Combination Therapy of Surgical Tumor Resection with Implantation of a Hydrogel Containing Camptothecin-Loaded Poly(lactic-co-glycolic acid) Microspheres in a C6 Rat Glioma Model

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We have developed a drug-loaded poly(lactic-co-glycolic acid) (PLGA) microsphere-containing thermoreversible gelation polymer (TGP) (drug/PLGA/TGP) formulation as a novel device for implantation after surgical glioma resection. TGP is a thermosensitive polymer that is a gel at body temperature and a sol at room temperature. When a drug/PLGA/TGP formulation is injected into a target site, PLGA microspheres in TGP gel localize at the injection site and do not diffuse across the entire brain tissue, and thus, sustained drug release from the PLGA microspheres at the target site is expected. Using in vivo imaging, we confirmed that the implantation of indocyanine green (ICG)/PLGA/TGP formulation exhibited a stronger localization of ICG at the injection site 28 d after injection compared with that of ICG/PLGA formulation. The therapeutic effect (mean survival) was evaluated in a C6 rat glioma model. Surgical tumor resection alone showed almost no effect on survival (controls, 18 d; surgical resection; 18.5 d). Survival was prolonged after the treatment with a camptothecin (CPT; 10 µg)/PLGA/TGP formulation (24 d). The combination treatment of surgical tumor resection and CPT/PLGA/TGP showed almost the same therapeutic effect (24 d) compared with CPT/PLGA/TGP alone, while the combination treatment produced long term survivors (>60 d). Therefore, the CPT/PLGA/TGP formulation can be an effective candidate for localized and sustained long-term glioma therapy.