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Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Published on: January 4, 2012
Nanoparticle delivery of a peptide targeting EGFR signaling
1Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Abstract:
EGFR serves as an important therapeutic target because of its over-expression in many cancers. In this study, we investigated a peptide-based therapy aimed at blocking intracellular protein-protein interactions during EGFR signaling and evaluated a targetable lipid carrier system that can deliver peptides to intracellular targets in human cancer cells. EEEEpYFELV (EV), a nonapeptide mimicking the Y845 site of EGFR which is responsible for STAT5b phosphorylation, was designed to block EGFR downstream signaling. EV was loaded onto LPH nanoparticles that are comprised of a membrane/core structure including a surface-grafted polyethylene glycol (PEG) used to evade the reticuloendothelial system (RES) and anisamide (AA) for targeting the sigma receptor over-expressed in H460 human lung cancer cells. EV formulated with PEGylated and targeted LPH (LPH-PEG-AA) was taken up by the tumor cells and trafficked to the cytoplasm with high efficiency. Using this approach, EV acted as a dominant negative inhibitor of STAT5b phosphorylation, arrested cell proliferation, and induced massive apoptosis. Intravenous administration of EV loaded in LPH-PEG-AA led to efficient EV peptide delivery to the tumor in a xenograft mouse model, and multiple injections inhibited tumor growth in a dose-dependent manner. Our findings offer proof-of-concept for an intracellular peptide-mediated cancer therapy that is delivered by carefully designed nanoparticles.
Insights
This study introduces a novel peptide therapy targeting EGFR signaling. Lipid nanoparticles effectively deliver this peptide into cancer cells, inhibiting tumor growth and offering a new cancer treatment strategy.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Epidermal Growth Factor Receptor (EGFR) is over-expressed in many cancers, making it a key therapeutic target.
- Blocking intracellular protein-protein interactions in EGFR signaling offers a potential therapeutic strategy.
- Developing effective delivery systems for intracellular peptide therapies is crucial.
Purpose of the Study:
- To investigate a peptide-based therapy targeting intracellular EGFR signaling.
- To evaluate a lipid nanoparticle system for delivering peptides to intracellular targets in cancer cells.
- To assess the therapeutic efficacy of this approach in preclinical cancer models.
Main Methods:
- Designed a nonapeptide (EV) mimicking EGFR's Y845 site to inhibit STAT5b phosphorylation.
- Loaded EV onto lipid-based nanoparticles (LPH) functionalized with PEG and anisamide (AA) for targeting and stealth.
- Evaluated nanoparticle uptake, intracellular trafficking, and therapeutic effects in human cancer cells and a xenograft mouse model.
Main Results:
- PEGylated and targeted LPH nanoparticles efficiently delivered EV to the cytoplasm of tumor cells.
- EV acted as a dominant-negative inhibitor of STAT5b phosphorylation, halting cell proliferation and inducing apoptosis.
- Intravenous administration of EV-loaded nanoparticles inhibited tumor growth in a dose-dependent manner in mice.
Conclusions:
- This study provides proof-of-concept for an intracellular peptide-mediated cancer therapy.
- Carefully designed nanoparticles can effectively deliver therapeutic peptides to intracellular targets.
- This approach holds promise for developing novel cancer treatments targeting EGFR signaling pathways.
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