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Ultrasmall nanoparticles for co-delivery of antisense oligonucleotides targeting miR-21 and miR-210 to treat
Ravi Raj Singh1,2,3, Ritu Kulshreshtha4, Amirali Popat5,6
1School of Pharmacy and Pharmaceutical Sciences, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Abstract:
Glioblastoma (GBM) is the most common and aggressive type of brain tumour, with less than 5% of patients surviving more than 5 years. Despite decades of research to understand the underlying pathophysiological causes, it has witnessed very slow progress in terms of clinical translation of therapies. This is partially due to the lack of effective delivery strategies for overcoming major obstacles such as blood-brain barrier (BBB) and blood tumour barrier (BTB). Out of the pool of the oncogenic microRNAs, miR-21 and miR-210 are known to regulate several hallmarks of GBM tumorigenesis. Targeting these dysregulated microRNAs using antisense oligonucleotides has a huge therapeutic potential for GBM therapy. However, such microRNAs cannot be delivered without an effective delivery system, which is one of the biggest hurdles in developing RNA-based therapeutics for GBM. Herein, we have developed ultra-small mesoporous silica nanoparticles (USMP) of ~ 40 nm size and modified with Polyethyleneimine (PEI) in a w/w ratio ranging from 1:1 to 1:0.01 (USMP-PEI). We have successfully demonstrated that by optimizing the PEI ratio with close to neutral surface charge, we were able to reduce PEI-induced cytotoxicity without compromising the transfection efficiency. Using the optimized USMP-PEI (1:0.025) w/w ratio and using it to further complex with different (w/w) ratios with antisense oligonucleotides (miR-21 and miR-210), we report a slow and sustained release of antisense oligonucleotides at pH 7.4. With the current strategy, we report significant cellular uptake of microRNAs in the 2D cellular model (LN229 cells) 1 h post-transfection as well as significant penetration of oligonucleotides deep within the hypoxic core of 3D GBM spheroids. The modified USMP complexed with antisense oligonucleotides possesses the inherent ability to transiently penetrate the BBB validated by transwell assay. Simultaneously, they were also able to significantly reduce the tumor spheroid size generated by LN229 GBM cells by around 30% and colony count by around 40% when anti-miRs were delivered in combination for effective GBM therapy. Taken together, these promising data will pave the way for further pre-clinical assessment of this newly developed nanomedicine for the delivery of microRNAs across the brain.
Insights
Researchers developed ultra-small mesoporous silica nanoparticles (USMP) to deliver antisense oligonucleotides targeting oncogenic microRNAs for glioblastoma (GBM) therapy. This novel nanomedicine effectively crosses the blood-brain barrier and reduces tumor size, offering a promising approach for treating aggressive brain tumors.
Area of Science:
- Nanomedicine
- Biotechnology
- Oncology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis, largely due to challenges in delivering therapeutics across the blood-brain barrier (BBB) and blood-tumor barrier (BTB).
- MicroRNAs, specifically miR-21 and miR-210, are implicated in GBM tumorigenesis, making them potential therapeutic targets.
- Antisense oligonucleotides offer therapeutic potential but require effective delivery systems to overcome biological barriers.
Purpose of the Study:
- To develop and optimize an effective nanodelivery system for antisense oligonucleotides targeting miR-21 and miR-210 in GBM.
- To evaluate the ability of the developed nanocarrier to overcome the BBB and penetrate GBM tumor models.
- To assess the therapeutic efficacy of the nanodelivery system in reducing GBM cell proliferation and tumor size.
Main Methods:
- Synthesis of ultra-small mesoporous silica nanoparticles (USMP) modified with polyethyleneimine (PEI) at varying ratios (USMP-PEI).
- Optimization of USMP-PEI formulation to balance transfection efficiency and reduce cytotoxicity.
- Complexation of optimized USMP-PEI with antisense oligonucleotides (anti-miR-21 and anti-miR-210) and evaluation of release kinetics, cellular uptake in 2D models, penetration in 3D GBM spheroids, and BBB penetration via transwell assay.
Main Results:
- Optimized USMP-PEI (1:0.025 w/w) demonstrated reduced cytotoxicity while maintaining high transfection efficiency.
- The nanocarrier facilitated slow and sustained release of antisense oligonucleotides at physiological pH.
- Significant cellular uptake and deep penetration into 3D GBM spheroids were observed; the formulation transiently penetrated the BBB and reduced tumor spheroid size by ~30% and colony count by ~40%.
Conclusions:
- The developed USMP-PEI nanocarrier system is effective for delivering antisense oligonucleotides targeting oncogenic microRNAs in GBM.
- This nanomedicine successfully overcomes key biological barriers, including the BBB, and demonstrates significant anti-tumor effects in vitro.
- The findings support further preclinical evaluation of this novel nanomedicine for advanced GBM therapy.
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