Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.
Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.
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DOI：
10.1021/mp5006917
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发表时间：
2015-06-01
影响因子：
4.9
通讯作者：
Anderson CJ
中科院分区：
文献类型：
--
作者：
Beaino W;Nedrow JR;Anderson CJ
恶性黑色素瘤是一种高度侵袭性的癌症，并且这种疾病的发病率在世界范围内以惊人的速度增加。尽管在黑色素瘤的治疗方面取得了进展，但患有转移性疾病的患者仍然具有不良预后和低存活率。包括靶向放疗在内的新策略将为对BRAF抑制剂等疗法产生耐药性的患者提供选择。极晚期抗原-4（VLA-4）在侵袭性和转移性更强的黑素瘤肿瘤细胞上以更高的水平表达，可能为药物递送和靶向放射治疗提供理想的靶点。在这项研究中，我们评估了177 Lu和68 Ga标记的DOTA-PEG 4-LLP 2A作为VLA-4靶向放射治疗与伴随PET剂用于诊断和监测转移性黑色素瘤治疗。通过固相合成来合成DOTA-PEG 4-LLP 2A。在B16 F10黑色素瘤细胞中分别通过饱和结合和竞争性结合测定测定177 Lu-和68 Ga-标记的DOTA-PEG 4-LLP 2A对VLA-4的亲和力。在携带B16 F10皮下肿瘤的C57 BL/6小鼠中测定LLP 2A缀合物的生物分布，同时在皮下和转移模型中进行PET/CT成像。177 Lu-DOTA-PEG 4-LLP 2A显示出对VLA-4的高亲和力，Kd为4.1 ± 1.5 nM，并在4小时后在B16 F10黑色素瘤肿瘤中显示出显著的积累（31.5 ± 7.8%ID/g）。177 Lu-DOTA-PEG 4-LLP 2A的肿瘤/血液比在24小时最高（185 ± 26）。用68 Ga-DOTA-PEG 4-LLP 2A对转移性黑色素瘤的PET成像显示转移部位的高摄取，并且与肿瘤的生物发光成像相关。这些数据表明，177 Lu-DOTA-PEG 4-LLP 2A具有作为治疗黑素瘤以及其它表达VLA-4的肿瘤的靶向治疗剂的潜力。此外，68 Ga-DOTA-PEG 4-LLP 2A是用于转移性黑素瘤成像的容易翻译的伴随PET示踪剂。
Malignant melanoma is a highly aggressive cancer, and the incidence of this disease is increasing worldwide at an alarming rate. Despite advances in the treatment of melanoma, patients with metastatic disease still have a poor prognosis and low survival rate. New strategies, including targeted radiotherapy, would provide options for patients who become resistant to therapies such as BRAF inhibitors. Very late antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels in more aggressive and metastatic disease and may provide an ideal target for drug delivery and targeted radiotherapy. In this study, we evaluated 177Lu- and 68Ga-labeled DOTA-PEG4-LLP2A as a VLA-4-targeted radiotherapeutic with a companion PET agent for diagnosis and monitoring metastatic melanoma treatment. DOTA-PEG4-LLP2A was synthesized by solid-phase synthesis. The affinity of 177Lu- and 68Ga-labeled DOTA-PEG4-LLP2A to VLA-4 was determined in B16F10 melanoma cells by saturation binding and competitive binding assays, respectively. Biodistribution of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10 subcutaneous tumors, while PET/CT imaging was performed in subcutaneous and metastatic models. 177Lu-DOTA-PEG4-LLP2A showed high affinity to VLA-4 with a Kd of 4.1 ± 1.5 nM and demonstrated significant accumulation in the B16F10 melanoma tumor after 4 h (31.5 ± 7.8%ID/g). The tumor/blood ratio of 177Lu-DOTA-PEG4-LLP2A was highest at 24 h (185 ± 26). PET imaging of metastatic melanoma with 68Ga-DOTA-PEG4-LLP2A showed high uptake in sites of metastases and correlated with bioluminescence imaging of the tumors. These data demonstrate that 177Lu-DOTA-PEG4-LLP2A has potential as a targeted therapeutic for treating melanoma as well as other VLA-4-expressing tumors. In addition, 68Ga-DOTA-PEG4-LLP2A is a readily translatable companion PET tracer for imaging of metastatic melanoma.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
8.4
作者：
Garbe, Claus;Peris, Ketty;Eggermont, Alexander M.
通讯作者：
Eggermont, Alexander M.
DOI：
10.2967/jnumed.114.144881
发表时间：
2014-11
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Beaino W;Anderson CJ
通讯作者：
Anderson CJ
影响因子：
64.8
作者：
通讯作者：
--
使用 64Cu- 和 68Ga-Somatostatin 拮抗剂对生长抑素受体阳性肿瘤进行 PET 研究： 螯合物的作用
影响因子：
9.3
作者：
Fani, Melpomeni;Del Pozzo, Luigi;Maecke, Helmut R.
通讯作者：
Maecke, Helmut R.