Preclinical evaluation of linear HPMA-doxorubicin conjugates with pH-sensitive drug release: efficacy, safety, and immunomodulating activity in murine model.
OBJECTIVE
In vivo efficacy and safety of HPMA-based copolymers armed with doxorubicin via a spacer containing pH-sensitive linkage that can be prepared within a broad range of attached drug contents (1) was tested in murine tumor models.


METHODS
Mice bearing T cell lymphoma EL4 or B cell lymphoma 38C13 were treated with a single dose of the conjugate (15, 25, and 75 mg Dox eq./kg i.v.) in a therapeutic regime. Anti-tumor resistance of the cured animals was proved by a second challenge with a lethal dose of tumor cells without additional treatment.


RESULTS
The content of drug bound to the polymer is an important parameter in relation to the conjugate therapeutic efficacy. The best anti-tumor effects were produced by conjugates with 10 - 13 wt% of bound doxorubicin. Free doxorubicin up to 4.6% relative to total drug content had no impact on the treatment efficacy and acute toxicity. The conjugates induced a complete cure of mice and regular treatment-dependent development of specific anti-tumor resistance. No myelosuppression or organ damage was observed.


CONCLUSIONS
A well-defined HPMA copolymer-doxorubicin conjugate with pH-sensitive drug release is a good candidate for clinical trials as it has remarkable anti-tumor efficacy and a favorable safety profile.
Sirova
Milada
M
Laboratory of Tumor Immunology, Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Vídenska 1083, 142 20, Prague 4, Czech Republic. sirova@biomed.cas.cz
Mrkvan
Tomas
T
Etrych
Tomas
T
Chytil
Petr
P
Rossmann
Pavel
P
Ibrahimova
Marketa
M
Kovar
Lubomir
L
Ulbrich
Karel
K
Rihova
Blanka
B
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D056747:Immunomodulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D011108:Polymers / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011109:Polymethacrylic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011108:Polymers; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D004317:Doxorubicin