Endosomolytic and Tumor-Penetrating Mesoporous Silica Nanoparticles for siRNA/miRNA Combination Cancer Therapy
2020
Combination therapies consisting
of multiple short therapeutic
RNAs, such as small interfering RNA (siRNA) and microRNA (miRNA),
have enormous potential in cancer treatment as they can precisely
silence a specific set of oncogenes and target multiple disease-related
pathways. However, clinical use of siRNA/miRNA combinations is limited
by the availability of safe and efficient systemic delivery systems
with sufficient tumor penetrating and endosomal escaping capabilities.
This study reports on the development of multifunctional tumor-penetrating
mesoporous silica nanoparticles (iMSNs) for simultaneous delivery
of siRNA (siPlk1) and miRNA (miR-200c), using encapsulation of a photosensitizer
indocyanine green (ICG) to facilitate endosomal escape and surface
conjugation of the iRGD peptide to enable deep tumor penetration.
Increased cell uptake of the nanoparticles was observed in both 3D
tumor spheroids in vitro and in orthotopic MDA-MB-231 breast tumors
in vivo. Using a galectin-8 recruitment assay, we showed that reactive
oxygen species generated by ICG upon light irradiation functioned
as an endosomolytic stimulus that caused release of the siRNA/miRNA
combination from endosomes. Co-delivery of the therapeutic RNAs displayed
combined cell killing activity in cancer cells. Systemic intravenous
treatment of metastatic breast cancer with the iMSNs loaded with siPlk1
and miR-200c resulted in a significant suppression of the primary
tumor growth and in marked reduction of metastasis upon short light
irradiation of the primary tumor. This work demonstrates that siRNA-miRNA
combination assisted by the photodynamic effect and tumor penetrating
delivery system may provide a promising approach for metastatic cancer
treatment.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
57
References
48
Citations
NaN
KQI