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Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma
Eun Ji Chung1, Yu Cheng, Ramin Morshed
1Institute for Molecular Engineering, The University of Chicago, 5747 S. Ellis Ave. Jones 222, Chicago, IL 60637, USA.
Abstract:
Glioblastoma-targeted drug delivery systems facilitate efficient delivery of chemotherapeutic agents to malignant gliomas, while minimizing systemic toxicity and side effects. Taking advantage of the fibrin deposition that is characteristic of tumors, we constructed spherical, Cy7-labeled, targeting micelles to glioblastoma through the addition of the fibrin-binding pentapeptide, cysteine-arginine-glutamic acid-lysine-alanine, or CREKA. Conjugation of the CREKA peptide to Cy7-micelles increased the average particle size and zeta potential. Upon intravenous administration to GL261 glioma bearing mice, Cy7-micelles passively accumulated at the brain tumor site via the enhanced permeability and retention (EPR) effect, and Cy7-CREKA-micelles displayed enhanced tumor homing via active targeting as early as 1 h after administration, as confirmed via in vivo and ex vivo imaging and immunohistochemistry. Biodistribution of micelles showed an accumulation within the liver and kidneys, leading to micelle elimination via renal clearance and the reticuloendothelial system (RES). Histological evaluation showed no signs of cytotoxicity or tissue damage, confirming the safety and utility of this nanoparticle system for delivery to glioblastoma. Our findings offer strong evidence for the glioblastoma-targeting potential of CREKA-micelles and provide the foundation for CREKA-mediated, targeted therapy of glioma.
Insights
Researchers developed targeted nanoparticles for glioblastoma treatment. These CREKA-micelles effectively target brain tumors, showing promise for safer and more efficient chemotherapy delivery with minimal side effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Glioblastoma treatment faces challenges with drug delivery and systemic toxicity.
- Targeted drug delivery systems are crucial for improving therapeutic efficacy.
- Tumor-specific characteristics, like fibrin deposition, can be exploited for targeted therapies.
Purpose of the Study:
- To develop and evaluate CREKA-peptide-conjugated micelles for targeted glioblastoma drug delivery.
- To assess the in vivo targeting efficiency and safety of these nanoparticles.
- To investigate the potential of CREKA-micelles for enhanced glioma therapy.
Main Methods:
- Construction of spherical, Cy7-labeled micelles conjugated with the fibrin-binding CREKA peptide.
- Intravenous administration of micelles to GL261 glioma-bearing mice.
- In vivo and ex vivo imaging, immunohistochemistry, and histological evaluation for biodistribution, targeting, and safety assessment.
Main Results:
- CREKA conjugation altered micelle particle size and zeta potential.
- Cy7-micelles showed passive accumulation via the EPR effect.
- Cy7-CREKA-micelles demonstrated enhanced active targeting to glioblastoma tumors within 1 hour.
- Biodistribution revealed accumulation in liver and kidneys, with clearance via renal and RES pathways.
- Histological analysis confirmed no cytotoxicity or tissue damage, indicating safety.
Conclusions:
- CREKA-micelles exhibit significant glioblastoma-targeting potential.
- The nanoparticle system is safe and effective for glioblastoma drug delivery.
- This approach provides a foundation for CREKA-mediated targeted glioma therapy.
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