POTENTIATION OF ANTICANCER EFFECTS OF MICROENCAPSULATED CARBOPLATIN BY HYDROXYPROPYL ALPHA-CYCLODEXTRIN

Cyclodextrins are cyclic oligosaccharides that can change physicochemi cal properties of drugs by forming inclusion complexes with them. Thes e changes may enhance the therapeutic potential of drugs by diminishin g their decomposition before they enter tissues and by altering how th ey enter tissue. Carboplatin is an anticancer drug that is active agai nst brain tumors and has recently been tested as a potential agent for interstitial chemotherapy. To test whether complex formulation with c yclodextrins would improve interstitial treatment with carboplatin, we studied the efficacy of carboplatin-cyclodextrin complexes, free and encapsulated, in an experimental rat glioma model. Carboplatin hydroxy propyl alpha-cyclodextrin complexes were incorporated into ethylcellul ose 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 alpha-cyclodextrin protected the carboplatin from degradation. Further, the complex was more effec tive than carboplatin alone when tested on monolayers of F98 glioma ce lls. For testing the efficacy of the carboplatin-hydroxypropyl cyclode xtrin complex in the rat glioma model, 56 Fischer rats were injected i n 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 rec eiving an intratumoral injection of carboplatin had a median survival of 1 day, indicating severe cytotoxicity. The third group receiving sy stemic carboplatin had a median survival of 34 days. Median survival o f the fourth group which received empty microcapsules was 24 days. The fifth group, treated with microcapsules loaded with hydroxypropyl alp ha-cyclodextrin alone, showed a median survival of 20 days. The sixth group, treated with microcapsules loaded with carboplatin alone, showe d a median survival of 34 days. The seventh group, treated with microc apsules loaded with carboplatin-hydroxypropyl alpha-cyclodextrin compl ex, showed a median survival of 51 days. This experiment demonstrated that the microencapsulated carboplatin-hydroxypropyl alpha-cyclodextri n complex is more effective than the nonencapsulated carboplatin. This study also shows that interstitial delivery of carboplatin-hydroxypro pyl cyclodextrin complexes from a microencapsulated formulation is eff ective against experimental brain tumors.