Potentiation of anticancer effects of microencapsulated carboplatin by hydroxypropyl α-cyclodextrin

Abstract

Cyclodextrins are cyclic oligosaccharides that can change physicochemical properties of drugs by forming inclusion complexes with them. These changes may enhance the therapeutic potential of drugs by diminishing their decomposition before they enter tissues and by altering how they enter tissue. Carboplatin is an anticancer drug that is active against brain tumors and has recently been tested as a potential agent for interstitial chemotherapy. To test whether complex formulation with cyclodextrins would improve interstitial treatment with carboplatin, we studied the efficacy of carboplatin-cyclodextrin complexes, free and encapsulated, in an experimental rat glioma model. Carboplatin hydroxypropyl α-cyclodextrin complexes were incorporated into ethylcellulose microcapsules at a 2.2% w/w loading. We found that carboplatin was released from these microcapsules in a sustained manner for at least 110 days in vitro, that the rate was faster than that of encapsulated carboplatin alone, and that hydroxypropyl α-cyclodextrin protected the carboplatin from degradation. Further, the complex was more effective than carboplatin alone when tested on monolayers of F98 glioma cells. For testing the efficacy of the carboplatin-hydroxypropyl cyclodextrin complex in the rat glioma model, 56 Fischer rats were injected in the left hemisphere with F98 glioma cells. Five days later the rats were randomly divided into seven groups. Median survival of the first control group receiving no treatment was 20 days. The second group receiving an intratumoral injection of carboplatin had a median survival of 1 day, indicating severe cytotoxicity. The third group receiving systemic carboplatin had a median survival of 34 days. Median survival of the fourth group which received empty microcapsules was 24 days. The fifth group, treated with microcapsules loaded with hydroxypropyl α-cyclodextrin alone, showed a median survival of 20 days. The sixth group, treated with microcapsules loaded with carboplatin alone, showed a median survival of 34 days. The seventh group, treated with microcapsules loaded with carboplatin-hydroxypropyl α-cyclodextrin complex, showed a median survival of 51 days. This experiment demonstrated that the microencapsulated carboplatin-hydroxypropyl α-cyclodextrin complex is more effective than the nonencapsulated carboplatin. This study also shows that interstitial delivery of carboplatin-hydroxypropyl cyclodextrin complexes from a microencapsulated formulation is effective against experimental brain tumors.