A pH-Responsive Cluster Metal-Organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect
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Updated: Aug 31, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Ruoyu Cheng1,2,3,4, Lingxi Jiang1,5, Han Gao2,4
1Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, P. R. China.
Abstract:
As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, metal-organic framework nanoparticles have inadequate accumulation in tumor tissues, limiting their 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 nanoshell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. The ZIF@SLN#L nanoparticle induces reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promotes intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibits tumor growth, increases the survival rate in mice, activates the tumor microenvironment, and improves the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice show normal tissue structure 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.
Insights
This study developed pH-responsive nanoparticles that enhance drug accumulation in tumors. The novel nanoparticles improve cancer treatment efficacy and increase survival rates in mice with minimal organ toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Materials Science
Background:
- Metal-organic framework nanoparticles show limited tumor accumulation due to off-target effects and protein corona.
- Targeted delivery systems are crucial for enhancing therapeutic efficacy in cancer treatment.
Purpose of the Study:
- To develop a pH-responsive nanoparticle system for improved tumor targeting and therapeutic effect.
- To investigate the efficacy of apilimod-loaded zeolitic imidazolate framework coated with solid lipid nanoshells and pH-responsive linkers.
Main Methods:
- Synthesized pH-responsive linkers by modifying oleylamine with MMfu and PEG.
- Encapsulated apilimod-loaded zeolitic imidazolate framework within solid lipid nanoshells, functionalized with pH-responsive linkers (Ap-ZIF@SLN#L).
- Evaluated nanoparticle uptake, tumor accumulation, therapeutic efficacy, and in vivo safety in tumor-bearing mice models.
Main Results:
- The pH-responsive linker facilitated nanoparticle disassembly in the tumor microenvironment, exposing hydrophobic moieties for enhanced cellular uptake and tumor accumulation.
- Ap-ZIF@SLN#L treatment significantly inhibited tumor growth, increased survival rates, and promoted anti-tumor immune responses by enhancing macrophage and T cell infiltration.
- Nanoparticle treatment demonstrated no significant toxicity to major organs, maintaining normal tissue structure and serum enzyme levels.
Conclusions:
- The developed pH-responsive nanoparticle system effectively targets tumors and enhances the therapeutic effects of apilimod.
- This strategy offers a promising approach for improving cancer therapy by overcoming nanoparticle delivery challenges.
- The nanoparticles exhibit favorable safety profiles, suggesting their potential for clinical translation.
