Doxorubicin-formaldehyde conjugates targeting alphavbeta3 integrin.
Doxorubicin-formaldehyde conjugates targeting alphavbeta3 integrin.
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发表时间：
2004-12
影响因子：
5.7
通讯作者：
D. J. Burkhart;Brian T. Kalet;M. Coleman;Glen C. Post;T. Koch
中科院分区：
文献类型：
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作者：
D. J. Burkhart;Brian T. Kalet;M. Coleman;Glen C. Post;T. Koch
我们报道了阿霉素活性代谢物前药的合成和生物学评价。在生理条件下，阿霉素和甲醛的偶联物活性代谢物的半衰期为1小时。为了将该前体药物导向肿瘤，我们设计了两种前体药物多沙必利与α-β3靶向多肽CDCRGDCFC(RGD-4C)和环-(N-Me-VRGDf)(Cilengiide)的结合物。我们现在报道了这些多糖类多肽结合物的合成，并用MDA-MB-435癌细胞进行了评估。用羟胺醚链将5‘’-甲酰基十二烷基磺酸盐以无环形式通过肟基连接到RGD-4C上。体外细胞黏附实验表明，所构建的无环RGD-4C-DOX对αvbeta3具有良好的亲和力(IC_(50)=10nmol/L)，对乳腺癌细胞具有良好的生长抑制作用(IC_(50)=50nmol/L)。在其双环形式中，RGD-4C对αvbeta3的亲和力较小，水溶性显著降低。用D-4-氨基苯丙氨酸取代D-苯丙氨酸对环-(N-Me-VRGDf)进行修饰，为环状(N-Me-VRGDf)提供了一个新的连接点。在玻璃体粘连蛋白细胞黏附实验中，环-(N-Me-VRGDf-NH)-DOXSSAGO对α-β_3(IC_(50)=5nmol/L)的亲和力比仅含系链肽的多肽(0.5nmol/L)高。抑制MDA-MB-435细胞生长的IC50为90nmoL/L，流式细胞仪和生长抑制实验表明，完整的药物结构不能穿透细胞膜，但活性代谢物可以从靶向组释出。这些药物结合物可以显著减少副作用，是在荷瘤小鼠身上进行体内评估的有前景的候选药物。
We have reported the synthesis and biological evaluation of a prodrug to a doxorubicin active metabolite. Under physiologic conditions, release of the active metabolite, a conjugate of doxorubicin with formaldehyde, occurs with a half-life of 1 hour. To direct this prodrug to tumor, we designed two conjugates of the prodrug, doxsaliform, with the alphavbeta3-targeting peptides, CDCRGDCFC (RGD-4C) and cyclic-(N-Me-VRGDf) (Cilengitide). We now report the synthesis of these doxsaliform-peptide conjugates and their evaluation using MDA-MB-435 cancer cells. A hydroxylamine ether tether was used to attach 5''-formyldoxsaliform to RGD-4C in its acyclic form via an oxime functional group. The construct acyclic-RGD-4C-doxsaliform showed good binding affinity for alphavbeta3 in the vitronection cell adhesion assay (IC50 = 10 nmol/L) and good growth inhibition of MDA-MB-435 breast cancer cells (IC50 = 50 nmol/L). In its bicyclic forms, RGD-4C showed less affinity for alphavbeta3 and significantly less water solubility. Cyclic-(N-Me-VRGDf) was modified by substitution of D-4-aminophenylalanine for D-phenylalanine to provide a novel attachment point for doxsaliform. The conjugate, cyclic-(N-Me-VRGDf-NH)-doxsaliform, maintained a high affinity for alphavbeta3 (IC50 = 5 nmol/L) in the vitronectin cell adhesion assay relative to the peptide bearing only the tether (0.5 nmol/L). The IC50 for growth inhibition of MDA-MB-435 cells was 90 nmol/L. Flow cytometry and growth inhibition experiments suggest that the complete drug construct does not penetrate through the plasma membrane, but the active metabolite does on release from the targeting group. These drug conjugates could have significantly reduced side effects and are promising candidates for in vivo evaluation in tumor-bearing mice.