期刊
JOURNAL OF CONTROLLED RELEASE
卷 267, 期 -, 页码 144-153出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.09.006
关键词
Glioblastoma; Invasive malignant glioma; Biodegradable nanoparticles; Targeted therapeutics; Fibroblast growth factor-inducible 14; Multiple particle tracking; Surface plasmon resonance
资金
- National Institutes of Health [K25 EB018370, K08 NS09043, R35 HL135743, RSG-16-012-01]
- Institutional Research Grant from the American Cancer Society [IRG-97-153-10]
- Elsa U. Pardee Foundation Research Grant [EP24503]
- AAPS Foundation New Investigator Grant Award
- NIH [T32 CA154274]
- NIGMS Initiative for Maximizing Student Development Grant [R25GM55036]
The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, 'sticky' microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as 'DART' therapeutics. In this work, we applied this information toward the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100 nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor - an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors.
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