An Orthogonal Protection Strategy for Synthesizing Scaffold-Modifiable Dendrons and Their Application in Drug...

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.