Versatile RNA Interference Nanoplatform for Systemic Delivery of RNAs
Open accessAbstract
Development of nontoxic, tumor-targetable, and potent in vivo RNA delivery systems remains an arduous challenge for clinical application of RNAi therapeutics. Herein, we report a versatile RNAi nanoplatform based on tumor-targeted and pH-responsive nanoformulas (NFs). The NF was engineered by combination of an artificial RNA receptor, Zn(II)-DPA, with a tumor-targetable and drug-loadable hyaluronic acid nanoparticle, which was further modified with a calcium phosphate (CaP) coating by in situ mineralization. The NF can encapsulate small-molecule drugs within its hydrophobic inner core and strongly secure various RNA molecules (siRNAs, miRNAs, and oligonucleotides) by utilizing Zn(II)-DPA and a robust CaP coating. We substantiated the versatility of the RNAi nanoplatform by demonstrating effective delivery of siRNA and miRNA for gene silencing or miRNA replacement into different human types of cancer cells in vitro and into tumor-bearing mice in vivo by intravenous administration. The therapeutic potential of NFs coloaded with an anticancer drug doxorubicin (Dox) and multidrug resistance 1 gene target siRNA (siMDR) was also demonstrated in this study. NFs loaded with Dox and siMDR could successfully sensitize drug-resistant OVCAR8/ADR cells to Dox and suppress OVCAR8/ADR tumor cell proliferation in vitro and tumor growth in vivo. This gene/drug delivery system appears to be a highly effective nonviral method to deliver chemo- and RNAi therapeutics into host cells.
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ABCG2 plays an important role in ABC-dependent drug efflux, is capable of transporting chemotherapeutic agents such as paclitaxel and doxorubicin, and confers drug resistance leading to high recurrence and poor survival in hepatocellular carcinoma patients.
“Among them, ABCG2, one of the initially discovered transporters, plays an important role in the ABC-dependent drug efflux, and is capable of transporting a broad range of chemotherapeutic agents such as paclitaxel and doxorubicin (DOX), thus conferring the drug resistance and further leading to high recurrence and poor survival of patients bearing HCC.11–13”
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- Authors
- Choi, K. Y., Silvestre, O. F., Huang, X., Min, K. H., Howard, G. P., Hida, N., Jin, A. J., Carvajal, N., Lee, S. W., Hong, J.-I., & Chen, X.
- Affiliations
- National Institutes of Health (US)
- National Institutes of Health Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, , , ,
- Koch Institute for Integrative Cancer Research At MIT (US)
- Seoul National University (KR)
- Corresponding author
- Chen, Xiaoyuan
- ORCID
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-04-29
- Volume
- 8
- Issue
- 5
- Pages
- 4559-4570
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- PMC
- PMC4046792
- OpenAlex
- W1846581508
- Cited by
- 104
- References
- 29
- Citations by year
- 2025: 4 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 12 · 2018: 15 · 2017: 12 · 2016: 11 · 2015: 10 · 2014: 6
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Nano (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Keywords
- RNA interference, siRNA delivery, microRNA delivery, hyaluronic acid nanoparticles, calcium phosphate coatings, pH-responsive nanoparticles, tumor targeting, intravenous delivery, doxorubicin, multidrug resistance 1, gene silencing
- MeSH terms
- Animals, Calcium, Doxorubicin, Drug Carriers, Endocytosis, Female, Humans, Hyaluronic Acid, Hyaluronoglucosaminidase, Hydrogen-Ion Concentration, Ions, Mice, Nude, Phosphates, RNA, Gene Transfer Techniques, Hyaluronan Receptors, Gene Silencing, RNA Interference, RNA, Small Interfering, MicroRNAs, Cell Line, Tumor, Cell Proliferation, Nanostructures, Mice, Nanoparticles
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