# Tumor Microenvironment-Responsive Nanoplatform of Cu-Doped ZIF‑8 Dual-Loaded with ICG and DOX for Photothermal-Enhanced Chemodynamic Therapy/Chemotherapy

## TL;DR

A new nanoplatform combines copper-doped ZIF-8 with ICG and DOX to target tumors using chemodynamic therapy, photothermal therapy, and chemotherapy.

## Contribution

A Cu-doped ZIF-8 nanoplatform is developed for multimodal cancer therapy with enhanced chemodynamic and photothermal effects.

## Key findings

- Cu-ZIF-8@ICG&DOX achieved 7.46% copper doping with 99.6 nm nanoparticle size.
- The nanoplatform showed pH-responsive degradation and generated reactive oxygen species under irradiation.
- CZID induced 95.36% apoptosis in MCF-7 cells while preserving normal cell viability.

## Abstract

Targeting tumor-specific
characteristics of acidic microenvironment,
elevated H2O2 levels, and thermosensitivity,
this study proposed and developed a copper-doped ZIF-8 nanoplatform
coloaded with indocyanine green (ICG) and doxorubicin hydrochloride
(DOX), designated as Cu-ZIF-8@ICG&DOX (CZID), to establish a multimodal
therapeutic system integrating chemodynamic therapy, photothermal
therapy, and chemotherapy. Results showed that the 25% copper doping
level optimized the structure, achieving 7.46% actual doping content
while limiting the average nanoparticle size to 99.6 nm. Dual loading
of ICG and DOX induced morphological transition to spherical core–shell
architectures, as confirmed by zeta potential reversal, with maximum
drug loading capacities of 23.01 μg/mg for ICG and 122.43 μg/mg
for DOX. The ZIF-8 framework exhibited pH-responsive degradation under
acidic conditions. Released Cu2+ ions mediated continuous
hydroxyl radical generation through glutathione-depletion redox cycling,
confirming chemodynamic efficacy. Under 808 nm laser irradiation,
ICG enabled enhanced photothermal conversion, showing concentration-
and power-dependent temperature elevation. Cellular assays revealed
efficient CZID internalization by MCF-7 cells, generating significantly
higher intracellular reactive oxygen species levels under irradiation
and more intense dead cell staining compared to CZI and CZD groups.
Such an enhancement was attributed to photothermally accelerated ZIF-8
degradation, promoting Cu2+ ions and DOX release, thereby
strengthening chemodynamic–chemotherapy synergy. At the working
concentration of 50 μg/mL, CZID induced 95.36% apoptosis in
MCF-7 cells while maintaining over 70% viability in MCF-10A normal
cells, validating its precise antitumor potential.