期刊
ACS NANO
卷 13, 期 5, 页码 5091-5102出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b08142
关键词
therapeutic peptides; Tie2; tumor acidic microenvironment; legumain; tumor relapse after chemotherapy
类别
资金
- National Key R&D Program of China [2018YFA0208900]
- Excellent Young Scientists Fund [31722021]
- National Natural Science Foundation of China [21877023, 51673051, 51861145302, 81630068, 31670881, 31671023, 81572339]
- Beijing Nova Program [Z171100001117010]
- Beijing Natural Science Foundation [7172164]
- Youth Innovation Promotion Association CAS [2017056]
- Innovation Research Group of the National Natural Science Foundation [11621505]
- Beijing Municipal Science & Technology Commission [Z161100000116035]
- Chinese Academy of Sciences [QYZDJ-SSW-SLH022]
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 (mPEG(1000)-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.
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