177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model.
177Lu-labeled HPMA copolymers utilizing cathepsin B and S cleavable linkers: synthesis, characterization and preliminary in vivo investigation in a pancreatic cancer model.
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DOI：
10.1016/j.nucmedbio.2013.01.011
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发表时间：
2013-07
影响因子：
3.1
通讯作者：
Garrison JC
中科院分区：
文献类型：
--
作者：
Ogbomo SM;Shi W;Wagh NK;Zhou Z;Brusnahan SK;Garrison JC
治疗性纳米药物发展的一个主要障碍是药物递送系统在与网状内皮系统相关的器官（特别是肝脏和脾脏）中的积累引起的非靶向毒性。在此，我们报告了基于肽的代谢活性接头（MALs）的开发，其被半胱氨酸组织蛋白酶B和S酶促切割，这两种蛋白酶在肝脏和脾脏中高度表达。该方法的总体目标是利用MAL降低放射性标记药物递送系统的非靶向滞留和毒性，从而产生更高的诊断和放射治疗功效。在本研究中，研究了三种MAL（MAL 0、MAL 1和MAL 2）。MAL 1和MAL 2分别由组织蛋白酶B和S的已知底物组成，而MAL 0是不可裂解的对照。MAL 1和MAL 2都显示出用适当的组织蛋白酶进行酶切割。在与HPMA共聚物缀合并用177 Lu放射性标记之后，肽-聚合物缀合物被重命名为177 Lu-代谢活性共聚物（177 Lu-MAC），具有相应的名称177 Lu-MAC 0、177 Lu-MAC 1和177 Lu-MAC 2。在HPAC人胰腺癌异种移植小鼠模型中进行177 Lu-MAC的体内评价。在注射后72小时，177 Lu-MAC 1和177 Lu-MAC 2分别表现出比对照（177 Lu-MAC 0）低3.1和2.1倍的肝脏保留。关于脾滞留，177 Lu-MAC 1和177 Lu-MAC 2在72小时时间点相对于对照各自表现出几乎四倍低的滞留。然而，在相同时间点，177 Lu-MAC 0的肿瘤积累比177 Lu-MAC 1和177 Lu-MAC 2大2至3倍。MAL方法证明了显著降低177 Lu标记的HPMA共聚物的非靶标保留的能力。虽然需要进一步的研究来优化177 Lu-MAC设计的药代动力学，但MAL显著降低非靶保留的能力确立了这种研究途径可能具有的改进诊断和放射性药物递送系统的潜力。
A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177Lu, the peptide-polymer conjugates were renamed 177Lu- metabolically active copolymers (177Lu-MACs) with the corresponding designation 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. In vivo evaluation of the 177Lu-MACs was performed in a HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72 h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72 h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. While further studies are needed to optimize the pharmacokinetics of the 177Lu-MACs design, the ability of the MAL to significantly decrease non-target retention establishes the potential this avenue of research may have for the improvement of diagnostic and radiotherapeutic drug delivery systems.
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影响因子：
10.8
作者：
Julyan, PJ;Seymour, LW;Kerr, DJ
通讯作者：
Kerr, DJ
影响因子：
10.8
作者：
Mitra, A;Mulholland, J;Line, BR
通讯作者：
Line, BR
DOI：
10.3181/0808-mr-250
发表时间：
2009-02
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
--
作者：
Blanco E;Kessinger CW;Sumer BD;Gao J
通讯作者：
Gao J
影响因子：
3.7
作者：
Mitra, A;Nan, A;Line, BR
通讯作者：
Line, BR
DOI：
10.1002/jbm.820211106
发表时间：
1987-11-01
期刊：
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH
影响因子：
--
作者：
SEYMOUR, LW;DUNCAN, R;KOPECEK, J
通讯作者：
KOPECEK, J