Wei Guoguang, Zhang Sihang, Yu Sheng, Lu Wei
Key Laboratory of Smart Drug Delivery, Ministry of Education & State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy & Minhang Hospital, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Pharmaceutics. 2023 Feb 3;15(2):519. doi: 10.3390/pharmaceutics15020519.
The principle of enhanced permeability and retention (EPR) effect has been used to design anti-cancer nanomedicines over decades. However, it is being challenged due to the poor clinical outcome of nanoparticles and controversial physiological foundation. Herein, we use a near-infrared-II (1000-1700 nm, NIR-II) fluorescence probe BPBBT to investigate the pathway for the entry of human serum albumin-bound nanoparticles (BPBBT-HSA NPs) into tumor compared with BPBBT micelles with phospholipid-poly (ethylene glycol) of the similar particle size about 110 nm. The plasma elimination half-life of BPBBT micelles was 2.8-fold of that of BPBBT-HSA NPs. However, the area under the BPBBT concentration in tumor-time curve to 48 h post-injection (AUC) of BPBBT-HSA NPs was 7.2-fold of that of BPBBT micelles. The intravital NIR-II fluorescence microscopy revealed that BPBBT-HSA NPs but not BPBBT micelles were transported from the tumor vasculature into tumor parenchyma with high efficiency, and endocytosed by the tumor cells within 3 h post-injection in vivo. This effect was blocked by cross-linking BPBBT-HSA NPs to denature HSA, resulting in the AUC decreased to 22% of that of BPBBT-HSA NPs. Our results demonstrated that the active process of endothelial transcytosis is the dominant pathway for albumin-bound nanoparticles' entry into tumor.
数十年来，增强渗透与滞留（EPR）效应原理一直被用于设计抗癌纳米药物。然而，由于纳米颗粒的临床效果不佳以及生理基础存在争议，该原理正受到挑战。在此，我们使用近红外二区（1000 - 1700 nm，NIR-II）荧光探针BPBBT，来研究与粒径约110 nm的具有磷脂 - 聚乙二醇的BPBBT胶束相比，人血清白蛋白结合纳米颗粒（BPBBT-HSA NPs）进入肿瘤的途径。BPBBT胶束的血浆消除半衰期是BPBBT-HSA NPs的2.8倍。然而，注射后48小时BPBBT-HSA NPs的肿瘤时间曲线下BPBBT浓度面积（AUC）是BPBBT胶束的7.2倍。活体近红外二区荧光显微镜显示，BPBBT-HSA NPs而非BPBBT胶束能高效地从肿瘤血管系统转运至肿瘤实质，并在体内注射后3小时内被肿瘤细胞内吞。通过交联BPBBT-HSA NPs使HSA变性可阻断此效应，导致AUC降至BPBBT-HSA NPs的22%。我们的结果表明，内皮转胞吞的主动过程是白蛋白结合纳米颗粒进入肿瘤的主要途径。
