Zhong Ping, Zhang Jian, Deng Chao, Cheng Ru, Meng Fenghua, Zhong Zhiyuan
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou, 215123, P. R. China.
Biomacromolecules. 2016 Nov 14;17(11):3602-3608. doi: 10.1021/acs.biomac.6b01094. Epub 2016 Oct 21.
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 IC 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.
低耐受性和肿瘤选择性限制了包括美登素在内的许多强效抗癌药物的广泛临床应用。在此，设计并开发了谷胱甘肽可激活的透明质酸-SS-美登素前药（HA-SS-DM1），以实现增强的耐受性和对CD44 +人乳腺肿瘤异种移植的靶向治疗。使用2-(2-吡啶基二硫代)-乙胺作为连接子，DM1很容易与HA偶联。值得注意的是，DM1含量为20 wt%的HA-SS-DM1在浓度高于0.2 mg/mL时平均粒径约为170 nm，而稀释至0.04 mg/mL时则转变为单体。HA-SS-DM1对MCF-7癌细胞表现出优异的靶向性，IC50极低，为0.13 μg DM1/mL。药代动力学研究表明，Cy5标记的HA-SS-DM1消除半衰期为2.12 h。值得注意的是，HA-SS-DM1表现出更好的耐受性，最大耐受剂量比游离DM1高4倍。Cy5标记的HA-SS-DM1迅速在MCF-7肿瘤中积累，其荧光强度在注射后24 h达到最大值，并在48 h内保持较强。肿瘤Cy5水平在24 h时达到8.17%ID/g。治疗结果表明，HA-SS-DM1在800 μg DM1当量/kg时有效抑制肿瘤生长，同时与游离DM1相比副作用减少。具有优异药物含量、出色靶向性、增强耐受性且易于大规模合成的谷胱甘肽可裂解HA-SS-DM1前药似乎是临床上用于靶向乳腺肿瘤治疗的曲妥珠单抗偶联物（T-DM1）的极有前景的替代物。
