HPMA copolymer-bound doxorubicin targeted to tumor-specific antigen of BCL1 mouse B cell leukemia

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing the anticancer drug doxorubicin and targeted with B1 monoclonal antibody (mAb) to BCL1 leukemia cells was synthesised and tested in vitro and in vivo. BCL1 leukemia growing in syngenic Balb/c mice was selected as a tumor model sys...

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Bibliographic Details
Published in:Journal of controlled release 2003-10, Vol.92 (3), p.315-330
Main Authors: Kovář, M, Mrkvan, T, Strohalm, J, Etrych, T, Ulbrich, K, Štastný, M, Řı́hová, B
Format: Article
Language:English
Subjects:
Acrylamides - chemistry
Acrylamides - therapeutic use
Animals
Antibodies, Anti-Idiotypic - analysis
Antibodies, Anti-Idiotypic - chemistry
Antibodies, Anti-Idiotypic - pharmacology
Antibodies, Monoclonal - analysis
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - pharmacology
Antigens, Neoplasm - immunology
Body Weight - drug effects
Cell Division - drug effects
Cell Line, Tumor
Doxorubicin
Doxorubicin - chemistry
Doxorubicin - therapeutic use
Drug Delivery Systems - methods
Drug targeting
Flow Cytometry
HPMA copolymer
Hydrogels - chemistry
Immunoconjugates - blood
Immunoconjugates - pharmacology
Immunoconjugates - therapeutic use
Inhibitory Concentration 50
Injections, Intraperitoneal
Injections, Intravenous
Leukemia, B-Cell - drug therapy
Leukemia, B-Cell - immunology
Leukemia, B-Cell - mortality
Leukocytes, Mononuclear - chemistry
Mice
Mice, Inbred BALB C
Monoclonal antibody
N-(2-Hydroxypropyl)methacrylamide
Reticulocyte Count
Spleen - chemistry
Survival Rate
Tumor-specific antigen
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Summary:N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing the anticancer drug doxorubicin and targeted with B1 monoclonal antibody (mAb) to BCL1 leukemia cells was synthesised and tested in vitro and in vivo. BCL1 leukemia growing in syngenic Balb/c mice was selected as a tumor model system. B1 mAb recognising the idiotype of surface IgM on BCL1 cells was used as a targeting moiety. Both B1 mAb and doxorubicin were conjugated to HPMA copolymer carrier by aminolysis through a tetrapeptidic Gly–Phe( d, l)–Leu–Gly spacer to ensure the intracellular delivery and controlled release of the drug. B1 mAb-targeted conjugate was shown to possess strictly tumor-specific binding capacity to target BCL1 cells in vitro. A similar conjugate, but containing human nonspecific Ig (HuIg) instead of B1 mAb, failed to bind to BCL1 cells. In vitro, B1 mAb-targeted conjugate demonstrated 40-fold higher cytotoxic effect than nontargeted or human nonspecific Ig-containing HPMA copolymer-bound doxorubicin. Conjugate targeted with B1 mAb was also shown to bind to target BCL1 cells in vivo. B1 mAb-targeted conjugate was shown to be more efficient in the treatment of established BCL1 leukemia than free doxorubicin, nontargeted and human nonspecific Ig-containing conjugate. Antibody-targeted polymeric drugs are thus promising conjugates for cancer treatment.
ISSN:0168-3659
1873-4995
DOI:10.1016/S0168-3659(03)00340-7