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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 MMP‐insensitive linker, at equivalent intraperitoneal dosages. The MMP‐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 …