Abstract
Components with self-assembly properties derived from plant viruses provide the opportunity to design biological nanoscaffolds for the ordered display of agents of diverse nature and with complementing functions. With the aim of designing a functionalized nanoscaffold to target cancer, the coat protein (CP) of Tobacco mosaic virus (TMV) was tested as nanocarrier for an insoluble, highly hydrophobic peptide that targets the transmembrane domain of the Neuropilin-1 (NRP1) receptor in cancer cells. The resulting construct CPL-K (CP-linker-“Kill”) binds to NRP1 in cancer cells and disrupts NRP1 complex formation with PlexA1 as well as downstream Akt survival signaling. The application of CPL-K also inhibits angiogenesis and cell migration. CP was also fused to a peptide that targets the extracellular domain of NRP1 and this fusion protein (CPL-F, CP-Linker-“Find”) is shown to bind to cultured cancer cells and to inhibit NRP1-dependent angiogenesis as well. CPL-K and CPL-F maintain their anti-angiogenic properties upon co-assembly to oligomers/nanoparticles together with CPL. The observations show that the CP of TMV can be employed to generate a functionalized nanoparticle with biological activity. Remarkably, fusion to CPL allowed us to solubilize the highly insoluble transmembrane NRP1 peptide and to retain its anti-angiogenic effect.
Highlights
Nanoparticles play an ever-increasing role as carriers for transporting drugs to specific tissues and cells to combat diseases [1,2], such as glioblastoma [3] and breast cancer [4] among others.Carrier-mediated drug delivery systems can offer many advantages over delivery of a physicalCancers 2019, 11, 1609; doi:10.3390/cancers11101609 www.mdpi.com/journal/cancersCancers 2019, 11, 1609 mixture of multiple drugs
We previously showed that the disruption of the NRP1/Plexin-A1 dimer suppresses vascular endothelial growth factor type A (VEGFA)-induced migration of glioblastoma U-118MG cells [54]
By Proximity ligation assays (PLA) using antibodies for MBP and NRP1, we addressed whether CPL-F finds NRP1 and revealed a significant number of interactions we addressed whether CPL-F finds NRP1 and revealed a significant number of interactions between CPL-F and NRP1 (Figure 5a,b)
Summary
Nanoparticles play an ever-increasing role as carriers for transporting drugs to specific tissues and cells to combat diseases [1,2], such as glioblastoma [3] and breast cancer [4] among others.Carrier-mediated drug delivery systems can offer many advantages over delivery of a physicalCancers 2019, 11, 1609; doi:10.3390/cancers11101609 www.mdpi.com/journal/cancersCancers 2019, 11, 1609 mixture of multiple drugs. Their size is in the nanometer range, enhancing permeability of tissues and retention in tumors [14,15,16,17] They are suitable for both chemical and genetic manipulation, allowing the viral coat to be tailored for specific cell or tissue types, imaging purposes, and as a carrier for therapeutic cargo. Their multivalent nature enables the incorporation of multiple molecules with different functions, allowing, for example, the combination of a cell targeting ligand and an imaging agent on the same nanoparticle [10]
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