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 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 MMP. MMP-insensitive conjugates, though able to inhibit tumor growth, caused toxicity in the small intestine and bone marrow. ' 2005 Wiley-Liss, Inc.Key words: methotrexate; dextran; matrix metalloproteinase; gelatinase; tumor; enhanced permeation and retention (EPR); tumor-associated enzymes; polymer-drug conjugate; cancer targeting Polymer-drug conjugates have shown promise as drug-delivery vehicles for targeting low molecular weight drugs to tumor tissues. 1 By tailoring the polymeric carriers, the pharmacokinetics and tumor target ratio of the attached drug molecules can be favorably altered. The key to the success of this application is that covalent attachment to the polymer enables passive targeting of the drug molecules. The high molecular weight of the polymer increases the size of the conjugate and slows the drug clearance by the kidneys. The drug concentration in the plasma is thereby maintained above the therapeutic level for a prolonged period of time. Additionally, many solid tumors display unique pathophysiology features, including highly permeable vasculature and impaired lymphatic drainage, that are absent in normal tissues. High molecular weight polymer-drug conjugates extravasate into the tumor tissues but not the normal tissues with less permeable vessels. Once inside the tumor tissues, the polymer-drug conjugates do not readily return to the general circulation because of the poor lymphatics. This phenomenon, termed enhanced permeation and retention (EPR), was first discovered by Maeda. 2 To take advantage of passive targeting and EPR, we have considered the necessary criteria in our design of a new polymer-peptide-drug conjugate. The polymer backbone needs to be biocompatible and biodegradable. It should be hydrophilic, not highly charged, and should have a size above the renal threshold limit to increase its circulation time. C...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.