Liu Changren, Wang Ruonan, Sun Ying, Yin Changfeng, Gu Zhewei, Wu Wei, Jiang Xiqun
Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China.
ACS Cent Sci. 2022 Feb 23;8(2):258-267. doi: 10.1021/acscentsci.1c01382. Epub 2022 Jan 26.
Dendrons have well-defined dendritic structures. However, it is a great challenge to preserve their high structural definition after multiple functionalization because the site-selective conjugation of different functional molecules is quite difficult. Scaffold-modifiable dendrons that have orthogonal reactive groups at the scaffold and periphery are ideal for achieving the site-specific bifunctionalization. In this paper, we present a new strategy for synthesizing scaffold-modifiable dendrons via orthogonal amino protection and a solid-phase synthesis method. This strategy renders the reactive sites at the scaffold and periphery of the dendrons a super selectivity, high reactivity, and wide applicability to various reaction types. The fourth-generation dendrons can be facilely synthesized within 2 days without structural defects as demonstrated by mass spectrometry. We conjugated doxorubicin (DOX) and phenylboronic acid (PBA) groups to the scaffold and periphery, respectively. Thanks to the PBA-enhanced lysosome escape, tumor targeting ability, and tumor permeability as well as the high drug loading content larger than 30%, the dendron-based prodrug exhibited extraordinary antitumor efficacy and could eradicate the tumors established in mice by multiple intravenous administration. This work provides a practical strategy for synthesizing scaffold-modifiable dendrons that can be a promising nanoplatform to achieve function integration in a precisely controlled manner.
树枝状分子具有明确的树枝状结构。然而，在多次功能化后保持其高结构清晰度是一项巨大的挑战，因为不同功能分子的位点选择性共轭相当困难。在支架和外围具有正交反应基团的可支架修饰树枝状分子是实现位点特异性双功能化的理想选择。在本文中，我们提出了一种通过正交氨基保护和固相合成方法合成可支架修饰树枝状分子的新策略。该策略使树枝状分子支架和外围的反应位点具有超高的选择性、高反应活性以及对各种反应类型的广泛适用性。如质谱所示，第四代树枝状分子可在2天内轻松合成且无结构缺陷。我们分别将阿霉素（DOX）和苯硼酸（PBA）基团共轭到支架和外围。由于PBA增强了溶酶体逃逸、肿瘤靶向能力和肿瘤渗透性，以及大于30%的高载药量，基于树枝状分子的前药表现出非凡的抗肿瘤功效，并且通过多次静脉给药能够根除在小鼠体内建立的肿瘤。这项工作为合成可支架修饰树枝状分子提供了一种实用策略，其有望成为一种能够以精确可控方式实现功能整合的纳米平台。
