Evaluation of dual P-gp-BCRP inhibitors as nanoparticle formulation

Area of Science:

• Pharmacology
• Nanotechnology
• Oncology

Background:

• Multidrug resistance (MDR) in cancer poses a significant therapeutic challenge, driven by efflux transporters like P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP1), and breast cancer resistance protein (BCRP).
• Two 4-anilinoquinazoline compounds have shown preliminary MDR reversal activity against BCRP and P-gp.

Purpose of the Study:

• To formulate two 4-anilinoquinazoline compounds as polymeric nanoparticles (NPs).
• To evaluate the MDR inhibitory activity of these NP formulations in BCRP and P-gp over-expressing cancer cell lines.

Main Methods:

• Polymeric nanoparticles (NPs) were formulated with two 4-anilinoquinazoline compounds, characterized for size and loading efficiency.
• MDR inhibitory activity was assessed using BCRP-specific assays (Hoechst 33342, pheophorbide A) and P-gp-specific assays (calcein AM, rhodamine-123).
• Cytotoxicity studies were performed to evaluate drug resistance reversal in relevant cell line models.

Main Results:

• Polymeric nanoparticles (NPs) in the size range of 300-365nm were successfully prepared with high loading efficiencies (69% for compound 1 NP, 77% for compound 2 NP).
• Both NP formulations demonstrated significant BCRP inhibition and notable P-gp inhibition.
• NP formulations showed enhanced drug resistance reversal compared to the free compounds, especially in P-gp over-expressing cells, suggesting prolonged drug presence and transporter sensitization.

Conclusions:

• The developed nanoparticle formulations exhibit promising dual-transporter inhibitory activity against BCRP and P-gp.
• These formulations represent a viable strategy for overcoming MDR in cancer, particularly against P-gp expressing cells.
• Further investigation in animal models is warranted due to the potential of these NPs as dual-transporter inhibitors in complex cancer settings.