Tumor microenvironment-labile polymer-doxorubicin conjugate thermogel combined with docetaxel for in situ synergistic chemotherapy of hepatoma.

Topical chemotherapy with complementary drugs is one of the most promising strategies to achieve an effective antitumor activity. Herein, a synergistic strategy for hepatoma therapy by the combination of tumor microenvironment-sensitive polymer-doxorubicin (DOX) conjugate thermogel, containing a DNA intercalator DOX, and docetaxel (DTX), a microtubule-interfering agent, was proposed. First, cis-aconitic anhydride-functionalized DOX (CAD) and succinic anhydride-modified DOX (SAD) were conjugated onto the terminal hydroxyl groups of poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), yielding the acid-sensitive CAD-PLGA-PEG-PLGA-CAD and the insensitive SAD-PLGA-PEG-PLGA-SAD conjugates, respectively. The prodrug aqueous solution exhibited a thermoreversible sol-gel transition between room and physiological temperature. Meantime, appropriate mechanical property, biodegradability, as well as a sustained release profile were revealed in such prodrug thermogels. More importantly, the addition of DTX to the DOX-conjugated thermogels (i.e., Gel-CAD and Gel-SAD) was verified with enhanced curative effect against tumor, where the antitumor efficacy of Gel-CAD+DTX was obviously higher than the other groups. A reliable security in vivo was also showed in the Gel-CAD+DTX group. Taken together, such combination of tumor microenvironment-labile prodrug thermogel and a complementary drug exhibited fascinating prospect for local synergistic antineoplastic therapy. STATEMENT OF SIGNIFICANCE: Multidrug chemotherapy with synergistic effect has been proposed recently for hepatoma treatment in the clinic. However, the quick release, fast elimination, and unselectivity of multidrugs in vivo always limit their further application. To solve this problem, a synergistic combination of tumor microenvironment-sensitive polymeric doxorubicin (DOX) prodrug thermogel for DNA intercalation and a microtubule-interfering agent docetaxel (DTX) is developed in the present study for the local chemotherapy of hepatoma. Interestingly, a pH-triggered sustained release behavior, an enhanced antitumor efficacy, and a favorable security in vivo are observed in the combined dual-drug delivery platform. Therefore, effectively combining tumor microenvironment-labile polymeric prodrug thermogel with a complementary drug provides an advanced system and a promising prospect for local synergistic hepatoma chemotherapy.