A pH and GSH dual responsive nanoparticle co-deliver Adriamycin and Olaparib enhanced the therapeutic efficacy on triple negative breast cancer

A mPEG-hyd-PLGA-SS-o-HA material was designed and synthesized to co-load chemotherapy drugs Adriamycin (ADR) and Olaparib (Ola). The nano particle (NP) accumulated at the tumor site through methyl polyethylene glycol (mPEG) mediated prolonged circulation and enhanced penetration and retention (EPR) effect. In the acidic tumor microenvironment, the hydrazone bond cleaved, causing mPEG detachment and subsequent exposure of o-HA. The exposed o-HA targeted CD44 receptors on TNBC cell surfaces to enhance NP internalization. Within TNBC cells, the high intracellular GSH concentration triggers disulfide bond cleavaged, releasing o-HA which inhibits metastasis. Simultaneously, ADR and Ola were released intracellularly and displayed synergistic anti-tumor effect. This dual (pH/GSH)-responsive NP system significantly enhanced the therapeutic efficacy while reducing the chemotherapy-associated toxicity. • The polyethylene glycol (PEG) kept the nanoparticle (NP) long circulating property in the systemic circulation to accumulate in tumor tissues. While it detached in the acidic microenvironment without decreasing cellular uptake. • The oligo hyaluronic acid (o-HA) has both tumor-targeting effect and inhibitory effects on tumor metastasis. • The NP combined toxicity and inhibiting metastasis to enhance the anti-tumor efficiency. A pH and GSH concentration dual responsive material was designed to address the insufficient efficacy and toxicity in triple negative breast cancer (TNBC) clinical chemotherapy. Methyl polyethylene glycol (mPEG) and oligomeric HA (o-HA) were conjugated to PLGA via hydrazone and disulfide bonds, respectively. The Adriamycin (ADR) and Olaparib (Ola) co-loaded dual responsive nano drug delivery system was prepared by double-emulsion method. The particle size was 173.78 ± 15.1 nm with a zeta potential of −9.88 ± 0.33 mV. Transmission electron microscopy revealed spherical nanoparticle (NP) with a bilayered structure. The encapsulation efficiencies for Adriamycin and Olaparib were 99.99 % and 73.91 %, respectively. The Drug loading was 4.76 % and 3.56 % accordingly. The particle size, potential and drug release profile demonstrated pH and GSH concentration sensitivity. The blank NP inhibited TNBC cells migration and invasion while showed good compatibility with L929 cell. The co-loaded NP showed exhibited synergistic cytotoxicity on TNBC cells and promoted apoptosis. The NP exhibited tumor targeting properties both in vitro and in vivo. Co-loaded NP showed significant stronger therapeutic effects in mice TNBC orthotopic tumor and lung metastasis models than the free drugs and the single-loaded NP with lower systemic toxicity.