Wang Hai, Agarwal Pranay, Zhao Gang, Ji Guang, Jewell Christopher M, Fisher John P, Lu Xiongbin, He Xiaoming
Fischell Department of Bioengineering and Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, Maryland 20742, United States.
Department of Biomedical Engineering and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States.
ACS Cent Sci. 2018 May 23;4(5):567-581. doi: 10.1021/acscentsci.8b00050. Epub 2018 Apr 17.
Drug resistance due to overexpression of membrane transporters in cancer cells and the existence of cancer stem cells (CSCs) is a major hurdle to effective and safe cancer chemotherapy. Nanoparticles have been explored to overcome cancer drug resistance. However, drug slowly released from nanoparticles can still be efficiently pumped out of drug-resistant cells. Here, a hybrid nanoparticle of phospholipid and polymers is developed to achieve cold-triggered burst release of encapsulated drug. With ice cooling to below ∼12 °C for both burst drug release and reduced membrane transporter activity, binding of the drug with its target in drug-resistant cells is evident, while it is minimal in the cells kept at 37 °C. Moreover, targeted drug delivery with the cold-responsive nanoparticles in combination with ice cooling not only can effectively kill drug-resistant ovarian cancer cells and their CSCs but also destroy both subcutaneous and orthotopic ovarian tumors with no evident systemic toxicity.
癌细胞中膜转运蛋白的过表达导致的耐药性以及癌症干细胞（CSCs）的存在是有效且安全的癌症化疗的主要障碍。人们已探索利用纳米颗粒来克服癌症耐药性。然而，从纳米颗粒缓慢释放的药物仍可被耐药细胞有效地泵出。在此，开发了一种磷脂和聚合物的混合纳米颗粒，以实现封装药物的冷触发突发释放。通过将冰冷却至约12°C以下以实现药物突发释放并降低膜转运蛋白活性，药物与耐药细胞中其靶点的结合很明显，而在保持在37°C的细胞中这种结合则最小。此外，冷响应纳米颗粒与冰冷却相结合的靶向药物递送不仅可以有效杀死耐药卵巢癌细胞及其CSCs，还可以破坏皮下和原位卵巢肿瘤，且无明显的全身毒性。
