State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials , China Pharmaceutical University , Nanjing 210009 , China.
Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States.
Nano Lett. 2018 Apr 11;18(4):2294-2303. doi: 10.1021/acs.nanolett.7b04976. Epub 2018 Mar 21.
Protein therapeutics hold increasing interest with the promise of revolutionizing the cancer treatment by virtue of a potent specific activity and reduced adverse effects. Nonetheless, the therapeutic efficacy of anticancer proteins is highly compromised by multiple successive physiological barriers to protein delivery. In addition, concurrent elimination of bulk tumor cells and highly tumorigenic cancer stem-like cells (CSCs) as a promising strategy has been evidenced to significantly improve cancer therapy. Here we show that a hierarchically assembled nanocomposite can self-adaptively transform its particulate property in response to endogenous tumor-associated signals to overcome the sequential barriers and achieve an enhanced antitumor efficacy by killing CSCs and bulk tumor cells synchronously. The nanoassemblies preferentially accumulate in tumors and dissociate under tumor microenvironmental acidity accompanied by the extracellular release of small-sized ribonuclease A (RNase A)-encapsulated nanocapsule (R-rNC) and small-molecule anti-CSC doxycycline (Doc), which exhibit increased tumor penetration and intracellular accumulation. The endocytosed R-rNC rapidly releases RNase A within both CSCs and tumor cells at intracellular reductive conditions, causing cell death by catalyzing RNA degradation, while Doc eradicates CSCs by inhibiting the mitochondrial biogenesis. The hierarchical assemblies show enhanced cytotoxicity on the CSC-enriched MDA-MB-231 mammospheres and an enhanced antitumor efficacy on the xenograft tumor mouse model.
蛋白质疗法因其强大的特异性和减少的不良反应而备受关注，有望彻底改变癌症治疗。然而，抗癌蛋白的治疗效果受到多种连续的蛋白质传递生理障碍的严重影响。此外，同时消除大量肿瘤细胞和高度致瘤性癌症干细胞样细胞（CSCs）作为一种有前途的策略，已被证明可以显著改善癌症治疗。在这里，我们展示了一种分层组装的纳米复合材料可以自适应地改变其颗粒特性，以响应内源性肿瘤相关信号，克服连续的障碍，并通过同步杀死 CSCs 和大量肿瘤细胞来实现增强的抗肿瘤疗效。纳米组装物优先在肿瘤中积累，并在肿瘤微环境酸度下解离，同时释放小尺寸的核糖核酸酶 A（RNase A）包封的纳米胶囊（R-rNC）和小分子抗 CSC 强力霉素（Doc），从而增加肿瘤穿透性和细胞内积累。内吞的 R-rNC 在 CSCs 和肿瘤细胞内的还原条件下迅速释放 RNase A，通过催化 RNA 降解导致细胞死亡，而 Doc 通过抑制线粒体生物发生来根除 CSCs。分层组装物在富含 CSC 的 MDA-MB-231 类球体上显示出增强的细胞毒性，并在异种移植肿瘤小鼠模型上显示出增强的抗肿瘤疗效。
