到细胞质中，部分定位在线粒体中，导致细胞肌动蛋白细胞骨架破坏。细胞凋亡也与纳米前药引起的线粒体电位降低有关。值得注意的是，与游离 DOX 相比，纳米前药具有明显延长的血液循环时间，消除半衰期为 9.8h，在肿瘤内高度积聚，并提高了对 4T1 异种移植肿瘤的体内治疗效果。肿瘤异种移植免疫组织化学研究清楚地表明，肿瘤抑制是通过抑制细胞增殖和抗血管生成作用实现的。我们的研究表明，具有可控分子结构的嵌段 pDHPMA-DOX 纳米前药有望减轻游离 DOX 的不良反应，并具有成为高效抗癌药物的巨大潜力。
在这项工作中，我们通过一锅法 RAFT 聚合和共轭化学制备了可生物降解的嵌段 DHPMA 聚合物-阿霉素偶联物。基于偶联物的纳米前药通过内吞作用被内化，在细胞内释放 DOX，并进一步诱导线粒体功能破坏、肌动蛋白细胞骨架改变和细胞凋亡。高分子量 (MW)(95kDa)的纳米前药表现出长血液循环时间，并实现了对肿瘤的高积累。纳米前药被降解成低于肾阈值的低 MW(约 45kDa)产物，这确保了其生物安全性。此外，多刺激响应纳米前药对 4T1 乳腺癌表现出增强的抗肿瘤疗效，并减轻了副作用，显示出作为高效、安全抗癌药物的巨大潜力。
