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 IC50 of 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: Ping Zhong, Jian Zhang, Chao Deng, Ru Cheng, Fenghua Meng, Zhiyuan Zhong
• Journal: Biomacromolecules (Biomacromolecules) Vol. 17 Issue 11 Pg. 3602-3608 (11 14 2016) ISSN: 1526-4602 [Electronic] United States
• PMID: 27723970 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• CD44 protein, human
• Hyaluronan Receptors
• Prodrugs
• Maytansine
• Hyaluronic Acid
• Glutathione
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine
• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, chemistry)
• Antineoplastic Agents (administration & dosage, chemical synthesis, chemistry)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Female
• Glutathione (administration & dosage, chemical synthesis, chemistry)
• Humans
• Hyaluronan Receptors (genetics)
• Hyaluronic Acid (administration & dosage, chemical synthesis, chemistry)
• MCF-7 Cells
• Maytansine (administration & dosage, analogs & derivatives, chemical synthesis, chemistry)
• Mice
• Prodrugs (administration & dosage, chemistry)
• Trastuzumab
• Xenograft Model Antitumor Assays