HPMA-based biodegradable hydrogels containing different forms of doxorubicin. Antitumor effects and biocompatibility

Novel hydrogels based on N-(2-hydroxypropyl)methacrylamide (HPMA) and N,O-dimethacryloylhydroxylamine containing either doxorubicin (DOX) or water-soluble HPMA carrier-bound doxorubicin (P-GlyPheLeuGly-DOX; HPMA-DOX) were synthesized. The cross-linkages are susceptible to hydrolytic cleavage at physiological pH 7.4. Hydrogels in the form of rods or discs loaded with DOX or P-GlyLeuGly-DOX were implanted subcutaneously on the back of C57BL/10 mice on day 1 or on day 9 after inoculation with EL4 mouse T-cell lymphoma. The implanted hydrogels varied in the total load of DOX and rate of hydrolysis, which is dependent on the crosslinking density of the gels. The effect of HPMA based hydrogels containing DOX or HPMA carrier-bound DOX on tumor growth, animal life span, leukocyte populations in peripheral blood and bone marrow function evaluated by reticulocyte count was investigated. It was shown that: a) DOX and HPMA carrier-bound DOX administered in the form of HPMA-based hydrogels has better antitumor activity against experimental EL4 mouse T-cell lymphoma than soluble forms of the drug, b) hydrogels with shorter degradation rate (16-17 h) show better antitumor activity than hydrogels with longer duration time (48-52 h), c) the therapeutic effect of hydrogels with rate 16-17 h is directly related to the doxorubicin content; the higher the doxorubicin content, the better antitumor activity, d) the gel containing free doxorubicin showed significant antitumor activity even when implanted on day 9, i.e., in the time when tumor growth is already established, e) the hydrogel matrix without drug does not induce release of IL-1 or IL-6 into peripheral blood, does not induce formation of antibodies, and it is not mitogenic. Use of doxorubicin in the form of HPMA-based hydrogels allows a several-fold increase in the administered dose compared to soluble forms without detectable serious toxic side-effects.