Dual inhibition of DNA damage repair sensitizes photodynamic therapy for triple negative breast cancer

Photodynamic therapy (PDT) has emerged as an ideal candidate among reactive oxygen species (ROS)-mediated tumor therapies. However, the self-repair of DNA, a hallmark of mechanism induced by excessive intracellular ROS is one of the leading causes of PDT resistance. To overcome this challenge, we construct a therapeutic system, Ce6@MSN-ZOP-HA, wrapped with hyaluronic acid (HA) for binding to the highly expressed CD44 on triple negative breast cancer (TNBC) and loaded with DNA damage repair inhibitor (olaparib) and p38 inhibitor (SB203580). After arriving at tumor site, HA mediates drug internalization, intracellular acid microenvironment mediated ZIF8 cleavage, thus releases olaparib and SB203580. Ce6 produces ROS under 650 nm laser, SB203580 as well as olaparib increase the expression of DNA damage related molecule γH2AX, and consequent cell apoptosis, dually enhancing the PDT sensitivity of TNBC. Eventually, Ce6@MSN-ZOP-HA provides a new thought for the development of PDT synergistic nanodrugs with low biotoxicity and high anti-tumor efficiency.