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含111铟-四氮杂环十二烷四乙酸基团及不同连接基团的人源大肠杆菌热稳定肽类似物的体外和体内比较

In vitro and in vivo comparison of human Escherichia coli heat-stable peptide analogues incorporating the 111In-DOTA group and distinct linker moieties.

作者信息

Giblin Michael F, Gali Hariprasad, Sieckman Gary L, Owen Nellie K, Hoffman Timothy J, Forte Leonard R, Volkert Wynn A

机构信息

Research Service, Harry S. Truman Memorial Veterans' Administration Hospital, Columbia, Missouri 65201, USA.

出版信息

Bioconjug Chem. 2004 Jul-Aug;15(4):872-80. doi: 10.1021/bc049974x.

Abstract

Three human Escherichia coli heat-stable peptide (STh) analogues, each containing a DOTA chelating group, were synthesized by SPPS and oxidative refolding and compared in in vitro and in vivo systems. One analogue, DOTA-F19-STh(1-19), contains an N-terminal DOTA group attached via an amide bond linkage to an STh moiety which is essentially wild-type except for a Tyr to Phe alteration at position 19 of the molecule. A second analogue, DOTA-R1,4,F19-STh(1-19), differs from the first in that asparagine residues in positions 1 and 4 have been altered to arginine residues in order to examine the effect of positively charged groups in the linker domain. A third analogue, DOTA-11AUN-F19-STh(1-19), differs from the first in that it incorporates an 11-aminoundecanoic acid spacer group between the DOTA group and the first asparagine residue. In vitro competitive binding assays utilizing T-84 human colon cancer cells demonstrated that significant alterations to the N-terminal region of the STh molecule were well tolerated and did not significantly affect binding affinity of STh for the guanylyl cyclase C (GC-C) receptor. Internalization and efflux studies of the indium-labeled species demonstrated that inclusion of positive charge in the linker moiety inhibits internalization of the compound within tumor cells. The characteristics of the three analogues were compared in an in vivo model utilizing T-84 human colon cancer cell xenografts in SCID mice. Clearance of all analogues was rapid, primarily via renal excretion into the urine, with >89% ID excreted into the urine at 1 h pi for all analogues. The 111In-DOTA-R1,4,F19-STh(1-19) and 111In-DOTA-11AUN-F19-STh(1-19) analogues both had longer residence times in the blood than did the 111In-DOTA-F19-STh(1-19) analogue, probably accounting for increased %ID/g values for tumors and nontarget tissues at 1 h pi. At 4 h pi, significant differences between analogues were only seen with respect to metabolic routes of excretion, indicating that increased blood residence time did not result in increased tumor residualization. Reduction of hepatic uptake of these compounds, however, could have significance in the development of agents for the imaging of hepatic metastases. The ability to manipulate in vivo pharmacodynamics and tumor uptake of radiolabeled STh peptides through modification of linker moieties is under continuing investigation in order to produce optimal imaging and therapeutic radiopharmaceuticals.

摘要

通过固相肽合成法(SPPS)和氧化重折叠法合成了三种含DOTA螯合基团的人源大肠杆菌热稳定肽(STh)类似物,并在体外和体内系统中进行了比较。一种类似物DOTA-F19-STh(1-19),其N端的DOTA基团通过酰胺键与STh部分相连,除了分子第19位的酪氨酸被苯丙氨酸取代外,STh部分基本为野生型。第二种类似物DOTA-R1,4,F19-STh(1-19)与第一种不同,其第1和第4位的天冬酰胺残基被改为精氨酸残基,以研究连接域中带正电基团的作用。第三种类似物DOTA-11AUN-F19-STh(1-19)与第一种不同,它在DOTA基团和第一个天冬酰胺残基之间引入了一个11-氨基十一酸间隔基团。利用T-84人结肠癌细胞进行的体外竞争性结合试验表明,STh分子N端区域的显著改变具有良好的耐受性,且对STh与鸟苷酸环化酶C(GC-C)受体的结合亲和力没有显著影响。对铟标记物的内化和外排研究表明,连接部分引入正电荷会抑制化合物在肿瘤细胞内的内化。在利用SCID小鼠体内T-84人结肠癌细胞异种移植瘤的体内模型中比较了这三种类似物的特性。所有类似物的清除都很快,主要通过肾脏排泄到尿液中,在注射后1小时,所有类似物超过89%的注射剂量被排泄到尿液中。铟-111标记的DOTA-R1,4,F19-STh(1-19)和铟-111标记的DOTA-11AUN-F19-STh(1-19)类似物在血液中的停留时间都比铟-111标记的DOTA-F19-STh(1-19)类似物长,这可能是注射后1小时肿瘤和非靶组织中注射剂量百分比增加值增加的原因。在注射后4小时,类似物之间仅在排泄代谢途径方面存在显著差异,这表明血液停留时间增加并未导致肿瘤残留增加。然而,减少这些化合物的肝脏摄取可能对肝转移成像剂的开发具有重要意义。通过修饰连接部分来操纵放射性标记的STh肽的体内药效学和肿瘤摄取的能力正在持续研究中,以便生产出最佳的成像和治疗性放射性药物。

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