Targeted nanoparticle delivery of therapeutic antisense microRNAs presensitizes glioblastoma cells to lower effective doses of temozolomide in vitro and in a mouse model
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// Meenakshi Malhotra 1 , Thillai Veerapazham Sekar 2 , Jeyarama S. Ananta 1 , Rammohan Devulapally 2 , Rayhaneh Afjei 1 , Husam A. Babikir 1 , Ramasamy Paulmurugan 2 and Tarik F. Massoud 1 1 Laboratory for Experimental and Molecular Neuroimaging (LEMNI), Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Cellular Pathway Imaging Laboratory (CPIL), Molecular Imaging Program at Stanford, Stanford University School of Medicine, Palo Alto, CA 94305, USA Correspondence to: Tarik F. Massoud, email: tmassoud@stanford.edu Ramasamy Paulmurugan, email: paulmur8@stanford.edu Keywords: antagomiR; chemotherapy; microRNA-21; microRNA-10b; PLGA Received: February 09, 2018 Accepted: March 28, 2018 Published: April 20, 2018 ABSTRACT Temozolomide (TMZ) chemotherapy for glioblastoma (GBM) is generally well tolerated at standard doses but it can cause side effects. GBMs overexpress microRNA-21 and microRNA-10b, two known oncomiRs that promote cancer development, progression and resistance to drug treatment. We hypothesized that systemic injection of antisense microRNAs (antagomiR-21 and antagomiR-10b) encapsulated in cRGD-tagged PEG-PLGA nanoparticles would result in high cellular delivery of intact functional antagomiRs, with consequent efficient therapeutic response and increased sensitivity of GBM cells to lower doses of TMZ. We synthesized both targeted and non-targeted nanoparticles, and characterized them for size, surface charge and encapsulation efficiency of antagomiRs. When using targeted nanoparticles in U87MG and Ln229 GBM cells, we showed higher uptake-associated improvement in sensitivity of these cells to lower concentrations of TMZ in medium. Co-inhibition of microRNA-21 and microRNA-10b reduced the number of viable cells and increased cell cycle arrest at G2/M phase upon TMZ treatment. We found a significant increase in expression of key target genes for microRNA-21 and microRNA-10b upon using targeted versus non-targeted nanoparticles. There was also significant reduction in tumor volume when using TMZ after pre-treatment with loaded nanoparticles in human GBM cell xenografts in mice. In vivo targeted nanoparticles plus different doses of TMZ showed a significant therapeutic response even at the lowest dose of TMZ, indicating that preloading cells with antagomiR-21 and antagomiR-10b increases cellular chemosensitivity towards lower TMZ doses. Future clinical applications of this combination therapy may result in improved GBM response by using lower doses of TMZ and reducing nonspecific treatment side effects.
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miR-21 is overexpressed in almost all cancer types, and its upregulation promotes cell proliferation, invasion, and metastatic behavior.
“miR-21 is a well-known miRNA, found to be overexpressed in almost all cancer types, where its upregulation promotes cell proliferation, invasion, and metastatic behavior.”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [23]
The Introduction identifies miR-21 as an oncomiR overexpressed in the majority of glioblastomas, and the Discussion links miR-21 downregulation to decreased proliferation. The source does not establish overexpression in almost all cancer types; its explicit account of increased invasion concerns miR-10b, while its mention of metastasis concerns miRNAs generally, not miR-21 specifically. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredmiR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways.
“miR-21 targets several genes such as PDCD4, TIMP3, and RECK, which are key regulators of apoptotic and metastatic pathways (17–23).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [23]
The Introduction (page unavailable) lists PDCD4, TIMP3, and RECK as associated targets of miR-21. The Discussion (page unavailable) links PDCD4 to increased apoptosis, but the paper does not identify TIMP3 or RECK as key regulators of apoptotic or metastatic pathways. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOverexpressed miR-21 in cell lines can increase the proliferation rate and malignant behavior of the cells.
“Our data on the effects of miR-21 enriched exosomes is in agreement with the previous reports demonstrating that overexpressed miR-21 in cell lines can increase the proliferation rate and malignant behavior of the cells (17–23).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [23]
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- Authors
- Malhotra, M., Sekar, T. V., Ananta, J. S., Devulapally, R., Afjei, R., Babikir, H. A., Paulmurugan, R., & Massoud, T. F.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Massoud, Tarik F.
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2018-04-20
- Volume
- 9
- Issue
- 30
- Pages
- 21478-21494
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5940368
- OpenAlex
- W2802627587
- Cited by
- 71
- References
- 42
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 12 · 2022: 7 · 2021: 15 · 2020: 12 · 2019: 15
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ben and Catherine Ivy Foundation
- National Institutes of Health
- National Cancer Institute (U54CA199075)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- glioblastoma, temozolomide, PLGA-PEG nanoparticles, nanoparticle drug delivery, chemosensitization, oncogenic microRNA, G2/M cell cycle arrest, tumor growth inhibition, xenograft mouse model, U87 cells
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