Journal
JOURNAL OF MATERIALS CHEMISTRY B
Volume 10, Issue 40, Pages 8193-8210Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2tb01812h
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Funding
- National Key Research and Development Program of China [2018YFA0208900, 2020YFA0211200, 2020YFA0710700]
- National Natural Science Foundation of China [82172757, 31972927]
- Scientific Research Foundation of Huazhong University of Science and Technology [3004170130]
- Program for HUST Academic Frontier Youth Team [2018QYTD01]
- HCP Program for HUST
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By loading drugs and targeting peptides in nanomaterials, we have developed a smart nanomedicine that can address the drug delivery issue in solid tumors and exhibit potent anti-tumor effects. This study reveals the importance of decomposing fibrin in modulating tumor mechanics.
Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.
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