Preclinical Evaluation of Linear HPMA-Doxorubicin Conjugates with pH-Sensitive Drug Release: Efficacy, Safety, and Immunomodulating Activity in Murine Model. Pharmaceutical research [Pharm Res] Journal article | | Title | Preclinical Evaluation of Linear HPMA-Doxorubicin Conjugates with pH-Sensitive Drug Release: Efficacy, Safety, and Immunomodulating Activity in Murine Model. | | Author(s) | Sirova M, Mrkvan T, Etrych T, Chytil P, Rossmann P, Ibrahimova M, Kovar L, Ulbrich K, Rihova B | | Institution | 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. | | Source | Pharm Res 2009 Nov 6. | | Abstract | PURPOSE: 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19894105 |
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