Anti-Lymphoma Efficacy Comparison of Anti-Cd20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug ConjugatesReport as inadecuate




Anti-Lymphoma Efficacy Comparison of Anti-Cd20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug Conjugates - Download this document for free, or read online. Document in PDF available to download.

1

Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic

2

Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53 Prague 2, Czech Republic

3

Department of Hematology, Charles University General Hospital in Prague, U Nemocnice 2, 128 08 Prague 2, Czech Republic





*

Author to whom correspondence should be addressed.



Academic Editor: Didier Astruc

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-hydroxypropylmethacrylamide 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. View Full-Text

Keywords: HPMA copolymers; drug delivery systems; doxorubicin; monoclonal antibody; drug targeting HPMA copolymers; drug delivery systems; doxorubicin; monoclonal antibody; drug targeting





Author: Ondřej Lidický 1, Olga Janoušková 1, Jiří Strohalm 1, Mahmudul Alam 2, Pavel Klener 2,3 and Tomáš Etrych 1,*

Source: http://mdpi.com/



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