Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry, College of Chemistry , Nankai University , Tianjin 300071 , China.
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) , Tianjin 300071 , China.
Nano Lett. 2019 Mar 13;19(3):1665-1674. doi: 10.1021/acs.nanolett.8b04645. Epub 2019 Mar 1.
Herein, we report a ligand-reversible-shielding strategy based on the mutual shielding of dual ligands tethered to the surface of nanoparticles. To exemplify this concept, phenylboronic acid-functionalized poly(ethylene glycol)- b-poly(ε-caprolactone) (PBA-PEG-PCL) and galactose-functionalized diblock polymer (Gal-PEG-PCL) were mixed to form dual-ligand micelles (PBA/Gal). PBA and Gal residues could form a complex at pH 7.4 and mutually shield their targeting function. At pH 6.8, the binding affinity between PBA and Gal weakened, and PBA preferred to bind with the sialic acid residues on the tumor cell surface rather than to Gal on the micellar surface; furthermore, the unbound Gal recovered its targeting ability toward the asialoglycoprotein receptor. When the pH decreased from 7.4 to 6.8, enzyme-linked immunosorbent assays exhibited that the percentage of exposed Gal on the micellar surface increased 1.9-fold, and flow cytometry showed that HepG2 cellular uptake increased 4.3-fold. More importantly, this process was reversible, confirming the reversible shielding and deshielding of dual ligands. With the encapsulation of a photosensitizer, zinc phthalocyanine (ZnPc), the reversible-shielding micelles showed a 48% improvement in the half-life ( t) in blood circulation, a 54% decrease in liver capture, a 40% increase in tumor accumulation, and a 10.3% improvement in the tumor inhibition rate compared to the Gal-coated irreversible micelles. This dual-ligand mutual-shielding strategy provides a new perspective on reversible tumor targeting.
在此，我们报告了一种基于连接到纳米颗粒表面的双重配体相互屏蔽的配体可逆屏蔽策略。为了说明这一概念，我们将苯硼酸功能化的聚乙二醇- b-聚（ε-己内酯）（PBA-PEG-PCL）和半乳糖功能化的两亲性嵌段共聚物（Gal-PEG-PCL）混合形成双配体胶束（PBA/Gal）。在 pH 7.4 时，PBA 和 Gal 残基可以形成复合物，并相互屏蔽其靶向功能。在 pH 6.8 时，PBA 与 Gal 之间的结合亲和力减弱，PBA 更倾向于与肿瘤细胞表面的唾液酸残基结合，而不是与胶束表面的 Gal 结合；此外，未结合的 Gal 恢复了其对糖蛋白受体的靶向能力。当 pH 从 7.4 降低到 6.8 时，酶联免疫吸附试验显示胶束表面暴露的 Gal 百分比增加了 1.9 倍，流式细胞术显示 HepG2 细胞摄取增加了 4.3 倍。更重要的是，这个过程是可逆的，证实了双重配体的可逆屏蔽和去屏蔽。通过封装光敏剂锌酞菁（ZnPc），可逆屏蔽胶束在血液循环中的半衰期（t）提高了 48%，肝捕获减少了 54%，肿瘤积累增加了 40%，肿瘤抑制率提高了 10.3%，与 Gal 涂层的不可逆胶束相比。这种双重配体相互屏蔽策略为可逆肿瘤靶向提供了新的视角。
