title: Multifunctional Hyaluronic Acid and Chondroitin Sulfate Nanoparticles: Impact of Glycosaminoglycan Presentation on Receptor Mediated Cellular Uptake and Immune Activation.
abstract: Hyaluronic acid (HA) and chondroitin sulfate (CS) polymers are extensively used for various biomedical applications, such as for tissue engineering, drug delivery, and gene delivery. Although both these biopolymers are known to target cell surface CD44 receptors, their relative cellular targeting properties and immune activation potential have never been evaluated. In this article, we present the synthesis and characterization of novel self-assembled supramolecular HA and CS nanoparticles (NPs). These NPs were developed using fluorescein as a hydrophobic component that induced amphiphilicity in biopolymers and also efficiently stabilized anticancer drug doxorubicin (DOX) promoting a near zero-order drug release. The cellular uptake and cytotoxicity studies of these NPs in different human cancer lines, namely, human colorectal carcinoma cell line HCT116 and human breast cancer cell line MCF-7 demonstrated dose dependent cytotoxicity. Interestingly, both NPs showed CD44 dependent cellular uptake with the CS-DOX NP displaying higher dose-dependent cytotoxicity than the HA-DOX NP in different mammalian cells tested. Immunological evaluation of these nanocarriers in an ex vivo human whole blood model revealed that unlike unmodified polymers, the HA NP and CS NP surprisingly showed platelet aggregation and thrombin-antithrombin complex formation at high concentrations (0.8 mg/mL). We also observed a clear difference in early- and late-stage complement activation (C3a and sC5b-9) with CS and CS NP triggering significant complement activation at high concentrations (0.08-0.8 mg/mL), unlike HA and HA NP. These results offer new insight into designing glycosaminoglycan-based NPs and understanding their hematological responses and targeting ability.
authors.affiliation: Department of Chemistry, Ångström Laboratory, Science for Life Laboratory, Uppsala University , S-75121 Uppsala, Sweden.|BioMediTech - Institute of Biosciences and Medical Technology, Bioengineering and Nanomedicine Group, Tampere University of Technology , 33520 Tampere, Finland.
authors.forename: Oommen P
authors.initials: OP
authors.lastname: Oommen
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University , S-75121 Uppsala, Sweden.
authors.forename: Claudia
authors.initials: C
authors.lastname: Duehrkop
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University , S-75121 Uppsala, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Department of Chemistry, Ångström Laboratory, Science for Life Laboratory, Uppsala University , S-75121 Uppsala, Sweden.
authors.forename: Jöns
authors.initials: J
authors.lastname: Hilborn
authors.affiliation: Department of Chemistry, Ångström Laboratory, Science for Life Laboratory, Uppsala University , S-75121 Uppsala, Sweden.
authors.forename: Oommen P
authors.initials: OP
authors.lastname: Varghese
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002809:Chondroitin Sulfates; D004317:Doxorubicin; D065546:Drug Liberation; D006801:Humans; D006820:Hyaluronic Acid; D053758:Nanoparticles
chemical_list: D004317:Doxorubicin; D006820:Hyaluronic Acid; D002809:Chondroitin Sulfates
keywords: Hyaluronic acid; cancer; chondroitin sulfate; drug delivery; immune activation; nanoparticles