title: Anti-Lymphoma Efficacy Comparison of Anti-Cd20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug Conjugates.
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.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic. lidicky@imc.cas.cz.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Lidický
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic. janouskova@imc.cas.cz.
authors.forename: Olga
authors.initials: O
authors.lastname: Janoušková
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic. strohalm@imc.cas.cz.
authors.forename: Jiří
authors.initials: J
authors.lastname: Strohalm
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53 Prague 2, Czech Republic. mahmuddso2004@gmail.com.
authors.forename: Mahmudul
authors.initials: M
authors.lastname: Alam
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 128 53 Prague 2, Czech Republic. pavel.klener@gmail.com.|Department of Hematology, Charles University General Hospital in Prague, U Nemocnice 2, 128 08 Prague 2, Czech Republic. pavel.klener@gmail.com.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic. etrych@imc.cas.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D051379:Mice; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D000069283:Rituximab / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D011355:Prodrugs; D000069283:Rituximab; D004317:Doxorubicin
keywords: HPMA copolymers; doxorubicin; drug delivery systems; drug targeting; monoclonal antibody