title: Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles.
abstract: Hyaluronan (HA), a naturally occurring high Mw (HMw) glycosaminoglycan, has been shown to play crucial roles in cell growth, embryonic development, healing processes, inflammation, and tumor development and progression. Low Mw (LMw, <10 kDa) HA has been reported to provoke inflammatory responses, such as induction of cytokines, chemokines, reactive nitrogen species and growth factors. Herein, we prepared and characterized two types of HA coated (LMw and HMw) lipid-based targeted and stabilized nanoparticles (tsNPs) and tested their binding to tumor cells expressing the HA receptor (CD44), systemic immunotoxicity, and biodistribution in tumor bearing mice. In vitro, the Mw of the surface anchored HA had a significant influence on the affinity towards CD44 on B16F10 murine melanoma cells. LMw HA-tsNPs exhibited weak binding, while binding of tsNPs coated with HMw HA was characterized by high binding. Both types of tsNPs had no measured effect on cytokine induction in vivo following intravenous administration to healthy C57BL/6 mice suggesting no immune activation. HMw HA-tsNPs showed enhanced circulation time and tumor targeting specificity, mainly by accumulating in the tumor and its vicinity compared with LMw HA-tsNPs. Finally, we show that methotrexate (MTX), a drug commonly used in cancer chemotherapy, entrapped in HMw HA-tsNPs slowly diffused from the particles with a half-life of 13.75 days, and improved the therapeutic outcome in a murine B16F10 melanoma model compared with NPs suggesting an active cellular targeting beyond the Enhanced Permeability and Retention (EPR) effect. Taken together, these findings have major implications for the use of high molecular weight HA in nanomedicine as a selective and safe active cellular targeting moiety.
authors.affiliation: Laboratory of NanoMedicine, Department of Cell Research and Immunology, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv 69978, Israel. peer@tauex.tau.ac.il.
authors.forename: Shoshy
authors.initials: S
authors.lastname: Mizrahy
authors.forename: Meir
authors.initials: M
authors.lastname: Goldsmith
authors.forename: Shani
authors.initials: S
authors.lastname: Leviatan-Ben-Arye
authors.forename: Einat
authors.initials: E
authors.lastname: Kisin-Finfer
authors.forename: Orit
authors.initials: O
authors.lastname: Redy
authors.forename: Srimeenakshi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Doron
authors.initials: D
authors.lastname: Shabat
authors.forename: Biana
authors.initials: B
authors.lastname: Godin
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D002232:Carbocyanines / Q000737:chemistry; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D002232:Carbocyanines; D016207:Cytokines; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D008055:Lipids; C085321:cyanine dye 5; D006820:Hyaluronic Acid; D008727:Methotrexate