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.

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.

Improvement of survival in C6 rat glioma model by a sustained drug release from localized PLGA microspheres in a thermoreversible hydrogel.

A local drug delivery system based on sustained drug release is an attractive approach to treat brain tumors. We have developed a novel device using drug-incorporated poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in thermoreversible gelation polymer (TGP) formulation (drug/PLGA/TGP formulation). TGP forms a gel at body temperature but sol at room temperature. Therefore, when this formulation is injected into the brain tumor, the PLGA microspheres in TGP gel are localized at the injection site and do not diffuse throughout the brain tissue; eventually, sustained drug release from PLGA microspheres is achieved at the target site. In this study, two chemotherapeutic drugs (camptothecin (CPT) or vincristine (VCR)) were incorporated into PLGA microspheres to prepare drug/PLGA/TGP formulations. VCR/PLGA microspheres exhibited the higher encapsulation efficiency than CPT/PLGA microspheres (70.1% versus 30.1%). In addition, VCR/PLGA microspheres showed a higher sustained release profile than CPT/PLGA microspheres (54.5% versus 72.5% release, at 28 days). Therapeutic effect (mean survival) was evaluated in the C6 rat glioma model (control group, 18 days; CPT/PLGA/TGP treatment group, 24 days; VCR/PLGA/TGP treatment group, 33 days). In particular, the VCR/PLGA/TGP formulation produced long-term survivors (>60 days). Therefore, this formulation can be therapeutically effective formulation for the glioma therapy.

Treatment of rat brain tumors using sustained-release of camptothecin from poly(lactic-co-glycolic acid) microspheres in a thermoreversible hydrogel.

A thermoreversible gelation polymer consisting of an aqueous solution in the sol state at room temperature and in the gel state near body temperature was examined for its use in the retention of microspheres and sustained, long-term delivery of anti-cancer drugs using a rat model of malignant glioma. The poly(lactic-co-glycolic acid) (PLGA) microspheres containing camptothecin at ratios of 1 : 33 or 1 : 50 mediated sustained release, with approximate 80% of camptothecin released after 28 d. Rats were inoculated in the brain with C6 glioma cells, followed 7 d later by injection in the tumor site with 1 : 33 and 1 : 50 PLGA microspheres dispersed in a thermoreversible gelation polymer (TGP) solution. Kaplan-Meier analysis showed that the mean survival period of the untreated group was 16 d, with a slight increase in rats treated with TGP-only solution, empty or 1 : 50 microspheres in phosphate-buffered saline. The mean survival period of rats treated with the camptothecin powder in TGP was 21 d, while that of rats treated with 1 : 33 and 1 : 50 microspheres in TGP was significantly longer than the untreated group; long-term survival rats were observed. These results suggest that the anti-tumor effect of camptothecin can be enhanced by long-term sustained release from microspheres retained in the rat brain by TGP gel.