Mukhopadhyay Sumitra, Barnés Carmen M, Haskel Ariel, Short Sarah M, Barnes Katie R, Lippard Stephen J
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Bioconjug Chem. 2008 Jan;19(1):39-49. doi: 10.1021/bc070031k. Epub 2007 Sep 11.
The integrins alpha vbeta3 and alpha vbeta5 and the membrane-spanning surface protein aminopeptidase N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono- and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing RGD, (CRGDC)c, (RGDfK)c, or NGR, is appended as a "tumor-homing device" to target tumor endothelial cells selectively over healthy cells. Platinum(IV)-peptide complexes with nonspecific amino acids or peptide moieties were prepared as controls. Concentration-response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinum-based chemotherapeutic agent. The Pt(IV)-RGD conjugates were highly and specifically cytotoxic to cell lines containing alpha vbeta3 and alpha vbeta5, approaching the activity of cisplatin. The Pt(IV)-NGR complexes were less active than Pt(IV)-RGD-containing compounds but more active than nonspecific Pt-peptide controls. Integrin alpha vbeta3 mediated, at least in part, the anti-proliferative effect of a Pt(IV)-RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of alpha vbeta3/alpha vbeta5-specific RGD pentapeptides or (2) transfected with RNAi for beta 3, but not beta 1, integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.
整合素αvβ3和αvβ5以及跨膜表面蛋白氨肽酶N（APN）在肿瘤诱导的血管生成中高度表达，这使它们成为治疗干预的有吸引力的靶点。整合素和APN分别识别广泛的含有RGD（精氨酸-甘氨酸-天冬氨酸）和NGR（天冬酰胺-甘氨酸-精氨酸）基序的肽。在此，我们描述了一系列单功能和双功能铂（IV）配合物的设计、合成和表征，其中含有RGD、（CRGDC）c、（RGDfK）c或NGR的共轭肽基序作为“肿瘤归巢装置”附加，以选择性地靶向肿瘤内皮细胞而非健康细胞。制备了带有非特异性氨基酸或肽部分的铂（IV）-肽配合物作为对照。评估了这些化合物对原代增殖内皮细胞和肿瘤细胞系的浓度-反应曲线，并与顺铂（一种广为人知的铂类化疗药物）的曲线进行了比较。Pt（IV）-RGD共轭物对含有αvβ3和αvβ5的细胞系具有高度特异性细胞毒性，接近顺铂的活性。Pt（IV）-NGR配合物的活性低于含Pt（IV）-RGD的化合物，但高于非特异性Pt-肽对照。整合素αvβ3至少部分介导了Pt（IV）-RGD共轭物的抗增殖作用，这表现为当内皮细胞（1）与过量的αvβ3/αvβ5特异性RGD五肽孵育或（2）用针对β3而非β1整合素的RNAi转染时，抑制反应降低。这些结果提示了一种通过将Pt（IV）-肽共轭物选择性递送至肿瘤区室来改进化疗的合理方法。
