CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, PR China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, PR China; Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen 361024, PR China.
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, PR China; Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Analytical Technology and Instrumentation, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China.
J Control Release. 2020 May 10;321:222-235. doi: 10.1016/j.jconrel.2020.02.025. Epub 2020 Feb 13.
Carrier-free nanodrug via small-molecule assembly is a promising alternative strategy for tumor therapy. Thus, developing a self-recognizing carrier-free nanodrug without introduction of foreign ligand is very attractive to meet both targeting and therapeutic requirements while reducing structural complexity. Here we fabricated a tumor microenvironment-activated self-targeting nanodrug, via co-assembly of hydroxycamptothecin (HCPT) and bi-functional methotrexate (MTX, not only has antitumor effect but also shows innate affinity towards folate receptors) followed by surface covering through acidity-responsive polyethylene glycol (PEG). Notably, the morphology and size of MTX-HCPT nanodrug could be tuned by varying the drug-to-drug ratio and assembly time. The PEG shell of our nanodrug could be detached in response to acidic tumor microenvironment, and then MTX could be exposed for self-targeting to enhance tumor cell uptake. Subsequently, the shell-detached nanodrug could be dissociated in relatively stronger acidic lysosomal environment, resulting in burst release of both drugs. Further in vitro and in vivo studies demonstrated that our nanodrug showed a ~2.98-fold increase in cancer cell uptake, a ~1.25-fold increase in drug accumulation at tumor site, a significantly lower CI value of ~0.3, a ~27.3% improvement in tumor inhibition comparing with the corresponding non-responsive nanodrug. Taken together, the here reported tumor microenvironment-activated self-recognizing nanodrug might be an extremely promising strategy for synergistically enhancing chemotherapy efficiency with minimized side effects.
无载体纳米药物通过小分子自组装是肿瘤治疗的一种很有前途的替代策略。因此，开发一种无需引入外来配体的自识别无载体纳米药物，既能满足靶向和治疗的要求，又能降低结构复杂性，这是非常有吸引力的。在这里，我们通过喜树碱（HCPT）和双功能甲氨蝶呤（MTX，不仅具有抗肿瘤作用，而且对叶酸受体具有天然亲和力）的共组装，然后通过酸响应性聚乙二醇（PEG）的表面覆盖，制备了一种肿瘤微环境激活的自靶向纳米药物。值得注意的是，MTX-HCPT 纳米药物的形态和尺寸可以通过改变药物与药物的比例和组装时间来调节。我们纳米药物的 PEG 壳可以响应酸性肿瘤微环境而脱落，然后 MTX 可以暴露出来进行自靶向，以增强肿瘤细胞摄取。随后，壳脱离的纳米药物可以在相对较强的酸性溶酶体环境中解离，导致两种药物的爆发释放。进一步的体外和体内研究表明，我们的纳米药物对癌细胞的摄取增加了约 2.98 倍，在肿瘤部位的药物积累增加了约 1.25 倍，CI 值显著降低至约 0.3，肿瘤抑制率提高了约 27.3%，与相应的非响应性纳米药物相比。总之，这里报道的肿瘤微环境激活的自识别纳米药物可能是一种极具前景的策略，可以协同提高化疗效率，同时最大限度地减少副作用。
