Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicines, Ministry of Education, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing 100193, PR China.
Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicines, Ministry of Education, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing 100193, PR China.
J Control Release. 2022 Oct;350:132-145. doi: 10.1016/j.jconrel.2022.08.003. Epub 2022 Aug 18.
Very little is currently known about how inhaled nanomedicine for lung cancer treatment overcomes biological barriers hampering the tumor availability of drug and nanoparticles. Here, we developed a size-transformable nanocarrier (~ 119 nm) in which small-size nanoparticles (~ 28 nm) were loaded in the large nanocarrier after the addition of modified hyaluronan and could be released upon size-transformation at tumor tissue. Subsequently, the pulmonary and tumor pharmacokinetics of the two nanocarriers containing 7-ethyl-10-hydroxycamptothecin (SN38) and a covalently linked fluorescent sonosensitizer were comparatively investigated after intratracheal instillation to mice bearing orthotopic Lewis lung carcinoma tumors. The results showed that both instilled nanoparticles seemed to transport drug to tumor by direct access and transcytosis of nanoparticles, and diffusion of the released drug with the latter accounting for a great proportion of the drug tumor bioavailability. Relative to the small-size nanocarrier, the size-transformable counterpart appeared to restrict the mucociliary and absorption clearances from the lung and the clearance from the tumor interstitium to circulation, leading to increases in lung and tumor bioavailability of SN38 by 58.5% and 199%, respectively. In addition, the size-transformable nanoformulation conferred deep tumor penetration and sustained levels of both sonosensitizer and SN38 within tumors and simultaneously exerted sonodynamic- and chemo-therapies. Overall, the pulmonary delivery of size-transformable nanocarrier could co-deliver sonosensitizer and drug to deep tumor sites with enhanced tumor accumulation to realize combination therapy in lung cancer.
目前对于吸入式纳米药物如何克服阻碍药物和纳米颗粒到达肿瘤的生物屏障以治疗肺癌知之甚少。在这里，我们开发了一种可尺寸转化的纳米载体（119nm），其中小尺寸的纳米颗粒（28nm）在添加修饰透明质酸后装载在大纳米载体中，并可在肿瘤组织中发生尺寸转化时释放。随后，在经气管内滴注到患有原位 Lewis 肺癌肿瘤的小鼠后，比较了两种含有 7-乙基-10-羟基喜树碱（SN38）和共价连接的荧光声敏剂的纳米载体的肺部和肿瘤药代动力学。结果表明，两种滴注的纳米颗粒似乎都通过纳米颗粒的直接进入和转胞作用以及释放药物的扩散将药物输送到肿瘤，而后者占药物肿瘤生物利用度的很大比例。与小尺寸的纳米载体相比，可尺寸转化的对应物似乎限制了纳米载体从肺部的黏液纤毛清除和吸收清除以及从肿瘤间质到循环的清除，从而使 SN38 的肺部和肿瘤生物利用度分别增加了 58.5%和 199%。此外，可尺寸转化的纳米制剂赋予了肿瘤更深的穿透能力和持续的声敏剂和 SN38 水平，同时发挥声动力和化学治疗作用。总的来说，可尺寸转化的纳米载体的肺部递送可以将声敏剂和药物共同递送到深部肿瘤部位，增加肿瘤的积累，从而实现肺癌的联合治疗。
