A Dual Bispecific Hydrolysis Peptide‐Drug Conjugate Responsive to Micro‐Acidic and Reduction Circumstance Promotes Antitumor Efficacy in Triple‐Negative Breast Cancer

Abstract Paclitaxel and its derivates are the first‐line chemotherapeutic agents of breast cancer, which also showed tremendous clinical value in many other diseases including ovarian cancer, lung cancer etc . However, there are many drawbacks for almost all paclitaxel or its derivates, including extremely short half‐life, poor solubility and adverse events, which significantly limits their clinical applications. In this work, we designed and constructed a bispecific hydrolysis PAP‐SS‐PTX (term as PDC), consisting with pro‐apoptosis peptide (PAP) and paclitaxel (PTX) that were conjugated together via disulfide and ester bonds. On the one hand, PAP could improve the solubility of PTX and promote cellular uptake for drugs. On the other hand, it was able to prolong the PTX half‐life. We performed series of chemo‐dynamical assays and showed that PDC would release active drug molecules under micro‐acidic and reduction circumstance. The further assays elucidated that PDC could interrupt DNA synthesis and arrest cell division through downregulating CDK4/6 and Histone methylation that inhibit tumor growth in vitro. What's more, it could not only inhibit 4T1 breast tumor growth, but also prolong the survival time of mice and exert antitumor efficacy in vivo . It may provide a new research idea for cancer therapies via controlled release strategy in tumor microenvironment.