Fan Li, Zhang Silu, Zhang Chunyuan, Yin Chun, Chu Zhiqin, Song Chaojun, Lin Ge, Li Quan
Department of Pharmaceutical Analysis The Fourth Military Medical University 169th Changle west road Xi'an Shaanxi 710032 China.
Department of Physics The Chinese University of Hong Kong Shatin New Territories Hong Kong.
Adv Sci (Weinh). 2017 Nov 9;5(2):1700289. doi: 10.1002/advs.201700289. eCollection 2018 Feb.
It is discovered that sustained cytosolic drug release at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drug efficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drug movement between the drug released from the carrier into the cytosol and the one removed from the cell interior. By adopting nanoparticle (NP) as the drug carrier, a reservoir of drug can be maintained inside the cells upon effective cellular uptake of these NPs via endocytosis. This study shows that gradual release of the drug from the NP carrier provides a feasible scheme for sustained drug release in cells, resulting in relatively stable cytosolic drug concentration level, particularly in the drug resistant case. By implementing an "optical switch" with light irradiation on photosensitizer in the same nanoparticle carrier, cytosolic drug release is further promoted, which increases cytosolic drug concentration with good concentration retention. Enhanced drug efficacy in drug sensitive as well as resistant models is demonstrated both in vitro and in vivo. Such a mechanism is shown to efficiently circumvent multidrug resistance, and at the same time largely reduce the systemic toxicity of the anticancer drug.
研究发现，在足够浓度下持续的胞质药物释放是规避多药耐药性并因此提高抗肿瘤药物疗效的有效机制。结果表明，实现这一机制的一种简单方法是在从载体释放到胞质溶胶中的药物与从细胞内部清除的药物之间达到药物运动的细胞内动力学平衡。通过采用纳米颗粒（NP）作为药物载体，在这些NP通过内吞作用被细胞有效摄取后，药物储库可在细胞内维持。本研究表明，药物从NP载体的逐渐释放为细胞内持续药物释放提供了一种可行方案，导致相对稳定的胞质药物浓度水平，尤其是在耐药情况下。通过对同一纳米颗粒载体中的光敏剂进行光照射来实现“光开关”，可进一步促进胞质药物释放，从而提高胞质药物浓度并保持良好的浓度。在体外和体内均证明了在药物敏感和耐药模型中药物疗效增强。这种机制被证明能有效规避多药耐药性，同时大大降低抗癌药物的全身毒性。
