Rational Construction of a Mitochondrial Targeting, Fluorescent Self-Reporting Drug-Delivery Platform for Combined Enhancement of Endogenous ROS Responsiveness
| Autor: | Meng-Qian Zhang, Meng-Yang Li, Yan-Hong Liu, Jun Li, Xiao-Qi Yu, Na Wang, Xian-Ling Yang, Yun-Jie Wei, Zu-E Hu, Wan-Xia Wu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Materials science
Cell Survival Polymers Surface Properties Endogeny 02 engineering and technology Mitochondrion 010402 general chemistry Endocytosis 01 natural sciences Fluorescence Cell Line Drug Delivery Systems Humans General Materials Science Particle Size Cytotoxicity Drug Carriers Antibiotics Antineoplastic Molecular Structure 021001 nanoscience & nanotechnology Mitochondria 0104 chemical sciences Doxorubicin Cancer cell Drug delivery Biophysics Nanoparticles Drug Screening Assays Antitumor Nanocarriers Reactive Oxygen Species 0210 nano-technology Intracellular HeLa Cells |
| Zdroj: | ACS Applied Materials & Interfaces. 12:32432-32445 |
| ISSN: | 1944-8252 1944-8244 |
| DOI: | 10.1021/acsami.0c08336 |
| Popis: | To maximize the utilization and response to the high oxidative stress environment of tumor sites while avoiding the dilemma of enhancing reactive oxygen species (ROS) response in a single way, mitochondrial targeting combined with fluorescent self-reporting polymeric nanocarriers (1K-TPP and 2K-TPP) with grafted structures were synthesized via a chemoenzymatic method in a high yield to simultaneously enhance the drug delivery of endogenous ROS responses. 1K-TPP and 2K-TPP loaded doxorubicin (DOX) at a high content over 12% and formed homogeneous spherical micelles. In vitro, both of them showed promising high sensitivity (detection limit below 200 nM H2O2), fast response, and ratiometric fluorescent self-reporting properties (fluorescent enhancement more than 200 times) to ROS and excellent stability under physiological conditions, while achieving a rapid release of the DOX in response to 1 mM H2O2. Cell co-localization experiments exhibited that they had favorable mitochondrial targeting, and mitochondrial isolation experiments also confirmed that the TPP-modified 1K-TPP selectively accumulated nearly three times in mitochondria than that in total cells. The internalization of 1K-TPP and 2K-TPP into cancer cells was greatly improved by nearly 200% compared to that of unmodified control (1K-OH and 2K-OH) and also explored a unique energy-dependent endocytosis. Furthermore, stimulation of endogenous ROS enhanced the green fluorescence intensity (up to 51.4%) of the linked probe so as to destroy the internal structure of the nanocarriers, achieving self-reporting of the drug's intracellular release and tracking of the intracellular location of nanocarriers. The cytotoxicity of DOX-loaded 1K-TPP and 2K-TPP in tumor cells with a higher ROS content showed statistical superiority to that of 1K-OH and 2K-OH, benefiting from the extremely good endogenous ROS response sensitivity leading to the differential selective release of drugs. These results demonstrate the potential of 1K-TPP and 2K-TPP, especially for 1K-TPP, as mitochondria-targeted, fluorescent self-reporting nanocarriers for combined enhancement of endogenous ROS responsiveness. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|