Abstract
Here we describe the synthesis and biological properties of two types of star-shaped polymer-doxorubicin conjugates: non-targeted conjugate prepared as long-circulating high-molecular-weight (HMW) polymer prodrugs with a dendrimer core and a targeted conjugate with the anti-CD20 monoclonal antibody (mAb) rituximab (RTX). The copolymers were linked to the dendrimer core or to the reduced mAb via one-point attachment forming a star-shaped structure with a central antibody or dendrimer surrounded by hydrophilic polymer chains. The anticancer drug doxorubicin (DOX) was attached to the N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer chain in star polymer systems via a pH-labile hydrazone linkage. Such polymer-DOX conjugates were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly acidic environments at pH 5–5.5 by hydrolysis of the hydrazone bonds. The cytotoxicity of the polymer conjugates was tested on several CD20-positive or negative human cell lines. Similar levels of in vitro cytotoxicity were observed for all tested polymer conjugates regardless of type or structure. In vivo experiments using primary cell-based murine xenograft models of human diffuse large B-cell lymphoma confirmed the superior anti-lymphoma efficacy of the polymer-bound DOX conjugate when compared with the original drug. Targeting with RTX did not further enhance the anti-lymphoma efficacy relative to the non-targeted star polymer conjugate. Two mechanisms could play roles in these findings: changes in the binding ability to the CD-20 receptor and a significant loss of the immunological properties of RTX in the polymer conjugates.
Highlights
A variety of drug delivery systems (DDS) suitable for improving the biodistribution and biological outcomes of drugs have been developed in the past few decades [1,2]
The results suggest that the anti-CD20 antibody rituximab does not represent an ideal monoclonal antibody (mAb) for targeting polymer prodrugs, especially in such patients who relapse after the failure of rituximab-based front-line therapies
We described the synthesis and characterisation of biological properties of non-targeted or anti-CD20 monoclonal antibody-targeted star-shaped HMW polymer-doxorubicin conjugates
Summary
A variety of drug delivery systems (DDS) suitable for improving the biodistribution and biological outcomes of drugs have been developed in the past few decades [1,2]. The synthesis was based on reducing the disulfide bridges of the mAb with dithiothreitol (DTT) under mild conditions followed by the one-point conjugation of semitelechelic polymers This synthetic route preserves the binding ability of the targeting antibody to its specific cell receptors even after the conjugation with the polymer precursor. Doxorubicin was bound to the polymer precursors through pH-sensitive, hydrolytically unstable hydrazone bonds tailored made for controlled drug release Both polymer conjugates were evaluated for physicochemical and biological properties (i.e., molecular weight; DOX in vitro release rate; in vitro cytotoxicity; mAb binding efficacy to CD20-positive and negative cells; and in vivo therapeutic efficacy). The pro-apoptotic and CD20-specific mAb RTX was selected as targeting moiety to evaluate potential use of RTX-targeted prodrug in the treatment of primary cell-based murine xenograft models of human diffuse large B-cell lymphomas, i.e., possible synergistic outcome of pro-apoptotic effect and increased cytotoxicity of targeted polymer prodrug
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