Li Weinan, Zhang Xiaoyu, Nan Yang, Jia Li, Sun Jialin, Zhang Lina, Wang Yanhong
School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China.
Department of Pharmacy, Heze Medical College, Heze, China.
Front Oncol. 2021 Dec 24;11:760423. doi: 10.3389/fonc.2021.760423. eCollection 2021.
pH-responsive and CD44 receptor-mediated targeted nanoparticles for eliminating cancer stem cells (CSCs) were developed based on complexes of PEG-poly(β-amino ester) (PEG-PBAE) micelles (PPM) coated with hyaluronic acid (HA) (HA-coated PPM complex, or HPPMc). Thioridazine (Thz) was loaded into HPPMc with a decent drug loading content. The release results of the drug showed that Thz was released from the HPPMc, which was stimulated by both the acidic pH and specific enzymes. Cytotoxicity studies on mammospheres (MS) revealed that the toxicity potential of Thz-loaded HPPMc (Thz-HPPMc) at pH 5.5 was better than drug solutions. Compared with that at pH 7.4, a higher cellular uptake of a coumarin-6 (C6)-labeled complex at pH 5.5 was observed, which demonstrated that complexes were efficiently taken up in MS. Meanwhile, free HA competitively inhibited the cellular uptake of HPPMc, which revealed that the uptake mechanism was CD44 receptor-mediated endocytosis. Within the acidic endolysosomal environment, the protonation of PBAE facilitated the escape of the complex from the lysosome and releases the drug. The results of distribution studies and tumor suppression experiments showed that HPMMc could stay in the tumor site of BALB/c nude mice for a longer period of time, and Thz-HPPMc could significantly improve the tumor-suppressing effect. All these results demonstrated the great potential of the multifunctional nanoparticle system for eliminating CSCs.
基于聚乙二醇-聚（β-氨基酯）（PEG-PBAE）胶束（PPM）与透明质酸（HA）包覆形成的复合物（HA包覆的PPM复合物，即HPPMc），开发了用于消除癌症干细胞（CSC）的pH响应性和CD44受体介导的靶向纳米颗粒。将硫利达嗪（Thz）以合适的载药量载入HPPMc中。药物释放结果表明，在酸性pH和特定酶的刺激下，Thz从HPPMc中释放出来。对乳腺球（MS）的细胞毒性研究表明，载有Thz的HPPMc（Thz-HPPMc）在pH 5.5时的毒性潜力优于药物溶液。与pH 7.4时相比，在pH 5.5时观察到香豆素-6（C6）标记的复合物有更高的细胞摄取量，这表明复合物在MS中被有效摄取。同时，游离HA竞争性抑制HPPMc的细胞摄取，这表明摄取机制是CD44受体介导的内吞作用。在酸性溶酶体环境中，PBAE的质子化促进了复合物从溶酶体中逃逸并释放药物。分布研究和肿瘤抑制实验结果表明，HPMMc可以在BALB/c裸鼠的肿瘤部位停留更长时间，并且Thz-HPPMc可以显著提高肿瘤抑制效果。所有这些结果证明了多功能纳米颗粒系统在消除CSC方面的巨大潜力。
