Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer.
Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer.
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DOI：
10.1007/s11095-009-9964-5
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发表时间：
2009-11
影响因子：
3.7
通讯作者：
Smith, Quentin R.
中科院分区：
文献类型：
--
作者：
Thomas, Fancy C.;Taskar, Kunal;Rudraraju, Vinay;Goda, Satyanarayana;Thorsheim, Helen R.;Gaasch, Julie A.;Mittapalli, Rajendar K.;Palmieri, Diane;Steeg, Patricia S.;Lockman, Paul R.;Smith, Quentin R.
我们评估了血管肽素-2紫杉醇缀合物ANG 1005在啮齿动物中进入脑和乳腺癌脑转移的摄取。大多数抗癌药物由于穿过血脑屏障（BBB）的运输有限而显示出对脑肿瘤的不良递送。为了克服这一点，开发了一种19个氨基酸的肽（血管肽-2），其结合BBB处的低密度脂蛋白受体相关蛋白（LRP）受体，并且具有通过受体介导的转运将药物递送至脑的潜力。采用大鼠原位脑灌注法测定脑内流的传递系数（Kin）。在携带乳腺癌脑内MDA-MB-231 BR转移的小鼠中静脉注射后30分钟测定药物分布。125 I-ANG 1005摄取的BBB Kin（7.3 ± 0.2 × 10−3 mL/s/g）超过3 H-紫杉醇（8.5 ± 0.5 × 10−5）的86倍。125 I-ANG 1005示踪剂在毛细血管耗竭或血管冲洗后70%以上停留在脑内。脑125 I-ANG 1005摄取被未标记的血管肽素-2载体和LRP配体降低，与受体转运一致。125 I-ANG 1005在血管校正的脑和脑转移瘤中的体内摄取超过14 C-紫杉醇4-54倍。结果表明，与游离紫杉醇相比，ANG 1005显示出显著改善的向乳腺癌的脑和脑转移的递送。
We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. The transfer coefficient (Kin) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer. The BBB Kin for 125I-ANG1005 uptake (7.3 ± 0.2 × 10−3 mL/s/g) exceeded that for 3H-paclitaxel (8.5 ± 0.5 × 10−5) by 86 fold. Over 70% of 125I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain 125I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of 125I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of 14C-paclitaxel by 4–54 fold. The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.
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影响因子：
4.7
作者：
Demeule, M;Poirier, J;Béliveau, R
通讯作者：
Béliveau, R
影响因子：
8.8
作者：
通讯作者：
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影响因子：
15.9
作者：
Fellner, S;Bauer, B;Fricker, G
通讯作者：
Fricker, G
影响因子：
4.7
作者：
Dauchy, Sandrine;Dutheil, Fabien;Decleves, Xavier
通讯作者：
Decleves, Xavier
影响因子：
3.9
作者：
Kalvass, J. Cory;Maurer, Tristan S.;Pollack, Gary M.
通讯作者：
Pollack, Gary M.