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

• Published in: Chembiochem : a European journal of chemical biology 2024-09, Vol.25 (18), p.e202400426-n/a
• Main Authors: Tang, Tingting, Liu, Naiyu, Wang, Lingjuan, Zuo, Kaiyue, Zhu, Xinjie
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor activity; Apoptosis; Apoptosis - drug effects; Breast cancer; Cancer therapies; Cell cycle; Cell division; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemical synthesis; Chemotherapy; Controlled release; DNA biosynthesis; DNA methylation; Drug Screening Assays, Antitumor; Effectiveness; Female; Histones; Humans; Hydrolysis; KLA peptide; Lung cancer; Lung diseases; Mice; Mice, Inbred BALB C; Ovarian cancer; Paclitaxel; Paclitaxel - chemistry; Paclitaxel - pharmacology; Peptide-drug conjugates; Peptides; Peptides - chemistry; Peptides - pharmacology; Prodrug; Solubility; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor microenvironment; Tumors
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.202400426

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. A bispecific hydrolysis PAP‐SS‐PTX prodrug is synthesized by conjugating PTX into PAP peptide via disulfide and ester bonds. The prodrug could release active drug molecule (PTX) under co‐stimulation with low pH and reduction circumstance and reduce the levels of histone methylations and CDK4/6 which lead to suppress tumor growth in vitro. Meanwhile, the prodrug had potential in antitumor efficacy for triple‐negative breast cancer as well as prolonged survival time in vivo.