T. Utsuki et al., POTENTIATION OF ANTICANCER EFFECTS OF MICROENCAPSULATED CARBOPLATIN BY HYDROXYPROPYL ALPHA-CYCLODEXTRIN, Journal of controlled release, 40(3), 1996, pp. 251-260
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.