An all-in-one nanoparticle for overcoming drug resistance: doxorubicin and elacridar co-loaded folate receptor targeted PLGA/MSN hybrid nanoparticles

OpenAlex İngilizce

Overexpression of permeability-glycoprotein (P-gp) transporter leads to multidrug resistance (MDR) through cellular exclusion of chemotherapeutics. Co-administration of P-gp inhibitors and chemotherapeutics is a promising approach for improving the efficacy of therapy. Nevertheless, problems in pharmacokinetics, toxicity, and solubility limit the application of P-gp inhibitors. Herein, we developed a novel all-in-one hybrid nanoparticle system to overcome MDR in doxorubicin-resistant breast cancer. Firstly, folic acid-modified doxorubicin-loaded mesoporous silica nanoparticles (MSN) were prepared and then loaded into PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles along with a P-gp inhibitor, elacridar. This hybrid nanoparticle system had high drug loading capacity, enabled both passive and active targeting of tumor tissues, and exhibited sequential and pH-triggered release of drugs. In vitro and in vivo studies in doxorubicin-resistant breast cancer demonstrated the ability of the hybrid nanoparticles to reverse P-gp-mediated drug resistance. The nanoparticles were efficiently taken up by the breast cancer cells and delivered elacridar, in vitro. Biodistribution studies demonstrated substantial accumulation of the folate receptor-targeted PLGA/MSN hybrid nanoparticles in tumor-bearing mice. Moreover, deceleration of the tumor growth was remarkable in the animals administered with the doxorubicin and elacridar co-loaded hybrid nanoparticles when compared to those treated with the marketed liposomal doxorubicin (Caelyx®) or its combination with elacridar.