Fabrication of an Injectable Star-polylactide/Thiolated Hyaluronate Hydrogel as a Double Drug-Delivery System for Cancer Treatment

[Image: see text] Unsatisfactory solid-tumor penetration or rapid metabolism of nanomaterials limits their therapeutic efficacy. Here, we designed an injectable thiolated hyaluronate (HA-SH) hydrogel as a stable drug-releasing platform for in situ tumor treatment. Biodegradable star-shaped polylactide (S-PLLA) was first synthesized and fabricated to porous microspheres to encapsulate hydrophobic curcumin (Cur@S-PLLA), which was then blended with hydrophilic doxorubicin (Dox) and the HA-SH precursor to form composite in situ formable hydrogels [Cur@S-PLLA/(Dox)HA-SH]. The results showed that adding the microspheres improved the performance of the hydrogel, such as decreasing the gelation time from 1080 s to 960 s and also the swelling ratio. The mechanical strength increased from 27 to 45 kPa. In addition, the double drug system guaranteed a sustained release of drugs, releasing Dox at the early stage, with the continuous later release of Cur after gel swelling or S-PLLA degradation to achieve long-lasting tumor suppression, which inhibits the survival of cancer cells. The inhibitory effects of the hydrogels on MCF-7 were studied. The cell activity in the double-loaded hydrogel was significantly lower than that of the control groups, and apparent dead cells appeared in 2 days and fewer living cells with time. Flow cytometry revealed that the Cur@S-PLLA/(Dox)HA-SH group had the highest apoptosis ratio of 86.60% at 12 h, and the drugs caused the cell cycle to be blocked in phase M to reduce cell division. In summary, the innovative release platform is expected to be used in long-lasting tumor suppression and provides more ideas for the design of drug carriers.