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CREKA peptide-conjugated dendrimer nanoparticles for glioblastoma multiforme delivery
Jingjing Zhao1, Bo Zhang1, Shun Shen1
1Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China; Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Abstract:
Glioblastoma multiforme (GBM) is the most aggressive central nervous system (CNS) tumor because of its fast development, poor prognosis, difficult control and terrible mortality. Poor penetration and retention in the glioblastoma parenchyma were crucial challenges in GBM nanomedicine therapy. Nanoparticle diameter can significantly influence the delivery efficiency in tumor tissue. Decreasing nanoparticle size can improve the nanoparticle penetration in tumor tissue but decrease the nanoparticle retention effect. Therefore, small nanoparticles with high retention effect in tumor are urgently needed for effective GBM drug delivery. In present study, a small nanoparticle drug delivery system was developed by conjugating fibrin-binding peptide CREKA to Polyamidoamine (PAMAM) dendrimer, where PEGylated PAMAM is used as drug carrier due to its small size and good penetration in tumor and CREKA is used to target the abundant fibrin in GBM for enhanced retention in tumor. In vitro binding ability tests demonstrated that CREKA can significantly enhanced nanoparticle binding with fibrin. In vivo fluorescence imaging of GBM bearing nude mice, ex vivo brain imaging and frozen slices fluorescence imaging further revealed that the CREKA-modified PAMAM achieved higher accumulation and deeper penetration in GBM tissue than unmodified one. These results indicated that the CREKA-modified PAMAM could penetrate the GBM tissue deeply and enhance the retention effect, which was a promising strategy for brain tumor therapy.
Insights
Researchers developed small nanoparticles by adding CREKA peptide to Polyamidoamine (PAMAM) dendrimers. This CREKA-modified PAMAM enhances drug delivery and retention in glioblastoma tumors, offering a promising brain tumor therapy strategy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor treatment outcomes.
- Effective drug delivery to GBM is hindered by poor nanoparticle penetration and retention in tumor tissue.
- Optimizing nanoparticle size is critical for balancing tumor penetration and retention.
Purpose of the Study:
- To develop a small nanoparticle drug delivery system for glioblastoma multiforme (GBM).
- To enhance nanoparticle penetration and retention within the GBM tumor microenvironment.
- To create a novel therapeutic strategy for brain tumor treatment.
Main Methods:
- Conjugation of fibrin-binding peptide CREKA to PEGylated Polyamidoamine (PAMAM) dendrimers.
- In vitro assessment of nanoparticle binding affinity to fibrin.
- In vivo and ex vivo fluorescence imaging in GBM-bearing mice to evaluate nanoparticle biodistribution and tumor penetration.
Main Results:
- CREKA modification significantly enhanced nanoparticle binding to fibrin.
- CREKA-modified PAMAM nanoparticles demonstrated superior accumulation and deeper penetration in GBM tissue compared to unmodified nanoparticles.
- The developed nanoparticles effectively targeted fibrin within the GBM parenchyma.
Conclusions:
- CREKA-modified PAMAM nanoparticles represent a promising strategy for improving drug delivery in glioblastoma.
- The enhanced penetration and retention capabilities offer a novel approach for brain tumor nanomedicine therapy.
- This targeted nanoparticle system holds potential for more effective glioblastoma treatment.
