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Preparation of Neutrally-charged, pH-responsive Polymeric Nanoparticles for Cytosolic siRNA Delivery
Published on: May 2, 2019
Actively-targeted polyion complex micelles stabilized by cholesterol and disulfide cross-linking for systemic
Yusuke Oe1, R James Christie1, Mitsuru Naito2
1Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract:
For small interfering RNA (siRNA)-based cancer therapies, we report an actively-targeted and stabilized polyion complex micelle designed to improve tumor accumulation and cancer cell uptake of siRNA following systemic administration. Improvement in micelle stability was achieved using two stabilization mechanisms; covalent disulfide cross-linking and non-covalent hydrophobic interactions. The polymer component was designed to provide disulfide cross-linking and cancer cell-targeting cyclic RGD peptide ligands, while cholesterol-modified siRNA (Chol-siRNA) provided additional hydrophobic stabilization to the micelle structure. Dynamic light scattering confirmed formation of nano-sized disulfide cross-linked micelles (<50 nm in diameter) with a narrow size distribution. Improved stability of Chol-siRNA-loaded micelles (Chol-siRNA micelles) was demonstrated by resistance to both the dilution in serum-containing medium and counter polyion exchange with dextran sulfate, compared to control micelles prepared with Chol-free siRNA (Chol-free micelles). Improved stability resulted in prolonged blood circulation time of Chol-siRNA micelles compared to Chol-free micelles. Furthermore, introduction of cRGD ligands onto Chol-siRNA micelles significantly facilitated accumulation of siRNA in a subcutaneous cervical cancer model following systemic administration. Ultimately, systemically administered cRGD/Chol-siRNA micelles exhibited significant gene silencing activity in the tumor, presumably due to their active targeting ability combined with the enhanced stability through both hydrophobic interactions of cholesterol and disulfide cross-linking.
Insights
We developed stable, targeted micelles for small interfering RNA (siRNA) cancer therapy. These micelles enhance siRNA delivery to tumors, improving gene silencing and cancer treatment efficacy.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapy
Background:
- Small interfering RNA (siRNA) holds promise for cancer therapy but faces challenges in delivery and stability.
- Systemic administration of siRNA requires effective strategies to prevent degradation and ensure tumor accumulation.
- Developing stable, targeted nanocarriers is crucial for successful siRNA-based cancer treatments.
Purpose of the Study:
- To design and characterize actively-targeted and stabilized polyion complex micelles for enhanced siRNA delivery in cancer therapy.
- To improve tumor accumulation and cancer cell uptake of siRNA via systemic administration.
- To evaluate the stability, pharmacokinetics, and gene silencing efficacy of the developed siRNA micelles.
Main Methods:
- Fabrication of polyion complex micelles using disulfide cross-linking and cholesterol-modified siRNA (Chol-siRNA) for enhanced stability.
- Incorporation of cyclic RGD (cRGD) peptides for active tumor targeting.
- Characterization of micelle size and stability using dynamic light scattering (DLS) and resistance assays.
- In vivo evaluation of micelle pharmacokinetics, tumor accumulation, and gene silencing in a subcutaneous cervical cancer model.
Main Results:
- Formation of nano-sized (<50 nm) disulfide cross-linked micelles with narrow size distribution.
- Chol-siRNA micelles demonstrated superior stability against serum dilution and polyion exchange compared to control micelles.
- Enhanced stability led to prolonged blood circulation times for Chol-siRNA micelles.
- Systemic administration of cRGD/Chol-siRNA micelles significantly increased siRNA accumulation in tumors.
- Significant gene silencing activity was observed in tumors treated with cRGD/Chol-siRNA micelles.
Conclusions:
- Actively-targeted and stabilized polyion complex micelles effectively enhance siRNA delivery for cancer therapy.
- Dual stabilization mechanisms (disulfide cross-linking and cholesterol modification) improve micelle stability and circulation time.
- Active targeting with cRGD ligands facilitates tumor accumulation and subsequent gene silencing.
- This nanomicelle platform shows significant potential for improving systemic siRNA-based cancer treatments.
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