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Kamada, H. et al.

Design of a pH-sensitive polymeric carrier for drug release and its application in cancer therapy.

PURPOSE: In this study, to optimize the polymeric drug delivery system for cancer chemotherapy, we developed a new pH-sensitive polymeric carrier, poly(vinylpyrrolidone-co-dimethylmaleic anhydride) [PVD], that could gradually release native form of drugs with full activity, from the conjugates in response to changes in pH. We examined the usefulness of PVD as a polymeric drug carrier. EXPERIMENTAL DESIGN: PVD was radically synthesized with vinylpyrrolidone and 2,3-dimethylmaleic anhydride, which is known to be a pH-reversible amino-protecting reagent. Conjugates between PVD and other drugs, such as Adriamycin (ADR), were prepared under the slightly basic conditions (pH 8.5). The drug-release pattern and the antitumor activity of PVD were examined. RESULTS: At pH 8.5, the release of the drugs from the conjugate was not observed. In contrast, PVD could release fully active drugs in the native form in response to the change in pH near neutrality, and gradually released drugs at neutral pH (7.0) and slightly acidic pH (6.0). The drug-release pattern in serum was almost similar to that observed during these physiological conditions. The PVD-conjugated ADR showed superior antitumor activity against sarcoma-180 solid tumor in mice, and it had less toxic side effects than free ADR. This enhancement in the antitumor therapeutic window may be due to not only the improvement of plasma half-lives and tumor accumulation of ADR, but also its controlled and sustained release from the conjugates in vivo. CONCLUSIONS: These results indicate that PVD is an effective polymeric carrier for optimizing cancer therapy.[1]

References

Design of a pH-sensitive polymeric carrier for drug release and its application in cancer therapy. Kamada, H., Tsutsumi, Y., Yoshioka, Y., Yamamoto, Y., Kodaira, H., Tsunoda, S., Okamoto, T., Mukai, Y., Shibata, H., Nakagawa, S., Mayumi, T. Clin. Cancer Res. (2004) [Pubmed]

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