Tumour targeted polymer nanoparticles co-loaded with docetaxel and siCCAT2 for combination therapy of lung cancer

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Multi-drug resistance (MDR) significantly hinders effective treatment for malignant lung cancer.
• Non-small cell lung cancer (NSCLC) frequently develops resistance to chemotherapy, necessitating innovative therapeutic strategies.

Purpose of the Study:

• To develop and evaluate novel nanoparticles co-loaded with docetaxel (DTX) and si-colon cancer-associated transcript-2 (siCCAT2) for overcoming DTX-resistant NSCLC.
• To investigate the anti-tumor efficacy and underlying mechanisms of these targeted nanoparticles.

Main Methods:

• Developed docetaxel-conjugated poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles co-loaded with siCCAT2 (NP-DTX/siCCAT2).
• Surface modification of nanoparticles with Transferrin (Tf) peptides for enhanced tumor targeting (TfNP-DTX/siCCAT2).
• Evaluated nanoparticle size, in vitro and in vivo anti-tumor effects, and molecular mechanisms including gene/protein expression and pathway analysis.

Main Results:

• TfNP-DTX/siCCAT2 nanoparticles exhibited optimal size characteristics and excellent tumor-targeting ability.
• Significant enhancement in anti-tumor activity was observed for NP-DTX/siCCAT2 compared to NP-DTX in both in vitro and in vivo models.
• Silencing CCAT2 downregulated P-glycoprotein (P-gp) and multidrug-resistance-associated proteins 1 (MRP1), overcoming drug resistance.
• Inhibition of CCAT2 increased miR-204-3p activity, leading to suppression of the IGFBP2/AKT/Bcl2 pathway.

Conclusions:

• Novel Tf-modified nanoparticles co-delivering DTX and siCCAT2 effectively target and treat DTX-resistant NSCLC.
• The therapeutic effect is mediated by CCAT2 silencing, which reduces drug resistance markers and modulates the miR-204-3p/IGFBP2/AKT/Bcl2 pathway.
• This nanoparticle system represents a promising strategy for overcoming multi-drug resistance in lung cancer treatment.