title: Dose-Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin-Coated PGMA Nanoparticles.
abstract: The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery.
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Ruhani
authors.initials: R
authors.lastname: Singh
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Marck
authors.initials: M
authors.lastname: Norret
authors.affiliation: School of Physics, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: House
authors.affiliation: School of Materials Science and Engineering, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Galabura
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Bradshaw
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Diwei
authors.initials: D
authors.lastname: Ho
authors.affiliation: School of Physics, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Woodward
authors.affiliation: School of Physics, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: St Pierre
authors.affiliation: School of Materials Science and Engineering, Clemson University, Clemson, SC, 29634, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Luzinov
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.|School of Animal Biology, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Smith
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Lee Yong
authors.initials: LY
authors.lastname: Lim
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, W. A., 6009, Australia.
authors.forename: Killugudi Swaminathan
authors.initials: KS
authors.lastname: Iyer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011109:Polymethacrylic Acids / Q000737:chemistry*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use; D014168:Transferrin / Q000737:chemistry*
chemical_list: D011109:Polymethacrylic Acids; D043823:Taxoids; D014168:Transferrin; D000077143:Docetaxel; C042535:polyglycidyl methacrylate
keywords: active targeting; castration-resistant prostate cancers; nanoparticles; passive targeting; targeted therapies, dosages