title: Glutathione-Sensitive Hyaluronic Acid-SS-Mertansine Prodrug with a High Drug Content: Facile Synthesis and Targeted Breast Tumor Therapy.
abstract: Low tolerability and tumor selectivity restricts many potent anticancer drugs including mertansine from wide clinical use. Here, glutathione-activatable hyaluronic acid-SS-mertansine prodrug (HA-SS-DM1) was designed and developed to achieve enhanced tolerability and targeted therapy of CD44+ human breast tumor xenografts. DM1 was readily conjugated to HA using 2-(2-pyridyldithio)-ethylamine as a linker. Notably, HA-SS-DM1 with a high DM1 content of 20 wt % had a mean size of ∼170 nm at concentrations above 0.2 mg/mL while transformed into unimers upon dilution to 0.04 mg/mL. HA-SS-DM1 exhibited a superior targetability to MCF-7 cancer cells with an exceptionally low IC50of 0.13 μg DM1/mL. The pharmacokinetic studies displayed that Cy5-labeled HA-SS-DM1 had an elimination half-life of 2.12 h. Notably, HA-SS-DM1 displayed better tolerability with a maximum-tolerated dose 4-fold higher than free DM1. Cy5-labeled HA-SS-DM1 quickly accumulated in the MCF-7 tumor, the fluorescence intensity of which was maximized at 24 h post injection and kept strong in 48 h. The tumor Cy5 level reached 8.17%ID/g at 24 h. The therapeutic results demonstrated that HA-SS-DM1 effectively inhibited tumor growth at 800 μg DM1 equiv/kg while causing reduced side effects as compared to free DM1. Glutathione-cleavable HA-SS-DM1 prodrug with superior drug content, excellent targetability, enhanced tolerability, and easy large-scale synthesis appears to be a highly promising alternative to clinically used Trastuzumab emtansine (T-DM1) for targeted breast tumor therapy.
authors.affiliation: Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Biomedical Polymers Laboratory, 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, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.affiliation: Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D061986:MCF-7 Cells; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D011355:Prodrugs; D008453:Maytansine; D006820:Hyaluronic Acid; D005978:Glutathione; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine