title: Tear-mediated delivery of nanoparticles through transcytosis of the lacrimal gland.
abstract: Rapid clearance from the tears presents a formidable obstacle to the delivery of peptide drugs to the eye surface. This impedes therapies for ocular infections, wound healing, and dry-eye disease that affect the vision of millions worldwide. To overcome this challenge, this manuscript explores a novel strategy to reach the ocular surface via receptor-mediated transcytosis across the lacrimal gland (LG), which produces the bulk of human tears. The LG abundantly expresses the coxsackievirus and adenovirus receptor (CAR); furthermore, we recently reported a peptide-based nanoparticle (KSI) that targets CAR on liver cells. This manuscript reports the unexpected finding that KSI both targets and transcytoses into the LG acinar lumen, which drains to tear ducts. When followed using ex vivo live cell imaging KSI rapidly accumulates in lumen formed by LG acinar cells. LG transduction with a myosin Vb tail, which is dominant negative towards transcytosis, inhibits lumenal accumulation. Transcytosis of KSI was confirmed in vivo by confocal and TEM imaging of LG tissue following administration of KSI nanoparticles. These findings suggest that it is possible to target nanomaterials to the tears by targeting certain receptors on the LG. This design strategy represents a new opportunity to overcome barriers to ocular delivery.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Pang-Yu
authors.initials: PY
authors.lastname: Hsueh
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Edman
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Guoyong
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Chemical and Biomolecular Engineering, John Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Lin
authors.affiliation: Department of Chemical and Biomolecular Engineering, John Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Honggang
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Hamm-Alvarez
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: jamackay@usc.edu.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: MacKay
mesh_terms: D061354:Acinar Cells / Q000187:drug effects; D000818:Animals; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000187:drug effects; D015352:Dry Eye Syndromes / Q000188:drug therapy; D004705:Endocytosis; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D007765:Lacrimal Apparatus / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers; D061251:Primary Cell Culture; D011817:Rabbits; D013666:Tears / Q000187:drug effects*; D057900:Transcytosis / Q000187:drug effects*
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D010455:Peptides; D011108:Polymers
keywords: Coxsackievirus and adenovirus receptor; Elastin-like polypeptide; Knob; Lacrimal gland; Transcytosis