Choi Yongwhan, Han Hyounkoo, Jeon Sangmin, Yoon Hong Yeol, Kim Hyuncheol, Kwon Ick Chan, Kim Kwangmeyung
KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
Pharmaceutics. 2020 Oct 15;12(10):974. doi: 10.3390/pharmaceutics12100974.
The dense extracellular matrix (ECM) in heterogeneous tumor tissues can prevent the deep tumor penetration of drug-loaded nanoparticles, resulting in a limited therapeutic efficacy in cancer treatment. Herein, we suggest that the deep tumor penetration of doxorubicin (DOX)-loaded glycol chitosan nanoparticles (CNPs) can be improved using high-intensity focused ultrasound (HIFU) technology. Firstly, we prepared amphiphilic glycol chitosan-5β-cholanic acid conjugates that can self-assemble to form stable nanoparticles with an average of 283.7 ± 5.3 nm. Next, the anticancer drug DOX was simply loaded into the CNPs via a dialysis method. DOX-loaded CNPs (DOX-CNPs) had stable nanoparticle structures with an average size of 265.9 ± 35.5 nm in aqueous condition. In cultured cells, HIFU-treated DOX-CNPs showed rapid drug release and enhanced cellular uptake in A549 cells, resulting in increased cytotoxicity, compared to untreated DOX-CNPs. In ECM-rich A549 tumor-bearing mice, the tumor-targeting efficacy of intravenously injected DOX-CNPs with HIFU treatment was 1.84 times higher than that of untreated DOX-CNPs. Furthermore, the deep tumor penetration of HIFU-treated DOX-CNPs was clearly observed at targeted tumor tissues, due to the destruction of the ECM structure via HIFU treatment. Finally, HIFU-treated DOX-CNPs greatly increased the therapeutic efficacy at ECM-rich A549 tumor-bearing mice, compared to free DOX and untreated DOX-CNPs. This deep penetration of drug-loaded nanoparticles via HIFU treatment is a promising strategy to treat heterogeneous tumors with dense ECM structures.
异质性肿瘤组织中致密的细胞外基质（ECM）会阻碍载药纳米颗粒深入肿瘤组织，导致癌症治疗的疗效有限。在此，我们提出使用高强度聚焦超声（HIFU）技术可提高载阿霉素（DOX）的壳聚糖纳米颗粒（CNPs）在肿瘤组织中的渗透深度。首先，我们制备了两亲性壳聚糖-5β-胆酸共轭物，其可自组装形成平均粒径为283.7±5.3 nm的稳定纳米颗粒。接下来，通过透析法将抗癌药物DOX简单地负载到CNPs中。载DOX的CNPs（DOX-CNPs）在水性条件下具有稳定的纳米颗粒结构，平均粒径为265.9±35.5 nm。在培养细胞中，与未处理的DOX-CNPs相比，经HIFU处理的DOX-CNPs在A549细胞中显示出快速的药物释放和增强的细胞摄取，从而导致细胞毒性增加。在富含ECM的A549荷瘤小鼠中，经HIFU处理的静脉注射DOX-CNPs的肿瘤靶向疗效比未处理的DOX-CNPs高1.84倍。此外，由于HIFU处理破坏了ECM结构，在靶向肿瘤组织中清楚地观察到经HIFU处理的DOX-CNPs具有更深的肿瘤渗透。最后，与游离DOX和未处理的DOX-CNPs相比，经HIFU处理的DOX-CNPs大大提高了富含ECM的A549荷瘤小鼠的治疗效果。通过HIFU处理实现载药纳米颗粒的这种深度渗透是治疗具有致密ECM结构的异质性肿瘤的一种有前景的策略。
