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J Am Chem Soc. 2018 Nov 7;140(44):14980-14989. doi: 10.1021/jacs.8b09396. Epub 2018 Oct 25.

Tumor Microenvironment-Responsive Ultrasmall Nanodrug Generators with Enhanced Tumor Delivery and Penetration.

Author information

1
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen 361102 , China.
2
State Key Laboratory of Physical Chemistry of Solid Surfaces & The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering , Xiamen University , Xiamen 361005 , China.
3
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering (NIBIB) , National Institutes of Health (NIH) , Bethesda , Maryland 20892 , United States.

Abstract

Tumor microenvironment-induced ultrasmall nanodrug generation (TMIUSNG) is an unprecedented approach to overcome the drug penetration barriers across complex biological systems, poor circulation stability and limited drug loading efficiency (DLE). Herein, a novel strategy was designed to synthesize metal-organic nanodrug complexes (MONCs) through supramolecular coassembly of photosensitizer sinoporphyrin sodium, chemotherapeutic drug doxorubicin and ferric ions. Compared with the free photosensitizer, MONCs produced 3-fold more reactive oxygen species (ROS) through the energy transfer-mediated fluorescence quenching. Remarkably, the self-delivering supramolecular MONCs with high DLE acted as a potent ultrasmall-nanodrug generator in response to the mild acidic tumor microenvironment to release ultrasmall nanodrugs (5-10 nm in diameter) from larger parental nanoparticles (140 nm in diameter), which in turn enhanced the intratumor permeability and therapeutic efficacy. The key mechanism of MONC synthesis was proposed, and we, for the first time, validated the generation of supramolecular scaffold intermediates between MONCs' assembly/disassembly states, as well as their involvement in multidrug ligands interactions. This proof-of-concept TMIUSNG strategy provides a foundation for the rational design of analogous carrier-free nanotheranostics through the combination of multiple therapeutic agents and metal ions with imaging functions.

PMID:
30359020
DOI:
10.1021/jacs.8b09396

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