Dual pH-responsive-charge-reversal micelle platform for enhanced anticancer therapy

Area of Science:

• Materials Science
• Nanotechnology
• Biomedical Engineering

Background:

• Developing effective nanodrug delivery systems (NDDS) is crucial for improving cancer therapy.
• Existing systems often face challenges with targeted delivery and cellular uptake.
• pH-responsive materials offer potential for triggered drug release in tumor microenvironments.

Purpose of the Study:

• To develop a novel dual pH-responsive nanodrug delivery system (NDDS) based on Poly(DEA)-block-Poly(PgMA) (PDPP) copolymers.
• To enhance the in vitro cellular uptake and anticancer efficacy of doxorubicin (DOX).
• To investigate the pH-responsive charge-reversal, stability, and drug release characteristics of the developed system.

Main Methods:

• Synthesis of a dual pH-responsive polymeric prodrug (mPEG-g-PDPP-g-hyd-DOX) using copper-catalyzed "Click chemistry".
• Self-assembly of the prodrug into core-shell polymeric micelles (M(DOX)) with a particle size of approximately 81 nm.
• Evaluation of charge-reversal, stability, drug release at varying pH, cytotoxicity (CCK-8 assay), cellular uptake, flow cytometry, and apoptosis assays on HeLa and SW480 cancer cell lines.

Main Results:

• The M(DOX) micelles exhibited a pH-responsive charge-reversal from negative (-6.64 mV) to positive (5.35 mV) as pH decreased from 7.4 to 6.5.
• Significant enhancement in cellular uptake and anticancer efficacy was observed at pH 6.5 compared to pH 7.4.
• The system demonstrated pH-responsive DOX release, facilitated by hydrazone linkage in acidic endo/lysosomal conditions.

Conclusions:

• The developed dual pH-responsive, charge-reversal micelle platform effectively enhances cellular uptake and anticancer efficacy.
• The charge-reversal mechanism, triggered by the acidic tumor microenvironment, facilitates improved interaction with cancer cells.
• This NDDS represents a promising strategy for developing more effective cancer therapeutics.