Targeted delivery of a novel palmitylated D-peptide for antiglioblastoma molecular therapy.
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.
School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Fudan University, Shanghai, China.
Chong
C
Li
Jie
J
Shen
Xiaoli
X
Wei
Cao
C
Xie
Weiyue
W
Lu
D000215:Acylation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004339:Drug Compounding; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D055666:Lipopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009842:Oligopeptides / Q000737:chemistry; D019308:Palmitic Acid / Q000737:chemistry; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D011897:Random Allocation; D013237:Stereoisomerism; D013499:Surface Properties; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004337:Drug Carriers; D055666:Lipopeptides; D008081:Liposomes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D016159:Tumor Suppressor Protein p53; D019308:Palmitic Acid; C047981:arginyl-glycyl-aspartic acid; D051736:Proto-Oncogene Proteins c-mdm2