Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models

被引:94
作者
Chau, Y
Padera, RF
Dang, NM
Langer, R
机构
[1] MIT, Dept Chem Engn, Cambridge, MA 02139 USA
[2] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
关键词
methotrexate; dextran; matrix metalloproteinase; gelatinase; tumor; enhanced permeation and retention (EPR); tumor-associated enzymes; polymer-drug conjugate; cancer targeting;
D O I
10.1002/ijc.21495
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1519 / 1526
页数:8
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