In recent years,
chemotherapy with
caffeine has manifested potently high efficacy against
osteosarcoma, although adverse effects have been observed. Recently, we developed a novel drug delivery system (DDS) with nonionic vesicles prepared from
Span 80 which have promising physicochemical properties as an attractive possible alternative to commonly used
liposomes. Herein, we demonstrated that
tumor-specific
caffeine-potentiated
chemotherapy for murine
osteosarcoma administered by a novel DDS with
Span 80 nano-vesicles showed significant antitumor effects as well as limited adverse effects. The
osteosarcoma cell line, LM8, was transplanted into C3H/HeJ mice which then were administered therapeutic agents.
Ifosfamide (IFO) was employed as well as
caffeine as an enhancer.
Span 80 vesicles containing IFO and/or
caffeine were freshly prepared. On days 0, 2 and 4, different combinations of the agents were administered to mice: IFO alone (direct i.v.), IFO vesicles (IV), IV+caffeine, IV+caffeine vesicles (CV), PBS alone vesicles (PV), and PBS alone as negative control (PBS i.v.). Then, the mice were sacrificed on day 7. Antitumor effects of the
reagents were also analyzed in vitro. Moreover, fertility examination was performed. In vitro, a combination of IV+CV showed significant induction of apoptosis in the early phase.
Tumor volumes in the IV+CV group were significantly reduced compared with the other groups. Histological analyses showed that the IV and IV+CV groups had significantly lower viable
tumor areas. The IFO direct i.v. group showed a certain grade of renal injury as well as marked suppression of spermatogenesis, while the IV or IV+CV group showed no marked changes. The fertility test revealed that the male mice with IV+CV administration had normal fertility, and no malformations were detected in their progeny. This DDS model is of potential importance for clinical application in the
therapy of metastatic
osteosarcoma.