Although hydrogel-based therapeutic agents have shown great potential for localized cancer treatments, the maximum tolerated dose (MTD) of these methods remains uncertain. To confirm this, doxorubicin (DOX) loaded PLGA-PEG-PLGA hydrogel was employed to investigate the MTD of DOX for localized osteosarcoma treatment. This hydrogel showed good injectable and biodegradable properties in vivo. And the drug remaining time was also obviously prolonged in the tumor site. Different doses of DOX (5.0, 15, 30 mg/kg) with/without hydrogel were adopted to the treatment of tumor-bearing mice. Despite both localized administrations of 5.0 mg/kg DOX showing no obvious systemic toxicity, this dose failed to control the persistent growth of tumors or prolong the survival time in comparison with the control groups. Localized administration of 30 mg/kg DOX showed a high efficacy for suppressing tumor growth, but exhibited obvious body weight losing at the same time. Correspondingly, the DOX-loaded hydrogel with the dose of 15 mg/kg achieved significantly improved anti-tumor efficacy and prolonged mean survival time compared with both the free DOX (15 mg/kg) and other control groups. Furthermore, during the whole therapeutic process, the mice showed no obvious body weight loss, major organs damage or death in this group. The MTD of DOX-loaded agent based on the PLGA-PEG-PLGA hydrogel gave a 2-fold increase compared to the MTD of free DOX (7.5 mg/kg, intravenous injection) for the mouse without significant systemic toxicity.
Keywords: Cancer therapy; Injectable hydrogel; Localized drug delivery; Maximum tolerated dose.
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