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Updated: Jul 15, 2026
Preparation of Neutrally-charged, pH-responsive Polymeric Nanoparticles for Cytosolic siRNA Delivery
Published on: May 2, 2019
Materializing the potential of small interfering RNA via a tumor-targeting nanodelivery system
Kathleen F Pirollo1, Antonina Rait, Qi Zhou
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA.
Abstract:
The field of small interfering RNA (siRNA) as potent sequence-selective inhibitors of transcription is rapidly developing. However, until now, low transfection efficiency, poor tissue penetration, and nonspecific immune stimulation by in vivo administered siRNAs have delayed their therapeutic application. Their potential as anticancer therapeutics hinges on the availability of a vehicle that can be systemically administered, safely and repeatedly, and will deliver the siRNA specifically and efficiently to the tumor, both primary tumors and metastases. We have developed a nanosized immunoliposome-based delivery complex (scL) that, when systemically administered, will preferentially target and deliver molecules useful in gene medicine, including plasmid DNA and antisense oligonucleotides, to tumor cells wherever they occur in the body. This tumor-targeting nanoparticle delivery vehicle can also deliver siRNA to both primary and metastatic disease. We have also enhanced the efficiency of this complex by the inclusion of a pH-sensitive histidine-lysine peptide in the complex (scL-HoKC) and by delivery of a modified hybrid (DNA-RNA) anti-HER-2 siRNA molecule. Scanning probe microscopy confirms that this modified complex maintains its nanoscale size. More importantly, we show that this nanoimmunoliposome anti-HER-2 siRNA complex can sensitize human tumor cells to chemotherapeutics, silence the target gene and affect its downstream pathway components in vivo, and significantly inhibit tumor growth in a pancreatic cancer model. Thus, this complex has the potential to help translate the potent effects of siRNA into a clinically viable anticancer therapeutic.
Insights
Researchers developed a novel nano-immunoliposome delivery system for small interfering RNA (siRNA) to target tumors. This advanced nanoparticle enhances siRNA delivery, showing significant potential for effective cancer therapy and improved treatment outcomes.
Area of Science:
- Nanotechnology in drug delivery
- RNA interference (RNAi) therapeutics
- Oncology and cancer research
Background:
- Small interfering RNA (siRNA) shows promise as a sequence-selective inhibitor of transcription.
- Therapeutic applications of siRNA are hindered by low transfection efficiency, poor tissue penetration, and immune stimulation.
- Effective delivery of siRNA to primary and metastatic tumors is crucial for anticancer therapeutics.
Purpose of the Study:
- To develop a systemically administrable, tumor-targeting delivery vehicle for siRNA.
- To enhance siRNA delivery efficiency and specificity for both primary and metastatic cancers.
- To evaluate the therapeutic potential of the developed siRNA delivery complex in a pancreatic cancer model.
Main Methods:
- Development of a nanosized immunoliposome-based delivery complex (scL) for targeting tumor cells.
- Enhancement of the delivery complex with a pH-sensitive histidine-lysine peptide (scL-HoKC).
- Utilized a modified hybrid (DNA-RNA) anti-HER-2 siRNA molecule.
- Confirmed nanoscale size using scanning probe microscopy.
- Evaluated in vivo gene silencing, downstream pathway effects, and tumor growth inhibition in a pancreatic cancer model.
Main Results:
- The developed nano-immunoliposome complex (scL-HoKC) effectively delivers siRNA to tumor cells, including primary and metastatic sites.
- The complex demonstrated the ability to sensitize human tumor cells to chemotherapeutics.
- In vivo studies showed significant inhibition of tumor growth in a pancreatic cancer model, alongside target gene silencing and affected downstream pathways.
Conclusions:
- The nano-immunoliposome siRNA delivery complex offers a promising solution to overcome existing challenges in siRNA therapeutics.
- This delivery system has the potential to enable specific and efficient targeting of siRNA to tumors.
- The developed complex represents a significant step towards translating siRNA's therapeutic potential into a clinically viable anticancer treatment.
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