Radiolabeled Divalent Peptidomimetic Vitronectin Receptor Antagonists as Potential Tumor Radiotherapeutic and Imaging Agents
详细信息 查看全文
- 作者：Thomas D. Harris ; Edward Cheesman ; Anthony R. Harris ; Richard Sachleben ; D. Scott Edwards ; Shuang Liu ; Judit Bartis ; Charles Ellars ; Dave Onthank ; Padmaja Yalamanchili ; Stuart Heminway ; Paula Silva ; S
- 刊名：Bioconjugate Chemistry
- 出版年：2007
- 出版时间：July 2007
- 年：2007
- 卷：18
- 期：4
- 页码：1266 - 1279
- 全文大小：562K
- 年卷期：v.18,no.4(July 2007)
- ISSN：1520-4812
文摘
The integrin receptor 
fchars/alpha.gif" BORDER=0>vfchars/beta2.gif" BORDER=0 ALIGN="middle">3 is overexpressed on the endothelial cells of growing tumors and on some tumor cellsthemselves. A radiolabeled fchars/alpha.gif" BORDER=0>vfchars/beta2.gif" BORDER=0 ALIGN="middle">3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138)was previously shown to exhibit high affinity for integrin fchars/alpha.gif" BORDER=0>vfchars/beta2.gif" BORDER=0 ALIGN="middle">3 and high selectivity versus other integrin receptors.111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and producedexcellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and theirevaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of thespacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteicacid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays,and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model.All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111Inderivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalentagents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratioswere improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver,with the agents having intermediate-length spacers (29-43 Å) showing the largest improvement. As an example,111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney,7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeuticindex for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalenteffect are discussed.
fchars/alpha.gif" BORDER=0>vfchars/beta2.gif" BORDER=0 ALIGN="middle">3 is overexpressed on the endothelial cells of growing tumors and on some tumor cellsthemselves. A radiolabeled fchars/alpha.gif" BORDER=0>vfchars/beta2.gif" BORDER=0 ALIGN="middle">3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138)was previously shown to exhibit high affinity for integrin fchars/alpha.gif" BORDER=0>vfchars/beta2.gif" BORDER=0 ALIGN="middle">3 and high selectivity versus other integrin receptors.111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and producedexcellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and theirevaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of thespacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteicacid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays,and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model.All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111Inderivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalentagents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratioswere improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver,with the agents having intermediate-length spacers (29-43 Å) showing the largest improvement. As an example,111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney,7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeuticindex for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalenteffect are discussed.