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Porous Silicon Microparticles for Delivery of siRNA Therapeutics
Published on: January 15, 2015
A Facile and Promising Delivery Platform for siRNA to Solid Tumors
Qixin Leng1, Aishwarya Anand1, A James Mixson1
1Department of Pathology, University of Maryland School of Medicine, 10 S. Pine St., Baltimore, MD 21201, USA.
Abstract:
Over 20 years have passed since siRNA was brought to the public's attention. Silencing genes with siRNA has been used for various purposes, from creating pest-resistant plants to treating human diseases. In the last six years, several siRNA therapies have been approved by the FDA, which solely target disease-inducing proteins in the liver. The extrahepatic utility of systemically delivered siRNA has been primarily limited to preclinical studies. While siRNA targeting the liver comprises relatively simple ligand-siRNA conjugates, siRNA treating extrahepatic diseases such as cancer often requires complex carriers. The complexity of these extrahepatic carriers of siRNA reduces the likelihood of their widespread clinical use. In the current report, we initially demonstrated that a linear histidine-lysine (HK) carrier of siRNA, injected intravenously, effectively silenced luciferase expressed by MDA-MB-435 tumors in a mouse model. This non-pegylated linear peptide carrier was easily synthesized compared to the complex cRGD-conjugated pegylated branched peptides our group used previously. Notably, the tumor-targeting component, KHHK, was embedded within the peptide, eliminating the need to conjugate the ligand to the carrier. Moreover, brief bath sonication significantly improved the in vitro and in vivo silencing of these HK siRNA polyplexes. Several other linear peptides containing the -KHHK- sequence were then screened with some carriers of siRNA, silencing 80% of the tumor luciferase marker. Additionally, silencing by these HK siRNA polyplexes was confirmed in a second tumor model. Not only was luciferase activity reduced, but these siRNA polyplexes also reduced the Raf-1 oncogene in the MDA-MB-231 xenografts. These simple-to-synthesize, effective, linear HK peptides are promising siRNA carriers for clinical use.
Insights
Simple linear peptide carriers effectively deliver small interfering RNA (siRNA) to tumors, offering a promising new strategy for extrahepatic gene silencing and potential cancer therapies.
Area of Science:
- Biotechnology
- Molecular Biology
- Cancer Research
Background:
- Small interfering RNA (siRNA) has potential for treating diseases, but systemic delivery for extrahepatic targets remains challenging.
- Current FDA-approved siRNA therapies primarily target the liver, often using complex carriers for extrahepatic applications.
- The complexity of existing carriers hinders the widespread clinical use of siRNA for treating diseases outside the liver.
Purpose of the Study:
- To develop and evaluate a simple, effective linear peptide carrier for systemic siRNA delivery to extrahepatic tumors.
- To assess the efficacy of histidine-lysine (HK) peptide-siRNA polyplexes in silencing tumor-specific gene expression in vivo.
- To investigate the impact of brief bath sonication on the silencing efficiency of HK siRNA polyplexes.
Main Methods:
- Systemic intravenous injection of linear histidine-lysine (HK) peptide-siRNA polyplexes in a mouse model with MDA-MB-435 tumors.
- Assessment of gene silencing by measuring luciferase activity in tumors.
- Screening of various linear peptides containing the -KHHK- sequence for siRNA delivery efficacy.
- Confirmation of silencing in a second tumor model (MDA-MB-231 xenografts) and evaluation of oncogene (Raf-1) reduction.
Main Results:
- Linear HK peptide-siRNA polyplexes effectively silenced luciferase expression in MDA-MB-435 tumors.
- Brief bath sonication significantly enhanced both in vitro and in vivo silencing.
- Screening identified several linear peptides with the -KHHK- sequence that silenced up to 80% of the tumor luciferase marker.
- Silencing was confirmed in a second tumor model, with significant reduction in both luciferase activity and Raf-1 oncogene expression.
Conclusions:
- Simple, easily synthesized linear HK peptides are effective carriers for systemic siRNA delivery to extrahepatic tumors.
- These HK siRNA polyplexes demonstrate significant gene silencing capabilities, including oncogene reduction, in preclinical models.
- The developed HK peptide carriers show great promise for future clinical applications in treating extrahepatic diseases like cancer.
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