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Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model
Rupa Juthani1, Brian Madajewski2, Barney Yoo3,4
1Department of Neurosurgery, Sloan Kettering Institute for Cancer Research, New York, New York.
Purpose:
Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy.
Experimental Design:
Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC.
Results:
Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition.
Conclusions:
These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.
Insights
Targeted nanoparticles improve drug delivery across the blood-brain barrier for brain tumors. This study shows engineered nanoparticles enhance drug accumulation and distribution in glioblastoma models.
Area of Science:
- Nanomedicine
- Biotechnology
- Cancer Research
Background:
- Central nervous system (CNS) metastases are common in solid cancers, with limited treatment advancements.
- Improving drug delivery across the blood-brain barrier (BBB) is crucial for treating CNS malignancies.
Purpose of the Study:
- To investigate the utility of dual-modality ultrasmall fluorescent core-shell silica nanoparticles (Cornell prime dots, C' dots) for enhancing drug accumulation, distribution, and retention (ADR) in a glioblastoma model.
- To assess the efficacy of targeted C' dots functionalized with αv integrin-binding peptides (cRGD) compared to nontargeted controls (cRAD).
- To evaluate the delivery of dasatinib via nanoparticle-drug conjugates (Das-NDCs) for downstream pathway inhibition.
Main Methods:
- Engineered C' dots with PET labels (124I) and targeting (cRGD) or nontargeting (cRAD) peptides were administered to a genetically engineered mouse model of glioblastoma (mGBM).
- Blood-brain barrier permeability was mapped using FITC-dextran, and drug delivery was assessed via ex vivo autoradiography, fluorescence microscopy, and immunohistochemistry (IHC).
- Dasatinib was attached to C' dots to create nanoparticle-drug conjugates (Das-NDCs) to assess targeted drug delivery and efficacy.
Main Results:
- Integrin-targeted C' dots demonstrated improved brain tumor delivery, penetration, and enhanced ADR compared to nontargeted controls.
- Successful drug delivery of dasatinib throughout the mGBM was achieved using Das-NDCs, evidenced by downstream pathway inhibition.
- Dual-modality cRGD-C' dots showed enhanced accumulation, distribution, and retention in the glioblastoma model.
Conclusions:
- Highly engineered C' dots show promise as drug delivery vehicles for brain tumors.
- These nanoparticles can effectively navigate complex physiological barriers, including the blood-brain barrier.
- Targeted nanoparticle-based drug delivery enhances therapeutic potential for CNS malignancies.
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