Influence of the Drug Position on Bioactivity in Angiopep-2—Daunomycin Conjugates

药品 药理学 柔红霉素 结合 化学 医学 化疗 内科学 数学 数学分析
作者
Lilla Pethő,Rita Oláh-Szabó,Gábor Mezó
出处
期刊:International Journal of Molecular Sciences [Multidisciplinary Digital Publishing Institute]
卷期号:24 (4): 3106-3106 被引量:7
标识
DOI:10.3390/ijms24043106
摘要

The blood–brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug–peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure–activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness.
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