title: Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.
abstract: Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA)-based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-β-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Han
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Zhenbao
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China; Municipal key laboratory of biopharmacetics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China. Electronic address: sunjin66@21cn.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Du
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Qiu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Ai
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: Chunnuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
authors.forename: He
authors.initials: H
authors.lastname: Lian
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China. Electronic address: hezhonggui@vip.163.com.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D059005:Topoisomerase II Inhibitors; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D006820:Hyaluronic Acid
keywords: Cellular uptake; Host–guest interaction; Hyaluronic acid; Long circulation times; Pegylation