Localized RNAi Therapeutics of Chemoresistant Grade IV Glioma Using Hyaluronan-Grafted Lipid-Based Nanoparticles
Abstract
Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP's surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM.
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The hyaluronic acid functionalized lipid nanoparticles delivered siRNA against PLK1, which is involved in the malignant transformation of glioma cells.
“These smart nanoparticles were employed to deliver siRNA against PLK1, which is involved in the malignant transformation of glioma cells.279”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [279]
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- Authors
- Cohen, Z. R., Ramishetti, S., Peshes-Yaloz, N., Goldsmith, M., Wohl, A., Zibly, Z., & Peer, D.
- Affiliations
- Sheba Medical Center (IL)
- Tel Aviv University (IL)
- Department of Neurosurgery, Sheba Medical Center, Ramat Gan, Israel
- Houston Methodist (US)
- Corresponding author
- Peer, Dan
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-01-08
- Volume
- 9
- Issue
- 2
- Pages
- 1581-1591
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- OpenAlex
- W2137042343
- Cited by
- 182
- References
- 52
- Citations by year
- 2026: 4 · 2025: 20 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 18 · 2020: 17 · 2019: 19 · 2018: 13 · 2017: 23 · 2016: 19 · 2015: 10
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel - MOST (880011)
- Israel Cancer Association (20130092)
- Israel Science Foundation (41/11)
- Leona M. and Harry B. Helmsley Charitable Trust (2012PG-ISL008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- glioblastoma, RNA interference, siRNA delivery, hyaluronic acid, lipid nanoparticles, CD44 receptor, PLK1, chemoresistance, blood-brain barrier, orthotopic xenograft, local drug delivery, nanoparticle functionalization, neurospheres
- MeSH terms
- RNAi Therapeutics, Polo-Like Kinase 1, Animals, Biological Transport, Cell Transformation, Neoplastic, Drug Carriers, Glioblastoma, Humans, Hyaluronic Acid, Lipids, Mice, Inbred BALB C, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Cell Death, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Hyaluronan Receptors, Drug Resistance, Neoplasm, Gene Silencing, Cell Line, Tumor, Mice, Nanoparticles, Neoplasm Grading
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