Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China.
Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, University of South China, Hengyang 421001, China.
J Control Release. 2022 Jul;347:400-413. doi: 10.1016/j.jconrel.2022.05.024. Epub 2022 May 18.
Successful hepatocellular carcinoma (HCC) therapy in vivo remains a significant challenge due to the down-regulated expression of the receptors on the surface of tumor cells for compromised active targeting efficiency and cellular uptake of nanoparticles (NPs)-based drug delivery systems (DDSs) and "accelerated blood clearance" and premature unpackaging of NPs in vivo induced by the poly(ethylene glycol)ylation (PEGylation). Inspired by the repeatedly highlighted prolonged blood circulation property of RBCm-camouflaged NPs, we hypothesis that the prolonged blood circulation property resulting from RBCm coating outperforms the active targeting mechanisms of various targeting ligands for enhanced HCC therapy in vivo. Clarification of this hypothesis is therefore of great significance and urgency to break the afore mentioned bottlenecks that hamper the efficient HCC treatment in vivo. For this purpose, we reported in this study the first identification of a determining factor of nanocarriers for enhanced HCC therapy in vivo by the use of the previously fabricated pectin-doxorubicin nanoparticles (PDC-NPs) as a typical example, i.e., the natural RBCm was used as a stealth coating of PDC-NPs for the fabrication of biomimetic DDSs, PDC@RBC-NPs via hypotonic dialysis and mechanical co-extrusion methods. Comprehensive in vitro and in vivo evaluation and comparison of the properties and performance of PDC@RBC-NPs and PDC-NPs were performed in terms of colloidal stability, biosafety, drug release profiles, macrophage escape, anti-HCC effect. The resulting PDC@RBC-NPs outperformed PDC-NPs for HCC therapy in vitro and in vivo. Notably, PDC@RBC-NPs-treated BALB/c nude mice showed a significantly smaller final average tumor volume of 613 mm after 16 days than the PDC-NPs-treated group with an average value of 957 mm. Therefore, the PDC@RBC-NPs developed herein showed great potential for clinical transformations due to the facile preparation and superior therapeutic efficiency against HCC. Most importantly, prolonged blood circulation was identified as a determining factor of nanocarriers instead of active targeting for enhanced HCC therapy in vivo, which could be used to direct the future design and development of advanced DDSs with greater therapeutic efficiency for HCC.
由于肿瘤细胞表面受体的表达下调，导致主动靶向效率降低和基于纳米粒子（NPs）的药物递送系统（DDS）的细胞摄取能力下降，以及聚乙二醇化（PEGylation）引起的“加速血液清除”和 NPs 体内过早解包，使得肝癌（HCC）的体内治疗仍然是一个重大挑战。受 RBCm 伪装的 NPs 反复强调的延长血液循环特性的启发，我们假设由于 RBCm 涂层导致的延长血液循环特性优于各种靶向配体的主动靶向机制，从而增强 HCC 的体内治疗效果。因此，阐明这一假设对于打破阻碍 HCC 体内高效治疗的上述瓶颈具有重要意义和紧迫性。为此，我们在本研究中首次报道了通过使用先前制备的果胶-阿霉素纳米粒（PDC-NPs）作为典型实例，确定了增强 HCC 体内治疗的纳米载体的决定因素，即天然 RBCm 被用作 PDC-NPs 的隐形涂层，以通过低渗透析和机械共挤出方法制备仿生 DDS，即 PDC@RBC-NPs。从胶体稳定性、生物安全性、药物释放曲线、巨噬细胞逃逸、抗 HCC 效果等方面对 PDC@RBC-NPs 和 PDC-NPs 的性质和性能进行了全面的体外和体内评价和比较。结果表明，PDC@RBC-NPs 在 HCC 的体外和体内治疗中优于 PDC-NPs。值得注意的是，与 PDC-NPs 治疗组相比，PDC@RBC-NPs 治疗的 BALB/c 裸鼠 16 天后的最终平均肿瘤体积明显较小，为 613mm3，而 PDC-NPs 治疗组的平均肿瘤体积为 957mm3。因此，由于其易于制备和对 HCC 的高效治疗效果，本文开发的 PDC@RBC-NPs 具有很大的临床转化潜力。最重要的是，与主动靶向相比，延长血液循环被鉴定为增强 HCC 体内治疗的纳米载体的决定因素，这可用于指导未来设计和开发具有更高 HCC 治疗效率的先进 DDS。
