title: ATN-161 Peptide Functionalized Reversibly Cross-Linked Polymersomes Mediate Targeted Doxorubicin Delivery into Melanoma-Bearing C57BL/6 Mice.
abstract: PHSCN peptide (licensed as ATN-161) is an effective α5β1integrin inhibitor that has advanced to phase II clinical trials to treat solid tumors. Here we developed ATN-161 functionalized self-cross-linkable and intracellularly de-cross-linkable polymersomes (ATN/SCID-Ps) for highly efficient and targeted delivery of doxorubicin hydrochloride (DOX·HCl) into B16F10 melanoma-bearing C57BL/6 mice. ATN/SCID-Ps exhibited a high loading capacity of DOX·HCl. The size of DOX-loaded ATN/SCID-Ps (DOX-ATN/SCID-Ps) decreased from 150 to 88 nm with increasing ATN surface densities from 0 to 100% (mol/mol). DOX-ATN/SCID-Ps were robust with low drug leakage under physiological conditions while quickly releasing DOX with the addition of 10 mM glutathione. MTT assay results displayed that DOX-ATN/SCID-Ps induced ATN density-dependent antitumor activity to α5β1integrin overexpressing B16F10 melanoma cells, in which 56% ATN-161 was optimal. Flow cytometry and CLSM studies revealed significantly more efficient internalization and cytoplasmic DOX release in B16F10 cells for DOX-ATN/SCID-Ps than for DOX-SCID-Ps (nontargeting control) as well as clinically used pegylated liposomal doxorubicin (DOX-LPs). DOX-ATN/SCID-Ps displayed a long blood circulation time (elimination half-life = 4.13 h) and 4 times higher DOX accumulation in B16F10 bearing C57BL/6 mice than DOX-LPs. Interestingly, DOX-ATN/SCID-Ps exhibited a superior maximum-tolerated dose of over 100 mg DOX·HCl/kg, 10 times higher than DOX-LPs. Remarkably, DOX-ATN/SCID-Ps could significantly inhibit the growth of aggressive B16F10 melanoma with little adverse effects via either multiple or single injection of total dosage of 100 mg DOX·HCl/kg, resulting in greatly improved survival rates as compared to DOX-LPs. ATN/SCID-Ps are appealing nanovehicles for targeted chemotherapy of α5β1integrin positive solid tumors.
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Weijing
authors.initials: W
authors.lastname: Yang
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Zhiyuan
authors.identifier: 0000-0003-4175-4741
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Fenghua
authors.identifier: 0000-0002-8608-7738
authors.initials: F
authors.lastname: Meng
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D006207:Half-Life; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010455:Peptides / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D010455:Peptides; D004317:Doxorubicin
keywords: antiangiogenic peptide; liposomal doxorubicin; melanoma; polymersomes; reduction-sensitive; tumor targeting