Imaging human pancreatic cancer xenografts by targeting mutant KRAS2 mRNA with [(111)In]DOTA(n)-poly(diamidopropanoyl)(m)-KRAS2 PNA-D(Cys-Ser-Lys-Cys) nanoparticles.
Imaging human pancreatic cancer xenografts by targeting mutant KRAS2 mRNA with [(111)In]DOTA(n)-poly(diamidopropanoyl)(m)-KRAS2 PNA-D(Cys-Ser-Lys-Cys) nanoparticles.
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DOI：
10.1021/bc900523c
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发表时间：
2010-04-21
影响因子：
4.7
通讯作者：
Wickstrom E
中科院分区：
文献类型：
--
作者：
Amirkhanov NV;Zhang K;Aruva MR;Thakur ML;Wickstrom E
95%的导管型胰腺癌患者的KRAS2癌基因存在第12位密码子激活突变。胰腺癌中突变的KRAS2基因的早期全身成像将有助于疾病的治疗。用于显示体内基因活性的闪烁杂交探针构成了分子成像的一种新范式。我们之前已经通过正电子发射断层扫描(PET)成像了胰腺癌移植瘤中突变的KRAS2 mRNA的激活。正电子发射断层扫描(PET)基于单个放射性金属64Cu，它与1，4，7，10-四(羧甲基)环十二烷(DOTA)螯合剂通过灵活的亲水性间隔物氨基-羟乙氧基乙酸乙酯(AEEA)连接到突变的KRAS2肽核酸(PNA)杂交探针的N端。胰岛素样生长因子1(IGF1)的多肽类似物连接到AEEA的C端，使受体介导的内吞作用成为可能。我们推测，随着DOTA螯合剂数量(N)的增加，从带有C端AEEA和IGF1类似物的突变的KRAS2 PNA通过AEEA延伸的聚二胺丙酰(PDAP)树枝状大分子(第m代)可以使高表达IGF1受体和突变的KRAS2mRNA的胰腺癌移植瘤能够进行更强烈的外部成像。制备了([111In]DOTA-AEEA)n-PDAPm-AEEA2-KRAS2 PNA-AEEA-IGF1类似物，静脉给药给荷人AsPC1(G12D)胰腺癌移植瘤的免疫缺陷小鼠。CAPAN2(G12V)胰腺癌移植瘤作为KRAS2细胞错配对照。在AsPC1(G12D)移植瘤中，互补的[111In]n-PDAPm-KRAS2 G12D探针的肿瘤/肌肉显像强度比从n=2(m=1)的3.1±0.2增加到n=8(m=3)的4.1±0.3，n=16(m=4)的6.2±0.4。单错配[111In]n-PDAPm-KRAS2 G12 V对照探针显示较低的肿瘤/肌肉比(n=2，m=1，2.6±0.9，n=8，m=3，n=16，m=4，3.7±0.3)。失配结果与不含PNA的[111In]DOTA对照结果相当。同时给予非放射性GDN-KRAS2 G12 V探针(n=2或8)可使[111In]8KRAS2 G12 V探针在胰腺癌CAPAN2移植瘤和其他组织中的积聚增加3-6倍，但肾脏的积聚减少2倍。肾/肿瘤111In摄取比值由174.8±17.5降至30.8±3.1，下降了5倍以上。因此，将多达16个DOTA螯合剂连接到PNA-IGF1类似物上的PDAP树状大分子，以及同时给予更高剂量的非放射性GDN-KRAS2 G12 V探针，可以增强肿瘤对[111In]nKRAS2 PNA探针的摄取。这些结果还表明，Gd(III)树枝状分子杂交探针可能适合于肿瘤基因表达的磁共振成像，因为较高世代的树枝状大分子，包括核磁共振对比的GDN-KRAS2 G12 V探针，提高了探针的肿瘤聚集性和肿瘤成像的特异性。
95% of patients with ductal pancreatic cancer carry 12th codon activating mutations in their KRAS2 oncogenes. Early whole body imaging of mutant KRAS2 mRNA activation in pancreatic cancer would contribute to disease management. Scintigraphic hybridization probes to visualize gene activity in vivo constitute a new paradigm in molecular imaging. We have previously imaged mutant KRAS2 mRNA activation in pancreatic cancer xenografts by positron emission tomography (PET) based on a single radiometal, 64Cu, chelated to a 1,4,7,10-tetra(carboxymethylaza)cyclododecane (DOTA) chelator, connected via a flexible, hydrophilic spacer, aminoet-hoxyethoxyacetate (AEEA), to the N-terminus of a mutant KRAS2 peptide nucleic acid (PNA) hybridization probe. A peptide analogue of insulin-like growth factor 1 (IGF1), connected to a C-terminal AEEA, enabled receptor-mediated endocytosis. We hypothesized that a polydiamidopropanoyl (PDAP) dendrimer (generation m), with increasing numbers (n) of DOTA chelators, extended via an N-terminal AEEA from a mutant KRAS2 PNA with a C-terminal AEEA and IGF1 analogue could enable more intense external imaging of pancreatic cancer xenografts that overexpress IGF1 receptor and mutant KRAS2 mRNA. ([111In]DOTA-AEEA)n-PDAPm-AEEA2-KRAS2 PNA-AEEA-IGF1 analogues were prepared and administered intravenously into immunocompromised mice bearing human AsPC1 (G12D) pancreatic cancer xenografts. CAPAN2 (G12 V) pancreatic cancer xenografts served as a cellular KRAS2 mismatch control. Scintigraphic tumor/muscle image intensity ratios for complementary [111In]n-PDAPm-KRAS2 G12D probes increased from 3.1 ± 0.2 at n = 2, m = 1, to 4.1 ± 0.3 at n = 8, m = 3, to 6.2 ± 0.4 at n = 16, m = 4, in AsPC1 (G12D) xenografts. Single mismatch [111In]n-PDAPm-KRAS2 G12 V control probes showed lower tumor/muscle ratios (3.0 ± 0.6 at n = 2, m = 1, 2.6 ± 0.9 at n = 8, m = 3, and 3.7 ± 0.3 at n = 16, m = 4). The mismatch results were comparable to the PNA-free [111In]DOTA control results. Simultaneous administration of nonradioactive Gdn-KRAS2 G12 V probes (n = 2 or 8) increased accumulation of [111In]8KRAS2 G12 V probes 3–6-fold in pancreatic cancer CAPAN2 xenografts and other tissues, except for a 2-fold decrease in the kidneys. As a result, tissue distribution tumor/muscle ratios of 111In uptake increased from 3.1 ± 0.5 to 6.5 ± 1.0, and the kidney/tumor ratio of 111In uptake decreased by more than 5-fold from 174.8 ± 17.5 to 30.8 ± 3.1. Thus, PDAP dendrimers with up to 16 DOTA chelators attached to PNA-IGF1 analogs, as well as simultaneous administration of the elevated dose of nonradioactive Gdn-KRAS2 G12 V probes, enhanced tumor uptake of [111In]nKRAS2 PNA probes. These results also imply that Gd(III) dendrimeric hybridization probes might be suitable for magnetic resonance imaging of gene expression in tumors, because the higher generations of the dendrimers, including the NMR contrast Gdn-KRAS2 G12 V probes, improved tumor accumulation of the probes and specificity of tumor imaging.
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