title: Hyaluronan polymer length, grafting density, and surface poly(ethylene glycol) coating influence in vivo circulation and tumor targeting of hyaluronan-grafted liposomes.
abstract: Hyaluronan-grafted liposomes (HA-liposomes) preferentially target CD44-overexpressing tumor cells in vitro via receptor-mediated endocytosis. We investigated the pharmacokinetics and biodistribution of HA-liposomes with various sizes of HA (MW 5-8, 50-60, and 175-350 kDa) in mice. Incorporation of negatively charged HA on the liposome surface compromised its blood circulation time, which led to decreased tumor accumulation in CD44+ human breast cancer MDA-MB-231 xenografts compared to PEGylated liposomes (PEG-5000). Clearance of HA-liposomes was HA polymer length-dependent; high MW (175-350 kDa, highest ligand binding affinity) HA-liposomes displayed faster clearance compared to low MW (5-8, 50-60 kDa) HA-liposomes or PEGylated liposomes. Surface HA ligand density can also affect clearance of HA-liposomes. Thus, HA is not an effective stealth coating material. When dual coating of PEG and HA was used, the PEG-HA-liposomes displayed similar blood circulation time and tumor accumulation to that of the PEGylated liposomes; however, the PEG-HA-liposomes displayed better cellular internalization capability in vivo. Tumor histology showed that PEG-HA-liposomes had a more direct association with CD44+ cancer cells, while PEGylated liposomes located predominantly in the tumor periphery, with less association with CD44+ cells. Flow cytometry analysis of ex vivo tumor cells showed that PEG-HA-liposomes had significantly higher tumor cell internalization compared to PEGylated liposomes. This study demonstrates that a long blood circulation time is critical for active tumor targeting. Furthermore, the use of the tumor-targeting ligand HA does not increase total tumor accumulation of actively targeted liposomes in solid tumors; however, it can enhance intracellular delivery.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center , Amarillo, Texas 79106, United States.
authors.forename: Hussaini Syed Sha
authors.initials: HS
authors.lastname: Qhattal
authors.forename: Tanvirul
authors.initials: T
authors.lastname: Hye
authors.forename: Amer
authors.initials: A
authors.lastname: Alali
authors.forename: Xinli
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D019540:Area Under Curve; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry; D006820:Hyaluronic Acid / Q000737:chemistry*; D008024:Ligands; D008027:Light; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine / Q000379:methods*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D010587:Phagocytosis; D011092:Polyethylene Glycols / Q000737:chemistry*; D012542:Scattering, Radiation; D013499:Surface Properties
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008024:Ligands; D008055:Lipids; D008081:Liposomes; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid