pH-Responsive Charge-Reversal Smart Nanoparticles for Co-Delivery of Mitoxantrone and Copper Ions to Enhance Breast Cancer Chemo-Chemodynamic Combination Therapy
Purpose: The limited delivery and poor penetration of nanoparticles into breast cancer tumors pose significant challenges to effective anticancer therapies. This study aimed to design a promising nanoplatform that enhances tumor targeting and penetration for more effective breast cancer treatment.
Methods: A pH-sensitive nanosystem, loaded with mitoxantrone (MTO) and copper ions (Cu2+), was developed and functionalized with cyclic CRGDfK and r9 peptides (TPRN-CM) for chemo-chemodynamic combination therapy. In blood circulation, the CRGDfK peptide maintains the nanoparticles in a quiescent state to improve targeting to the tumor. Upon reaching the acidic tumor microenvironment, the nanoparticle undergoes structural changes, exposing the r9 peptide, which induces a charge reversal, promoting deeper tumor penetration and enhanced cancer cell internalization. Transmission electron microscopy, dynamic light scattering, flame atomic absorption, and other techniques were used for characterization. The drug release behavior, anti-tumor effects in vitro and in vivo, and biosafety of the nanoplatform were also assessed.
Results: TPRN-CM demonstrated excellent stability in serum, effectively loading MTO and Cu2+. The system exhibited pH-responsive charge reversal, drug release, and the generation of toxic hydroxyl radicals in the presence of glutathione (GSH) and hydrogen peroxide (H2O2). In vitro, TPRN-CM significantly inhibited cell proliferation, migration, invasion, and 3D tumor sphere growth. In vivo, the TPRN-CM nanoplatform was effectively delivered to breast cancer tumors, achieving deep tumor penetration and significantly reducing tumor growth and lung metastasis, with no apparent side effects.
Conclusion: The TPRN-CM nanoplatform, integrating tumor targeting, penetration, drug-responsive release, and chemo-chemodynamic therapy, offers an intelligent drug delivery strategy that enhances the efficacy of breast cancer treatment.