Targeted delivery of a novel palmitylated D-peptide for antiglioblastoma molecular therapy

Abstract

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.

Keywords::

• Glioblastoma
• p53
• D-peptide
• lipophilic peptide
• cyclic-RGD decorated liposomes

Acknowledgments

The authors thank the financial supports by the “National Basic Research Program of China” (973 Program No. 2007CB935800 and No. 2010CB934000), the “Key New Drug Creation Program” 2009ZX09310-006, Shanghai Postdoctoral Scientific Program 10R21410800, and School of Pharmacy, Fudan University and The Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China.

Declaration of interest

Funding was provided by National Natural Science Foundation of China 81128015, The International Cooperation Projects of Shanghai Science and Technology Committee 11430707900.