EXTH-13. IN VIVO THERAPEUTIC POTENTIAL OF IL13-LIPDXR IN A MALIGNANT PERIPHERAL NERVE SHEATH TUMOR MOUSE MODEL Free

Malignant peripheral nerve sheath tumor is a soft tissue sarcoma that poses tremendous challenges for effective therapy. Several therapeutic approaches using drugs such as doxorubicin and rapamycin have been tried in the past with minimum success. Therapeutic resistant property mediated by MDR proteins, in combination with DNA damage repair was proposed as a major cause leading to therapeutic inefficacy of chemotherapeutics in MPNST tumors. To overcome this issue, we encapsulated doxorubicin in lipid nanovesicles and targeted to IL13Rα2, a receptor that is selectively overexpressed in several malignant peripheral nerve sheath tumor cell lines. In the present investigation, a MPNST mouse model was developed using STS26T-Luc cell line stably transfected with luciferase reporter gene. These cells were implanted into the sciatic nerve that could be imaged by Intravital Imaging Spectroscopy (IVIS). After confirming the tumor formation, the mice were injected with 7 mg/kg body weight of (a) IL13 linked liposomal doxorubicin (IL3LIPDXR) (b) unconjugated liposomal doxorubicin (LIPDXR) and (c) control mice injected with equal volume of saline. The mice were treated weekly once for 7 weeks. The mice which received IL13LIPDXR and LIPDXR showed significant reduction in tumor volume compared to the control group. Among the targeted and non-targeted liposomes, IL13LIPDXR showed rapid tumor regression. However, beyond 4 weeks, the drug was ineffective in shrinking or maintaining the tumor volume. This concludes that although the targeted delivery of doxorubicin, seems to be effective initially however in the later course of treatment they are ineffective in controlling the tumor progression. Approaches such as combining doxorubicin with a small molecule Ras inhibitor or other agents in the liposome formulation which are currently underway may help to improve the therapeutic efficacy.