Mitochondrial-Targeting Zwitterionic Nanomedicine Based on Tertiary Amine N-oxide Polymers for Triple-Negative Breast...

Area of Science:

• Biomaterials Science
• Nanomedicine
• Oncology

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its aggressive nature and lack of targeted treatments.
• The PI3K/AKT/mTOR pathway is frequently hyperactivated in TNBC, representing a key molecular target.
• Conventional nanocarriers like PEGylated micelles face issues such as rapid clearance and lysosomal sequestration, limiting their clinical utility.

Purpose of the Study:

• To develop and evaluate a novel zwitterionic nanocarrier system for enhanced triple-negative breast cancer (TNBC) therapy.
• To investigate the potential of OPDMA-PCL micelles for improved drug delivery, tumor targeting, and reduced immunogenicity compared to PEG-PCL micelles.
• To assess the efficacy of gambogenic acid (GNA)-loaded OPDMA-PCL micelles in targeting mitochondria and inhibiting the PI3K/AKT/mTOR pathway in TNBC cells and xenograft models.

Main Methods:

• Synthesis of zwitterionic poly(2-(N-oxide-dimethylamino)ethyl methacrylate)-block-poly(ε-caprolactone) (OPDMA-PCL) via one-pot living anionic polymerization.
• Preparation and characterization of OPDMA-PCL and PEG-PCL micelles loaded with gambogenic acid (GNA).
• In vitro evaluation of micelle circulation time, cellular uptake, mitochondria targeting, and apoptosis induction in MDA-MB-231 cells; in vivo efficacy and toxicity assessment in TNBC xenograft models.

Main Results:

• OPDMA-PCL micelles demonstrated prolonged systemic circulation, enhanced tumor accumulation, and reduced immunogenicity compared to PEG-PCL micelles.
• In vitro studies confirmed mitochondria-targeting capabilities and significant apoptosis induction in TNBC cells via PI3K/AKT/mTOR pathway inhibition by OPDMA-PCL-GNA.
• In vivo studies showed 91.2% tumor growth inhibition in xenograft models with no observable systemic toxicity.

Conclusions:

• Zwitterionic OPDMA-PCL micelles represent a superior platform for TNBC therapy compared to conventional PEGylated systems.
• This nanocarrier system effectively delivers gambogenic acid to tumor mitochondria, inhibiting the PI3K/AKT/mTOR pathway and achieving significant tumor regression.
• OPDMA-PCL micelles offer a promising strategy for organelle-specific drug delivery in TNBC treatment, overcoming key limitations of existing nanocarriers.