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Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug
Enping Chen1, Ting Wang1, Junmei Zhang1
1Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, China.
Abstract:
Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy.
Insights
This study developed a novel nanogel to combat multidrug resistance (MDR) in cancer. The nanogel delivers lonidamine (LND) and paclitaxel (PTX) to cancer cell mitochondria, restoring chemotherapy effectiveness.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Multidrug resistance (MDR) in cancer chemotherapy is a major challenge, often caused by drug efflux pumps.
- Overcoming MDR is crucial for improving patient outcomes in cancer treatment.
Purpose of the Study:
- To develop a novel mitochondrial-directed, pH-sensitive nanogel system for MDR reversal.
- To combine the hexokinase inhibitor lonidamine (LND) with paclitaxel (PTX) for synergistic anti-tumor effects.
Main Methods:
- Synthesized polyvinyl alcohol (PVA) nanogels incorporating LND and PTX, functionalized with 2-dimethylaminoethanethiol (DMA).
- Evaluated nanogel pH-sensitivity, drug loading, lysosomal escape, and mitochondrial targeting.
- Assessed the combined effect of LND and PTX on MCF-7/MDR cells, including mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation.
Main Results:
- The DMA-modified nanogels enhanced drug loading and facilitated lysosomal escape.
- Mitochondrial targeting led to acid-triggered release of LND and PTX within cancer cells.
- LND disrupted mitochondrial function, increasing MCF-7/MDR cell susceptibility to PTX, leading to apoptosis.
Conclusions:
- The developed nanoplatform effectively reverses multidrug resistance by targeting mitochondria.
- This combination therapy demonstrates enhanced anti-tumor efficacy against drug-resistant cancer cells.
- Mitochondrial-directed nanogels offer a promising strategy for overcoming chemotherapy resistance.
