期刊
MOLECULAR PHARMACEUTICS
卷 4, 期 5, 页码 659-667出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp070049c
关键词
folate receptor; targeting; endocytosis; chemotherapy; Vinca alkaloid; mitomycin
资金
- NCI NIH HHS [5R44 CA 096020-03] Funding Source: Medline
We have designed a new type of tumor-targeted agent by tethering two different drug molecules, with distinct biological mechanisms of action, to the same ligand. This compound, named EC0225, represents the first in class multidrug, folate receptor (FR)-targeted agent to be disclosed. It was constructed with a single folate molecule, extended by a hydrophilic peptide-based spacer, which was in turn attached to mitomycin and Vinca alkaloid units via two separate disulfide-containing linkers. EC0225 produced potent, dose-responsive activity in vitro, and curative activity was observed against FIR-positive syngeneic and xenograft tumors following the administration of well-tolerated dosing regimens. Multiple complete responses and cures were also noted when EC0225 was used to treat mice initially bearing tumors as large as 750 mm(3) in volume. Overall, EC0225's impressive preclinical activity allowed for its selection as a development candidate and for the start of Phase 1 clinical trials, which began in March of 2007, for the treatment of advanced malignancies.
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