A pH-Responsive Cluster Metal-organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect

Abstract As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, the metal-organic framework nanoparticles have inadequate accumulation in the tumor tissues, limiting the therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly (ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nano-shell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLNL. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLNL, increasing their uptake in cancer cells and accumulation in the tumor. ZIF@SLNL nanoparticle induced reactive oxygen species (ROS). Ap released from Ap-ZIF@SLNL significantly promoted intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLNL inhibited tumor growth, increased the survival rate in mice, activated the tumor microenvironment, and improved the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLNTL. Furthermore, mice showed normal physiological responses of the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects. This article is protected by copyright. All rights reserved