pH-Triggered delivery of pirarubicin–gemcitabine duo using polymeric nanoparticles for synergistic breast cancer therapy

Combination chemotherapy using nanocarriers presents a promising approach to overcome the restrictions associated with conventional chemotherapy, particularly by enhancing drug stability in the bloodstream, modulating pharmacokinetics to improve therapeutic efficacy and minimizing adverse side effects on the patient's health. In pursuit of an optical treatment approach for breast cancer, various chemotherapeutic drug combinations with advanced nanocarriers are being extensively explored. This study investigated the development of pirarubicin and gemcitabine co-loaded polymeric nanoparticles for synergistic activity against breast cancer cells. To enable sustained and site-specific delivery within the tumor microenvironment, both pirarubicin and gemcitabine were chemically conjugated to a polylactic acid-based block copolymer <i>via</i> a pH-responsive "Schiff's base" linkage. The synthesized polymer-drug conjugates were subsequently formulated into Pira-Gem co-loaded block copolymeric nanoparticles, demonstrating good stability and minimal toxicity towards non-cancerous cells. Pira-Gem co-loaded nanoparticles exhibited a significantly higher percentage of drug release under acidic pH conditions, (characteristic of tumor microenvironments) compared with physiological pH conditions. Furthermore, they showed superior cellular uptake on 2D adherent cancer cell lines relative to free drugs in <i>in vitro</i> studies. Both apoptotic analysis and cell proliferation inhibition studies revealed that the co-loaded nanoparticles exhibited a synergistic therapeutic effect across multiple breast cancer cell lines, surpassing the efficacy of Pira/Gem single drug-loaded nanoparticles and their free drug counterparts. These findings suggest that the Pira-Gem co-loaded nanoformulation holds considerable promise for breast cancer therapy and requires further exploration as a potential treatment strategy.