Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models
Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models
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DOI：
10.1002/ijc.21495
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发表时间：
2006-03-15
影响因子：
6.4
通讯作者：
Langer, R
中科院分区：
文献类型：
--
作者：
Chau, Y;Padera, RF;Langer, R
我们设计了一种新的葡聚糖-肽-甲氨蝶呤偶联物，以实现化疗药物的肿瘤靶向递送。选择葡聚糖载体以允许被动靶向和增强的渗透和保留（EPR）。肽接头也已被优化，以允许在基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）（2种重要的肿瘤相关酶）存在下释放药物。评估了新缀合物的体内抗肿瘤功效和全身副作用。将其与游离甲氨蝶呤（MTX）和类似的缀合物进行比较，不同之处在于NIMP不敏感的接头，在同等的腹膜内剂量下。在过表达MMP的2个单独的肿瘤模型（HT-1080和U-87）中的每一个中，NIMP敏感性缀合物显示出可耐受的体内副作用和对体内肿瘤生长的83%的有效抑制。该药物的抗增殖作用有助于抑制肿瘤生长。相比之下，在相同的模型中，游离MTX没有导致显著的肿瘤减少。游离MTX和偶联物均未在携带RT-112的小鼠中引起任何肿瘤抑制，RT-112是一种生长较慢的模型，不过度表达NIMP。对NIMP不敏感的缀合物虽然能够抑制肿瘤生长，但在小肠和骨髓中引起毒性。(c)2005 Wiley-Liss，Inc.
We have designed a new dextran-peptide-methotrexate conjugate to achieve tumor-targeted delivery of chemotherapeutics. The dextran carrier was selected to allow passive targeting and enhanced permeation and retention (EPR). The peptide linker has also been optimized to allow drug release in the presence of matrix-metalloproteinase-2 (MMP-2) and matrix-metalloproteinase-9 (MMP-9), 2 important tumor-associated enzymes. The new conjugate was assessed for its in vivo antitumor efficacy and systemic side effects. It was compared with free methotrexate (MTX) and a similar conjugate, differing by an NIMP-insensitive linker, at equivalent intraperitoneal dosages. The NIMP-sensitive conjugate demonstrated tolerable in vivo side effects and effective inhibition of in vivo tumor growth by 83% in each of the 2 separate tumor models that overexpress MMP (HT-1080 and U-87). The antiproliferative effect of the drug contributed to the inhibition of tumor growth. In contrast, free MTX resulted in no significant tumor reduction in the same models. Neither free MTX nor the conjugate caused any tumor inhibition in the mice bearing RT-112, a slower growing model that does not overexpress NIMP. NIMP-insensitive conjugates, though able to inhibit tumor growth, caused toxicity in the small intestine and bone marrow. (c) 2005 Wiley-Liss, Inc.