School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, People's Republic of China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, China.
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China.
J Control Release. 2017 Dec 28;268:225-236. doi: 10.1016/j.jconrel.2017.10.029. Epub 2017 Oct 18.
Tumor vascular endothelium and extracellular matrix (ECM) as the major barriers of anticancer nanomedicine greatly limited the anticancer efficacy of treatment, but few strategies were available to overcome them simultaneously. Thus, herein a strategy was presented to utilize reversible vasodilatation effect of nitric oxide (NO) and size-controlled characteristic of ultrasound responsive liposome (URL) to construct a non-destructive nanomedicine, which was able to cross both obstacles simultaneously. In this work, URL was built as a carrier via forming a gas layer between lipid bilayer to encapsulate small particles PAMAM@DOX (PD, ~10nm) and NO donation-nitrosoglutathione (GSNO). Under ultrasound (US) stimulation, GSNO fastly generated NO that acting on tumor vascular smooth muscle, resulting in tumor vascular vasodilatation, meanwhile the URL lipid bilayer was destroyed, leading to release sharply of small nanoparticles PD. Combination vasodilatory effect of NO and size-controlled characteristic of URL allowed vast drugs to extravasate through endothelial gap and penetrate into tumor deep. Upon different types of cancers vary greatly in vascular structure, two distinctly different tumor, MCF-7 human breast carcinoma and MiaPaCa-2 human pancreatic carcinoma, were chosen to test the anticancer efficacy of URL. As a result, URL-based nanosystem was significantly more effective than the conventional liposome (CL) in tumor treatment, particularly in much less leaky MiaPaCa-2 tumor treatment (tumor therapeutic efficiency of URL/PD/GSNO+US increased by 32.5% and 56.5% compared to CL/DOX in MCF-7 and MiaPaCa-2 tumor treatment). This study offers a new method to enhance tumor drug accumulation along with minimal toxicity for future clinical cancer treatments.
肿瘤血管内皮细胞和细胞外基质（ECM）作为抗癌纳米医学的主要障碍，极大地限制了治疗的抗癌疗效，但很少有策略可以同时克服它们。因此，本文提出了一种利用一氧化氮（NO）的可逆血管扩张作用和超声响应脂质体（URL）的尺寸控制特性构建一种非破坏性纳米医学的策略，该策略能够同时克服这两个障碍。在这项工作中，通过在脂质双层之间形成气体层来构建 URL，以包裹小颗粒 PAMAM@DOX（PD，约 10nm）和一氧化氮供体-亚硝基谷胱甘肽（GSNO）。在超声（US）刺激下，GSNO 快速生成 NO，作用于肿瘤血管平滑肌，导致肿瘤血管扩张，同时 URL 脂质双层被破坏，导致小纳米颗粒 PD 急剧释放。NO 的血管扩张作用和 URL 的尺寸控制特性的组合允许大量药物通过内皮间隙逸出并渗透到肿瘤深部。由于不同类型的癌症在血管结构上有很大的差异，因此选择了两种截然不同的肿瘤，MCF-7 人乳腺癌和 MiaPaCa-2 人胰腺癌细胞，来测试 URL 的抗癌疗效。结果表明，基于 URL 的纳米系统在肿瘤治疗中的效果明显优于常规脂质体（CL），特别是在渗漏性较弱的 MiaPaCa-2 肿瘤治疗中（与 CL/DOX 相比，URL/PD/GSNO+US 在 MCF-7 和 MiaPaCa-2 肿瘤治疗中的肿瘤治疗效率分别增加了 32.5%和 56.5%）。该研究为未来的临床癌症治疗提供了一种增强肿瘤药物积累同时最小化毒性的新方法。
