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Targeted delivery of a novel palmitylated D-peptide for antiglioblastoma molecular therapy
Chong Li1, Jie Shen, Xiaoli Wei
1School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Fudan University, Shanghai, China.
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.
Insights
A novel lipophilic D-peptide derivative, pDP, delivered via RGD-modified liposomes, effectively targets glioblastoma by inhibiting the p53-MDM2 interaction. This approach shows reduced toxicity and improved survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Nanomedicine
Background:
- Glioblastoma treatment faces challenges due to low toxicity and specific therapeutic targets.
- The p53-MDM2 interaction is a promising target, especially in glioblastomas with wild-type p53 and overexpressed MDM2.
- Existing D-peptide inhibitors like D-PMIβ have limitations in cell penetration and delivery.
Purpose of the Study:
- To develop a novel lipophilic derivative of D-PMIβ (pDP) for enhanced glioblastoma therapy.
- To utilize liposomes as a delivery system for pDP, decorated with c(RGDyK) for targeting glioblastoma.
- To evaluate the efficacy and safety of RGD-liposomal pDP in preclinical glioblastoma models.
Main Methods:
- N-terminal modification of D-PMIβ with palmitic acid to create pDP.
- Encapsulation of pDP into liposomes functionalized with c(RGDyK) targeting moiety.
- In vitro assays (Western blot) to confirm MDM2 antagonism and p53 reactivation; IC50 determination.
- In vivo studies using intracranial U87 glioblastoma xenografts in nude mice to assess survival.
Main Results:
- RGD-liposomal pDP achieved high encapsulation (approx. 100%) and loading (10%) efficiencies.
- Palmitylated D-peptide demonstrated specific MDM2 antagonism and p53 reactivation in vitro.
- RGD-liposomal pDP exhibited significantly lower toxicity towards normal cells compared to U87 tumor cells (10x IC50 ratio).
- Intravenous administration of RGD-liposomal pDP significantly increased median survival in glioblastoma-bearing mice (29 days vs. 23 days).
Conclusions:
- Liposomal delivery of a palmitylated D-peptide inhibitor (pDP) targeting the p53-MDM2 pathway is a viable strategy for glioblastoma.
- The RGD targeting moiety enhances specificity and therapeutic potential.
- This combination therapy offers a promising low-toxicity molecular approach for glioblastoma treatment.
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