School of Pharmacy , Guangdong Pharmaceutical University , Guangzhou , Guangdong 510006 , China.
School of Traditional Chinese Medicine , Guangdong Pharmaceutical University , Guangzhou 510006 , China.
ACS Appl Mater Interfaces. 2018 Oct 3;10(39):33464-33473. doi: 10.1021/acsami.8b11974. Epub 2018 Sep 18.
P-Glycoprotein (Pgp)-medicated multidrug resistance (MDR) remains a formidable challenge to cancer therapy. As conventional approaches using small-molecule inhibitors failed in clinical development because of the lack of cancer specificity, we develop Pgp-targeted carbon nanotubes to achieve highly cancer-specific therapy through combining antibody-based cancer targeting and locoregional tumor ablation with photothermal therapy. Through a dense coating with phospholipid-poly(ethylene glycol), we have engineered multiwalled carbon nanotubes (MWCNTs) which show minimum nonspecific cell interactions and maximum intercellular diffusion. After chemically modifying with an anti-Pgp antibody, these MWCNTs showed highly Pgp-specific cellular uptake. Treatment of the targeted MWCNTs caused dramatic cytotoxicity in MDR cancer cells upon photoirradiation, whereas they did not cause any toxicity in the dark or phototoxicity toward normal cells that do not express Pgp. Because of excellent intratumor diffusion and Pgp-specific cellular uptake, the targeted MWCNTs produced strong phototoxicity in tumor spheroids of MDR cancer cells, a 3-D tumor model for studying tumor penetration and therapy. In conclusion, we have developed highly Pgp-specific MWCNTs that may provide an effective therapy for MDR cancers where other approaches have failed.
P-糖蛋白（Pgp）介导的多药耐药（MDR）仍然是癌症治疗的一个巨大挑战。由于缺乏癌症特异性，传统的小分子抑制剂方法在临床开发中失败了，因此我们开发了 Pgp 靶向的碳纳米管，通过结合基于抗体的癌症靶向和局部肿瘤消融与光热疗法，实现高度癌症特异性治疗。通过与磷脂-聚乙二醇（PEG）的密集涂层，我们已经设计了多壁碳纳米管（MWCNTs），其具有最小的非特异性细胞相互作用和最大的细胞间扩散。经过化学修饰与抗 Pgp 抗体后，这些 MWCNTs 表现出高度的 Pgp 特异性细胞摄取。在光照射下，靶向 MWCNTs 的处理导致 MDR 癌细胞的剧烈细胞毒性，而在黑暗中或对不表达 Pgp 的正常细胞没有任何毒性或光毒性。由于优异的肿瘤内扩散和 Pgp 特异性细胞摄取，靶向 MWCNTs 在 MDR 癌细胞的肿瘤球体中产生了强烈的光毒性，这是一种用于研究肿瘤穿透和治疗的 3D 肿瘤模型。总之，我们已经开发出了高度 Pgp 特异性的 MWCNTs，这可能为其他方法失败的 MDR 癌症提供有效的治疗方法。
