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Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified
Jean Felix Mukerabigwi1,2, Rui Tang3, Yufei Cao1
1School of Chemistry, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China.
Abstract:
The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (∼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (∼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release.
Insights
This study introduces a dual-targeting polyprodrug to overcome multi-drug resistance (MDR) in cancer. The novel drug delivery system targets cancer cells and mitochondria, enhancing chemotherapy effectiveness against resistant tumors.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multi-drug resistance (MDR) in cancer is a major obstacle to effective chemotherapy, leading to treatment failure and mortality.
- Targeting mitochondria, with their limited DNA repair capacity, offers a promising strategy to overcome MDR.
- Developing novel drug delivery systems is crucial for enhancing anticancer efficacy and minimizing side effects.
Purpose of the Study:
- To design and synthesize a novel polyprodrug capable of dual targeting of cancer cells and mitochondria.
- To investigate the drug release mechanism triggered by endosomal acidity and reactive oxygen species (ROS).
- To evaluate the efficacy of the developed polyprodrug in inhibiting the growth of drug-resistant cancer tumors.
Main Methods:
- Synthesis of amphiphilic block copolymer prodrugs conjugated with folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties.
- Self-assembly of the prodrugs into micelles (TF@CNM + DOX) for targeted delivery.
- In vitro and in vivo evaluation of cellular uptake, drug release kinetics, ROS generation, and anticancer efficacy in DOX-resistant MCF-7 ADR tumors.
Main Results:
- The TF@CNM + DOX micelles demonstrated efficient accumulation in tumor tissues and subsequent cellular and mitochondrial uptake.
- Endosomal acidity triggered the release of cinnamaldehyde (CNM), facilitating mitochondrial targeting via TPP.
- Intramitochondrial drug release was induced by ROS, leading to significant inhibition of DOX-resistant tumor growth with minimal side effects.
Conclusions:
- The developed dual-targeting polyprodrug system effectively overcomes cancer MDR by exploiting sequential targeting and ROS-responsive drug release.
- Mitochondrial drug delivery enhances therapeutic outcomes by leveraging the cancer cell's intrinsic vulnerabilities.
- This innovative strategy holds significant potential for the development of next-generation cancer therapeutics against resistant malignancies.
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