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Published on: June 13, 2014
Cancer Therapy with Nanoparticle-Medicated Intracellular Expression of Peptide CRM1-Inhibitor
Min Sui1, Meimei Xiong2, Yuling Li1
1Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, People's Republic of China.
Introduction:
Peptides can be rationally designed as non-covalent inhibitors for molecularly targeted therapy. However, it remains challenging to efficiently deliver the peptides into the targeted cells, which often severely affects their therapeutic efficiency.
Methods:
Herein, we created a novel non-covalent peptide inhibitor against nuclear export factor CRM1 by a structure-guided drug design method and targetedly delivered the peptide into cancer cells by a nanoparticle-mediated gene expression system for use as a cancer therapy.
Results:
The nuclear export signal (NES)-optimized CRM1 peptide inhibitor colocalized with CRM1 to the nuclear envelope and inhibited nuclear export in cancer cell lines in vitro. The crystal structures of the inhibitors complexed with CRM1 were solved. In contrast to the covalent inhibitors, the peptides were similarly effective against cells harboring the CRM1 C528S mutation. Moreover, a plasmid encoding the peptides was delivered by a iRGD-modified nanoparticle to efficiently target and transfect the cancer cells in vivo after intravenous administration. The peptides could be selectively expressed in the tumor, resulting in the efficient inhibition of subcutaneous melanoma xenografts without obvious systemic toxicity.
Discussion:
This work provides an effective strategy to design peptide-based molecularly targeted therapeutics, which could lead to the development of future targeted therapy.
Insights
This study developed a novel peptide inhibitor for cancer therapy that effectively targets cancer cells using nanoparticles. The peptide successfully inhibited tumor growth in vivo with minimal toxicity, offering a promising new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Peptides offer potential as non-covalent inhibitors for targeted cancer therapy.
- Efficient intracellular delivery of peptide inhibitors remains a significant challenge, limiting therapeutic efficacy.
Purpose of the Study:
- To design a novel non-covalent peptide inhibitor targeting the nuclear export factor CRM1.
- To develop a nanoparticle-mediated system for targeted delivery and expression of the peptide inhibitor in cancer cells for therapeutic purposes.
Main Methods:
- Structure-guided drug design was employed to create a peptide inhibitor against CRM1.
- A nanoparticle-mediated gene expression system, modified with iRGD, was utilized for targeted delivery.
- In vitro and in vivo studies were conducted to evaluate the inhibitor's efficacy and toxicity.
Main Results:
- The CRM1 peptide inhibitor demonstrated effective inhibition of nuclear export in cancer cell lines.
- Crystal structures revealed inhibitor-CRM1 complexes, showing efficacy against CRM1 mutations.
- In vivo studies showed targeted delivery and selective expression in tumors, leading to significant inhibition of melanoma xenografts with low systemic toxicity.
Conclusions:
- This research presents a viable strategy for designing peptide-based targeted therapeutics.
- The developed nanoparticle delivery system enhances the therapeutic potential of peptide inhibitors.
- This approach may pave the way for advanced targeted cancer therapies.
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