Self-targeting carrier-free coordination nanotherapeutics for tumor microenvironment modulation and enhanced
Zhongxiong Fan1, Fukai Zhu2, Feng Wu3
1School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi 830017, China.
Abstract:
Reactive oxygen species (ROS)-based emerging antitumor modality had garnered increasing attentions. Nevertheless, the low delivery efficiency and poor selection of chemotherapeutic agents, and hypoxia and elevated glutathione (GSH) in the tumor microenvironment (TME) had severely restricted the therapeutic efficacy. Herein, we designed a carrier-free self-targeting nanotherapeutic PEM-CuII-MET (PCM), which was obtained through coordination-driven self-assembly of the pemetrexed (PEM, a dual-acting small molecule drug), Fenton-like agent copper ion (CuⅡ), and metformin (MET, a mitochondrial respiratory inhibitor). Through the folate receptor of tumor cells and TME stimulations (lysosomal acid and overexpressed GSH), PCM could efficiently accumulate in tumor regions and internalize into tumor cells followed by rapid drug disassembly. The released MET could significantly inhibit the consumption of O2 to relieve tumor hypoxia by suppressing mitochondrial respiration. Additionally, oxygen-enriched environment could elevate H2O2 content through the reaction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) and superoxide dismutase (SOD). Meanwhile, the released CuⅡ facilitates the depletion of GSH, which could boost ROS accumulation to improve the efficacy of chemodynamic (CDT). In summary, such nanotherapeutic that achieves multiple ROS amplification could improve TME and enhance CDT oncotherapy.
Insights
This study introduces a novel nanotherapeutic (PEM-CuII-MET) that enhances cancer treatment by increasing reactive oxygen species (ROS) and overcoming tumor microenvironment challenges like hypoxia and glutathione. It improves efficacy for chemodynamic therapy (CDT).
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Reactive oxygen species (ROS)-based cancer therapy is promising but limited by low drug delivery efficiency and tumor microenvironment (TME) factors like hypoxia and high glutathione (GSH).
- Developing targeted nanotherapeutics is crucial to overcome these limitations and enhance antitumor efficacy.
Purpose of the Study:
- To design and evaluate a carrier-free, self-targeting nanotherapeutic (PEM-CuII-MET) for enhanced ROS generation and improved chemodynamic therapy (CDT).
- To address challenges of drug delivery, tumor hypoxia, and GSH levels in the TME.
Main Methods:
- Coordination-driven self-assembly of pemetrexed (PEM), copper ions (CuII), and metformin (MET) to form the PEM-CuII-MET (PCM) nanotherapeutic.
- Utilizing folate receptor targeting and TME stimuli (lysosomal acid, GSH) for targeted accumulation and drug release.
- Investigating the effects of MET on oxygen consumption, ROS generation via NADPH oxidases (NOXs) and superoxide dismutase (SOD), and CuII-mediated GSH depletion.
Main Results:
- PCM demonstrated efficient tumor accumulation and cellular internalization, followed by rapid drug release.
- Released MET effectively alleviated tumor hypoxia by inhibiting mitochondrial respiration, leading to an oxygen-enriched environment.
- The nanotherapeutic successfully boosted hydrogen peroxide (H2O2) levels and facilitated GSH depletion, significantly enhancing ROS accumulation for improved CDT efficacy.
Conclusions:
- The developed nanotherapeutic (PCM) effectively amplifies ROS generation through multiple mechanisms.
- PCM demonstrates potential to reprogram the TME and significantly enhance the efficacy of chemodynamic oncotherapy.
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