NIR-vis-Induced pH-Sensitive TiO₂ Immobilized Carbon Dot for Controllable Membrane-Nuclei Targeting and Photothermal Therapy of Cancer Cells

Abstract

This study investigated a selective and sensitive theragnosis system for the specific targeting of the membrane and nuclei based on visible-light and pH-responsive TiO2-integrated cross-linked carbon dot (C-CD/TiO2) for tumor detection and controllable photothermal therapy. The cross-linking system was formed by boronate ester linkages between the TiO2-immobilized Dopa-decyl (D-CD) and zwitterionic-formed CD (Z-CD) for nuclear targeting, which showed fluorescence “off” at physiological pH. The fluorescence recovered to the “on” state in acidic cancer cells owing to cleavages of the boronate ester bonds, resulting in the disruption of the Förster resonance energy transfer that generated different CDs useful for tumor-selective biosensors and therapy. D-CD, which is hydrophobic, can penetrate the hydrophobic sites of the cell membrane; it caused a loss in the hydrophobicity of these sites after visible-light irradiation. This was achieved by the photocatalytic activity of the TiO2 modulating energy bandgap, whereas the Z-CD targeted the nucleus, as confirmed by merged confocal microscopy images. D-CD augmented by photothermal heat also exhibited selective anticancer activity in the acidic tumor condition but showed only minimal effects at a normal site at pH 7.4. After C-CD/TiO2 injection to an in vivo tumor model, C-CD/TiO2 efficiently ablated tumors under NIR light irradiation. The C-CD/TiO2 group showed up-regulation of the pro-apoptotic markers such as P53 and BAX in tumor. This material exhibited its potential as a theragnostic sensor with excellent biocompatibility, high sensitivity, selective imaging, and direct anticancer activity via photothermal therapy.

Recent progress of carbon dots in targeted bioimaging and cancer therapy

“…In addition to the charge interaction, pH-responsive interaction was indicated another factor to increase the cellular uptake selectivity of free CDs. For example, Phuong et al developed a selective and sensitive nanotheranostic nanoplatform based on the pH-responsive TiO 2 -integrated cross-linked CDs (C-CD/TiO 2 ) for tumor diagnosis by the specific targeted capability of the tumor cell membrane and nuclei (Figure 5 D) 139 . In their work, researchers designed the zwitterionic-formed CD (Z-CD) which could target the nucleus and the hydrophobic Dopa-decyl (D-CD) which could penetrate the hydrophobic sites of cell membrane.…”

“…Adapted with permission from 190 , copyright 2019 John Wiley & Sons Ltd. (D) Scheme of the design and application of pH-responsive C-CD/TiO 2 for targeted bioimaging via cellular membrane-nucleus translocation in response to visible-light irradiation. Adapted with permission from 139 , copyright 2020 American Chemical Society.…”

Sequential Drug Delivery in Targeted Cancer Therapy

“…In addition, the unique properties of the drug carrier surface can help the vectors straightly go through the cell membrane. For example, the hydrophobicity of TiO 2 -immobilized dopa-decyl that can penetrate cell membrane [ 54 ] and nucleolin’s active transport property of aptamer on liposome surface [ 55 ]. From the cell membrane to the nucleus, active nuclear targeting is needed to avoid being swallowed by lysosomes that may digest the drug.…”

“…The pH values are different between normal tissue and tumor microenvironment. Normal tissue’s pH is about 7.4, while tumor cell tissue’s pH is around 6.8 [ 54 ]. Meanwhile, the intracellular pH values are different between cytosol and the nucleus.…”

Carbonized polymer dots with dual‐wavelength emission for labeling nucleoli in live cells through hydrogen bonding‐induced aggregation

“…Among the various application fields of CDs introduced above, bioimaging has been attracting the most attention due to the significance for the study on live organisms, 12,13 since CDs have much lower toxicity and better biocompatibility compared with traditional fluorescent materials 14,15 . For instance, bioimaging based on CDs has been developed for the study on the diagnostics of tumors that highly affect people's health and life span 16,17 .…”