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Preclinical Evaluation of Linear HPMA-Doxorubicin Conjugates with pH-Sensitive Drug Release: Efficacy, Safety, and Immunomodulating Activity in Murine Model

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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.

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Abbreviations

B/6:

C57BL/6

CRT:

calreticulin

Dox:

doxorubicin

HMGB1:

high mobility group box-1

HPMA:

N-(2-hydroxypropyl)methacrylamide

PBS:

phosphate buffered saline

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ACKNOWLEDGEMENTS

The work was supported by grant KAN 200200651, Premium Academiae, and Institutional Research Concept AV0Z50200510. Authors appreciate the funding support from pharmaceutical company Zentiva, k.s. (Czech Republic), and thank Mrs. Helena Mišurcová and Ms. Pavlína Jungrová for excellent technical assistance.

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Authors and Affiliations

  1. 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

    Milada Sirova, Tomas Mrkvan, Pavel Rossmann, Marketa Ibrahimova, Lubomir Kovar & Blanka Rihova

  2. Department of Biomedicinal Polymers, Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic

    Tomas Etrych, Petr Chytil & Karel Ulbrich

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  1. Milada Sirova
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  2. Tomas Mrkvan
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  3. Tomas Etrych
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Correspondence to Milada Sirova.

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Sirova, M., Mrkvan, T., Etrych, T. et al. Preclinical Evaluation of Linear HPMA-Doxorubicin Conjugates with pH-Sensitive Drug Release: Efficacy, Safety, and Immunomodulating Activity in Murine Model. Pharm Res 27, 200–208 (2010). https://doi.org/10.1007/s11095-009-9999-7

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  • DOI: https://doi.org/10.1007/s11095-009-9999-7

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