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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth
1Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Abstract:
The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles (PH@LipoMET nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, PH@LipoMET NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing.
Insights
This study introduces LipoMET, a novel dual-functional liposome for cancer therapy. It enhances small interfering RNA (siRNA) delivery, improving gene silencing and tumor suppression for better cancer treatment outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Small interfering RNA (siRNA) delivery for cancer therapy faces challenges due to instability and poor cellular uptake.
- Existing cationic carriers are insufficient for clinical siRNA applications.
- A dual-functional liposome is developed to overcome these limitations.
Purpose of the Study:
- To develop a novel dual-functional liposome (LipoMET) for enhanced siRNA delivery and cancer therapy.
- To leverage metformin's properties for improved anti-oncogenic effects.
- To create an effective system for delivering vascular endothelial growth factor (VEGF)-specific siRNAs.
Main Methods:
- siRNA condensation with polycation and hyaluronate to form a ternary nanocomplex.
- Envelopment of the nanocomplex by LipoMET via membrane fusion, creating PH@LipoMET nanoparticles (NPs).
- In vitro cellular uptake and endosomal escape studies, and in vivo studies using NCI-H460 xenograft models.
Main Results:
- PH@LipoMET NPs demonstrated rapid cellular internalization and effective endosomal escape of siRNA.
- Systemic administration of LipoMET induced apoptosis and inhibited tumor growth.
- PH@LipoMET NPs carrying VEGF-specific siRNA significantly downregulated VEGF expression and enhanced tumor suppression in vivo.
Conclusions:
- LipoMET-based envelope-type nanoparticles represent a promising dual-functional siRNA delivery system.
- This system improves the therapeutic efficacy of oncogene silencing for cancer treatment.
- The combined approach offers a potential strategy for advanced cancer therapy.
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