TY - JOUR
T1 - Cooperatively Responsive Peptide Nanotherapeutic that Regulates Angiopoietin Receptor Tie2 Activity in Tumor Microenvironment to Prevent Breast Tumor Relapse after Chemotherapy
AU - Zhang, Lijing
AU - Qi, Yingqiu
AU - Min, Huan
AU - Ni, Chen
AU - Wang, Fei
AU - Wang, Bin
AU - Qin, Hao
AU - Zhang, Yinlong
AU - Liu, Guangna
AU - Qin, Yue
AU - Duan, Xixi
AU - Li, Feng
AU - Han, Xuexiang
AU - Tao, Ning
AU - Zhang, Lirong
AU - Qin, Zhihai
AU - Zhao, Ying
AU - Nie, Guangjun
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG1000-K(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tumor tissue. Compared with free T4, P-T4 decreases vessel density significantly (free T4: 2.44 ± 1.20%, P-T4: 0.90 ± 0.75%), delays tumor regrowth after chemotherapy (free T4: 43.2 ± 11.8%, P-T4: 63.6 ± 13.9%), and reduces distant metastasis formation (free T4: 4.50 ± 2.40%, P-T4: 0.67 ± 0.32%). These effects of P-T4 are produced by the local blockage of Tie2 signals in Tie2-positive macrophages and endothelial cells. In addition to describing a potential strategy to enhance circulation half-life and the accumulation of an active peptide at tumor sites, our approach exemplifies the successful targeting of multiple cell types that overexpress a key molecule in conditions associated with tumors.
AB - Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG1000-K(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tumor tissue. Compared with free T4, P-T4 decreases vessel density significantly (free T4: 2.44 ± 1.20%, P-T4: 0.90 ± 0.75%), delays tumor regrowth after chemotherapy (free T4: 43.2 ± 11.8%, P-T4: 63.6 ± 13.9%), and reduces distant metastasis formation (free T4: 4.50 ± 2.40%, P-T4: 0.67 ± 0.32%). These effects of P-T4 are produced by the local blockage of Tie2 signals in Tie2-positive macrophages and endothelial cells. In addition to describing a potential strategy to enhance circulation half-life and the accumulation of an active peptide at tumor sites, our approach exemplifies the successful targeting of multiple cell types that overexpress a key molecule in conditions associated with tumors.
KW - Tie2
KW - legumain
KW - therapeutic peptides
KW - tumor acidic microenvironment
KW - tumor relapse after chemotherapy
UR - http://www.scopus.com/inward/record.url?scp=85065989337&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065989337&partnerID=8YFLogxK
U2 - 10.1021/acsnano.8b08142
DO - 10.1021/acsnano.8b08142
M3 - Article
C2 - 30986342
AN - SCOPUS:85065989337
VL - 13
SP - 5091
EP - 5102
JO - ACS Nano
JF - ACS Nano
SN - 1936-0851
IS - 5
ER -