title: Spatiotemporal Targeting of a Dual-Ligand Nanoparticle to Cancer Metastasis.
abstract: Various targeting strategies and ligands have been employed to direct nanoparticles to tumors that upregulate specific cell-surface molecules. However, tumors display a dynamic, heterogeneous microenvironment, which undergoes spatiotemporal changes including the expression of targetable cell-surface biomarkers. Here, we investigated a dual-ligand nanoparticle to effectively target two receptors overexpressed in aggressive tumors. By using two different chemical specificities, the dual-ligand strategy considered the spatiotemporal alterations in the expression patterns of the receptors in cancer sites. As a case study, we used two mouse models of metastasis of triple-negative breast cancer using the MDA-MB-231 and 4T1 cells. The dual-ligand system utilized two peptides targeting P-selectin and αvβ3 integrin, which are functionally linked to different stages of the development of metastatic disease at a distal site. Using in vivo multimodal imaging and post mortem histological analyses, this study shows that the dual-ligand nanoparticle effectively targeted metastatic disease that was otherwise missed by single-ligand strategies. The dual-ligand nanoparticle was capable of capturing different metastatic sites within the same animal that overexpressed either receptor or both of them. Furthermore, the highly efficient targeting resulted in 22% of the injected dual-ligand nanoparticles being deposited in early-stage metastases within 2 h after injection.
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Doolittle
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Pubudu M
authors.initials: PM
authors.lastname: Peiris
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Gilad
authors.initials: G
authors.lastname: Doron
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Goldberg
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Samantha
authors.initials: S
authors.lastname: Tucci
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Swetha
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Meilyn
authors.initials: M
authors.lastname: Sylvestre
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Priya
authors.initials: P
authors.lastname: Govender
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Oguz
authors.initials: O
authors.lastname: Turan
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
authors.affiliation: Department of Biomedical Engineering, ‡Department of Radiology, §Case Center for Imaging Research, and ∥Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland 44106, Ohio, United States.
authors.forename: Efstathios
authors.initials: E
authors.lastname: Karathanasis
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D003952:Diagnostic Imaging / Q000379:methods*; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D015870:Gene Expression; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology
chemical_list: D039302:Integrin alphaVbeta3; D019007:P-Selectin; D011994:Recombinant Proteins; D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol
keywords: cancer metastasis; dual-ligand nanoparticle; triple-negative breast cancer; vascular targeting