Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.
Key Laboratory of Molecular Imaging, the State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China.
Theranostics. 2018 Apr 3;8(10):2634-2645. doi: 10.7150/thno.24705. eCollection 2018.
Near-infrared (NIR)-absorbing conjugated polymer nanoparticles are interesting for imaging-guided combination therapy, especially for synergistic photothermal therapy and chemotherapy; however, most of them target tumours passively through the enhanced permeability and retention (EPR) effect, leading to low utilization efficiency. To address this problem, we report an active tumour-targeting strategy of tumour-homing chimeric polypeptide-conjugated NIR-absorbing conjugated-polymer nanoparticles as a new class of drug nanocarriers for imaging-guided combination therapy of cancer. A tumour-homing chimeric polypeptide C-ELP-F3 was genetically engineered, and chemoselectively conjugated to polypyrrole (PPy) nanoparticles via a facile thiol-maleimide coupling reaction to form ELP-F3 conjugated PPy (PPy-ELP-F3) nanoparticles. Doxorubicin (DOX) was physically adsorbed onto PPy-ELP-F3 nanoparticles to yield DOX-loaded PPy-ELP-F3 (DOX/PPy-ELP-F3) nanoparticles. The physicochemical properties of DOX/PPy-ELP-F3 were characterized. The pharmacokinetics of DOX/PPy-ELP-F3 was studied in a mouse model. The photoacoustic imaging and photothermal imaging of tumours were tested in a melanoma-bearing mouse model. The photothermal-chemical combination therapy of tumours was investigated by using melanoma cells and in a melanoma-bearing mouse model. DOX/PPy-ELP-F3 nanoparticles showed enhanced cytotoxicity to melanoma cells and improved tumour-targeting efficiency , as compared with both DOX/PPy-ELP nanoparticles without the tumour-homing function and free DOX. The photothermal effect of DOX/PPy-ELP-F3 nanoparticles could accelerate the release of DOX from PPy-ELP-F3. Under the guidance of photoacoustic and photothermal imaging, the synergy of photothermal and chemical therapy could completely abolish tumours without detectable systemic toxicity. Tumour-homing chimeric polypeptide-conjugated NIR-absorbing conjugated-polymer nanoparticles are promising as a new multifunctional drug delivery platform for highly-efficient imaging guided combination therapy.
近红外（NIR）吸收共轭聚合物纳米粒子在影像引导联合治疗中很有应用前景，尤其是在协同光热治疗和化学治疗方面；然而，大多数通过增强的通透性和保留（EPR）效应被动靶向肿瘤，导致利用率低。为了解决这个问题，我们报道了一种主动肿瘤靶向策略，即用肿瘤归巢嵌合多肽共轭的近红外吸收共轭聚合物纳米粒子作为一种新的药物纳米载体，用于癌症的影像引导联合治疗。通过基因工程设计了一种肿瘤归巢嵌合多肽 C-ELP-F3，并通过简便的巯基-马来酰亚胺偶联反应选择性地共轭到聚吡咯（PPy）纳米粒子上，形成 ELP-F3 共轭 PPy（PPy-ELP-F3）纳米粒子。阿霉素（DOX）通过物理吸附到 PPy-ELP-F3 纳米粒子上，得到载 DOX 的 PPy-ELP-F3（DOX/PPy-ELP-F3）纳米粒子。对 DOX/PPy-ELP-F3 的理化性质进行了表征。在小鼠模型中研究了 DOX/PPy-ELP-F3 的药代动力学。在黑色素瘤荷瘤小鼠模型中进行了肿瘤的光声成像和光热成像测试。利用黑色素瘤细胞和黑色素瘤荷瘤小鼠模型研究了肿瘤的光热化学联合治疗。与没有肿瘤归巢功能的 DOX/PPy-ELP 纳米粒子和游离 DOX 相比，DOX/PPy-ELP-F3 纳米粒子对黑色素瘤细胞显示出增强的细胞毒性和提高的肿瘤靶向效率。DOX/PPy-ELP-F3 纳米粒子的光热效应可以加速 DOX 从 PPy-ELP-F3 中的释放。在光声和光热成像的引导下，光热和化学治疗的协同作用可以完全消除肿瘤，而没有可检测到的系统毒性。肿瘤归巢嵌合多肽共轭近红外吸收共轭聚合物纳米粒子作为一种新的高效影像引导联合治疗多功能药物递送平台具有广阔的应用前景。
