pH and redox dual-responsive nanoparticles based on disulfide-containing poly(β-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer

Abstract

Background Multidrug resistance (MDR) generally leads to breast cancer treatment failure. The most common mechanism of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein (P-gp) that reduce the intracellular accumulation of various chemotherapeutic agents. Celecoxib (CXB), a selective COX-2 inhibitor, can dramatically enhance the cytotoxicity of doxorubicin (DOX) in breast cancer cells overexpressing P-gp. Thus it can be seen that the combination of DOX and CXB maybe obtain synergistic effects against breast cancer by overcoming drug resistance. Results In this study, we designed a pH and redox dual-responsive nanocarrier system to combine synergistic effects of DOX and CXB against drug resistant breast cancer. This nanocarrier system denoted as HPPDC nanoparticles showed good in vitro stability and significantly accelerated drug releases under the acidic and redox conditions. In drug-resistant human breast cancer MCF-7/ADR cells, HPPDC nanoparticles significantly enhanced the cellular uptake of DOX through the endocytosis mediated by CD44/HA specific binding and the down-regulated P-gp expression induced by COX-2 inhibition, and thus notably increased the cytotoxicity and apoptosis-inducing activity of DOX. In MCF-7/ADR tumor-bearing nude mice, HPPDC nanoparticles showed excellent tumor-targeting ability, remarkably enhanced tumor chemosensitivity and reduced COX-2 and P-gp expressions in tumor tissues. Conclusion All results demonstrated that HPPDC nanoparticles can efficiently overcome drug resistance in breast cancer both in vitro and in vivo by combining chemotherapy and COX-2 inhibitor. In a summary, HPPDC nanoparticles show a great potential for combination treatment of drug resistant breast cancer.

Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance

“…As COX-2 has been shown to be involved in P-gp-mediated multidrug resistance in cancer, a selective COX-2 inhibitor can down-regulate the P-gp expression (Sui et al, 2011). Indeed, a recent study conducted by Zhang S. et al (2019) confirmed that co-delivery of COX-2 inhibitors and doxorubicin by NPs reversed the multidrug resistance of breast cancer cells. Furthermore, several studies have revealed that codelivery of P-gp-targeted siRNA and anticancer drugs by NPs helps overcome drug-resistant cancers, which is exerted through inhibiting the expression of ABC transporters (Patil et al, 2010;Navarro et al, 2012).…”

“…Efflux transporters Bypass efflux transporters NP itself (Murakami et al, 2011) Inhibit efflux transporters COX-2 inhibitors (Zhang S. et al, 2019) P-gp-targeted siRNA (Patil et al, 2010;Navarro et al, 2012) miRNA-495 (He et al, 2019) Apoptosis Inhibit anti-apoptosis pathway Bcl-2-targeted siRNA (Wang et al, 2006;Saad et al, 2008;Chen et al, 2009;Choi et al, 2019) NF-κB inhibitors (pyrrolidine dithiocarbamate/curcumin) (Fan et al, 2010;Misra and Sahoo, 2011;Zhao et al, 2019) Activate pro-apoptosis pathway Ceramide (Devalapally et al, 2007;van Vlerken et al, 2010) p53 gene therapy (Prabha and Labhasetwar, 2004;Choi et al, 2008) Efflux transporters and apoptosis…”

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

“…Monotherapy and combinatory therapy with COX inhibitors have been reported in the treatment of various types of cancers. Cell cycle progression, migration, invasion, angiogenesis, autophagy, apoptosis, and resistance can be classified as biochemical events that are vulnerable to either direct or indirect actions of COX inhibitors [ 4 , 5 , 6 , 7 , 8 ]. While COX inhibitors appear to induce adverse effects and off-target actions, they also display chemo-preventive properties that warrant further investigation.…”

Tumor Microenvironment-Stimuli Responsive Nanoparticles for Anticancer Therapy

“…Hyaluronic acid based nanoparticles were synthesized for loading multi drug resistance (MDR) blocking drug (Cyclooxygenase 2) and doxorubicin to treat against MDR resistant tumor. This nanoparticle contain core of sPBAE, PLGA Cyclooxygenase 2 (CXB) and doxorubicin (Zhang S. et al, 2019).…”