Self-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells

Area of Science:

• Oncology
• Nanomedicine
• Cancer Metabolism

Background:

• Multidrug resistance (MDR) in cancer is often mediated by ATP binding cassette (ABC) transporters, leading to treatment failure.
• Targeting cancer cell metabolism is a promising strategy to overcome MDR, but existing metabolic modifiers can be toxic in vivo.
• Zoledronic acid inhibits hypoxia-inducible factor-1α (HIF-1α), a key regulator of cancer metabolism, but achieves low intratumor concentrations.

Purpose of the Study:

• To synthesize and evaluate nanoparticle formulations of zoledronic acid as a non-toxic metabolic modifier and chemosensitizing agent against human MDR cancer cells.
• To investigate the in vitro and in vivo efficacy of these nanoparticles in overcoming MDR.
• To elucidate the underlying mechanisms of action, including effects on cancer cell metabolism and ABC transporter activity.

Main Methods:

• Synthesis of nanoparticle formulations of zoledronic acid for enhanced intratumor delivery.
• In vitro and in vivo studies using human MDR cancer cells.
• Assessment of metabolic changes including isoprenoid synthesis, HIF-1α activation, glycolysis, mitochondrial respiration, and ATP synthesis.
• Evaluation of chemosensitization to various cytotoxic drugs and ABC transporter activity.
• Studies involving farnesyl pyrophosphate synthase (FPPS)-silenced tumors.

Main Results:

• Nanoparticle zoledronic acid effectively chemosensitized MDR cancer cells to multiple drugs at non-toxic doses, irrespective of the ABC transporter type.
• The nanoparticles inhibited isoprenoid synthesis and HIF-1α activation, reduced glycolytic enzyme activity and glucose flux, decreased mitochondrial electron transport, and lowered ATP synthesis.
• These metabolic alterations led to reduced ATP-dependent ABC transporter activity, enhancing chemotherapy efficacy in both MDR cells and in vivo.
• The observed effects were linked to the inhibition of FPPS, particularly in FPPS-silenced tumors.

Conclusions:

• Nanoparticle formulations of zoledronic acid represent a novel, non-toxic strategy for metabolic modification in cancer.
• This approach effectively overcomes MDR by targeting cancer cell energy metabolism and reducing ABC transporter function.
• These findings support the potential of nanoparticle zoledronic acid as a therapeutic agent to improve chemotherapy outcomes in MDR tumors.