Overcoming cancer drug resistance by targeted production of reactive oxygen species in mitochondria
T2017-111 A nanoparticle capable of causing targeted reactive oxygen species damage to the energy-producing organelles that sustain plasma membrane efflux pump function, allowing for intracellular retention of anticancer drugs
Multidrug resistance, the ability of cancer cells to develop resistance to chemotherapy drugs, is a major cause of tumor recurrence and cancer metastasis. One of the primary contributors to cancer cells developing this resistance is overexpression of membrane transporter-based efflux pumps in a cell's plasma membrane. These pumps reduce chemotherapeutic efficacy by catalyzing the rapid efflux of various anticancer drugs from cancer cells. Existing nanoparticle (NP) approaches for intracellular delivery of cancer drugs are incapable of directly inhibiting efflux pump function.
The most extensively characterized pumps belong to the ATP-binding cassette (ABC) transporter superfamily. Therefore, a method of inhibiting the function of ABC transporters would work to overcome cancer drug resistance. As ATP is indispensable for the ABC efflux pumps/transporters to function, a rational target for such a method would be inhibiting the production of ATP in cancer cells..
Researchers at Ohio State University and the University of Maryland have developed a lipid membrane-coated silica-carbon (LSC) hybrid nanoparticle that targets the monocarboxylate transporters on mitochondria through pyruvate groups on the surface of the LSC. Under NIR irradiation, the NPs then produce reactive oxygen species (ROS) to oxidize NADH to NAD+, which compromises ATP production, reducing the amount of ATP available for the ABC transporters. This results in dysfunction of the efflux pumps that persists for at least five days following laser irradiation, opening a valuable window for chemotherapy. In addition, In vivo data demonstrate that the drug-laden LSC nanoparticles in combination with NIR laser irradiation can efficiently inhibit drug-resistant tumor growth with no evident systemic toxicity.
- Cancer treatment
- Enables NPs to deliver more chemotherapy drugs to target site within cancer cells while compromising ability of cells to expell drugs
- Cells lose multidrug resistance capabilities for days at a time, creating a therapeutic window for chemotherapy to combat drug-resistent cancer cells
- May allow lower-dose chemotherapy, minimizing drug toxicity to healthy organs
- Reduces expression of efflux pumps and decreases their distribution on the plasma membrane
- Drug-laden NPs (DOX/PTX/CPT-11) irradiated with NIR inhibit tumor growth with no evident systemic toxicity
- NP size allows preferential accumulation in tumor (EPR effect)