Binding and cytotoxicity of HPMA copolymer conjugates to lymphocytes mediated by receptor-binding epitopes.
OBJECTIVE
Studies on the recognition of epitopes presented on a template peptide showed the potential of nonapeptide-related sequences to act as biorecognition sites for the B-cell CD21 receptor. This study was intended to evaluate the capability of three epitope sequences to mediate specific cell binding and to enhance the cytotoxicity of HPMA copolymer conjugates.


METHODS
HPMA copolymer conjugates were synthesized containing three different epitopes at various contents and either a fluorescent marker or doxorubicin (DOX). The binding and cytotoxicity of the conjugates to CD21+ Raji B cells and CD21- HSB-2 T cells were evaluated.


RESULTS
The epitope-containing conjugates were found to bind to Raji cells at different apparent affinities depending on epitope structure and content. The conjugates generally possessed higher affinities for Raji cells than for HSB-2 cells. Targeted HPMA copolymer-DOX conjugates exhibited higher cytotoxicities than the nontargeted conjugate, likely indicative of enhanced internalization by receptor-mediated endocytosis. HSB-2 cells were more sensitive to both free and polymer-bound DOX than Raji cells; however, the enhancement of cytotoxicity of the conjugates by incorporation of epitopes was more pronounced for Raji cells.


CONCLUSIONS
The results verified the concept of using receptor-binding epitopes as targeting moieties in HPMA copolymer conjugates for the delivery of anticancer drugs to lymphoma cells.
Tang
Aijun
A
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Kopeiková
Pavla
P
Kopeckevá
Jindrich
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D016503:Drug Delivery Systems; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D011108:Polymers; D011109:Polymethacrylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000378:metabolism*
D000970:Antineoplastic Agents; D004337:Drug Carriers; D000939:Epitopes; D011108:Polymers; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; C481858:fluorescein isothiocyanate-HPMA copolymer conjugate; D004317:Doxorubicin; D016650:Fluorescein-5-isothiocyanate