Effective
glioblastoma treatment with low toxicity is one of the most difficult challenges in
cancer therapy. The interaction between
tumor suppressor protein p53 and its negative regulator murine double minute 2 (MDM2) provides a promising target for specific
therapy because an important subtype of
glioblastoma harbors wild-type p53 and overexpressed MDM2. Several D-
peptides have been previously reported to effectively antagonize MDM2 for binding to p53 with high affinity and unsurpassed specificity. However, poor cell penetration and lack of efficient delivery method hampered the therapeutic applicability of the most potent D-
peptide, D-PMIβ. In this study, a novel lipophilic derivate of D-PMIβ (pDP) was developed.
Liposome was chosen as a carrier for pDP, and cyclic pentapeptide c(RGDyK) was used as a targeting moiety for the treatment of
glioblastoma. D-PMIβ was N-terminally modified with
palmitic acid and the resultant c(RGDyK) decorated
liposomes (RGD-liposomal pDP) showed almost 100% encapsulation efficiency and 10% loading efficiency. The abilities of palmitylated D-
peptide to antagonize MDM2 and reactivate p53 specifically were confirmed by the western blot assay. The IC50 ratio of RGD-liposomal pDP in treating human umbilical vascular endothelial normal cells vs. U87
tumor cells was 10 times higher than that of RGD-
liposomal doxorubicin. After
intravenous administration, the median survival time of intracranial U87
glioblastoma-bearing nude mice treated with RGD-liposomal pDP (29 days) was significant longer than that of mice treated with blank RGD-
liposome (23 days) (p<0.001). These results indicated that palmitylated D-
peptide inhibitor of p53-MDM2 combined with RGD modified
liposomes provided a potential molecular
therapy for
glioblastoma.