title: Functionalized heparin-protamine based self-assembled nanocomplex for efficient anti-angiogenic therapy.
abstract: Angiogenesis is a key feature of cancer development, thus it is a good target for cancer therapy. However, drugs that have been designed to block angiogenesis mainly capture growth factors in circulation, resulting not only in the transient inhibition of tumor progression but also in producing undesirable side effects. Nanoparticular drug delivery systems, on the other hand, may help overcome such drawbacks and improve the efficacy of anti-angiogenic therapies by altering the biodistribution and pharmacokinetics, improving tumor targeting ability, and reducing side effects. In this light, we propose a new approach of anti-angiogenic therapy that combines strategies of long circulating, passive tumor targeting, and anti-angiogenesis efficacy using a new polyelectrolyte complex system that combines LHT7, a previously developed heparin-based angiogenesis inhibitor, with a protamine to form a self-assembling nanocomplex with a mean diameter of 200nm, which is effective for anti-angiogenesis therapy. At first, LHT7 was modified with polyethylene glycol (PEG). We observed that PEG-LHT7/protamine nanocomplex was stable in buffer and slowly dissociated in plasma (9% dissociation for 24h). Compared to the free form of PEG-LHT7, the mean residence time of PEG-LHT7/protamine nanocomplex was found higher (15.9h) with its increased accumulation in tumor. Most importantly, PEG-LHT7/protamine nanocomplex was diffused and extravasated through the dense collagen matrix of the tumor. Thus, the study describes a successful application of functionalized PEG-LHT/protamine nanocomplex that can inhibit angiogenesis with long circulating, passive targeting, and tumor extravasating ability.
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Jooho
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
authors.forename: Foyez
authors.initials: F
authors.lastname: Mahmud
authors.affiliation: Department of Biomedical Engineering, Computer and Biomedical Engineering, Yonsei University, Gangwon, South Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Seo
authors.affiliation: Department of Biomedical Engineering, Computer and Biomedical Engineering, Yonsei University, Gangwon, South Korea.
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; College of Pharmacy, Seoul National University, Seoul, South Korea. Electronic address: yrbyun@snu.ac.kr.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D008297:Male; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011479:Protamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D006495:Heparin, Low-Molecular-Weight; C580866:LHT7 compound; D011479:Protamines; D011092:Polyethylene Glycols; D013656:Taurocholic Acid
keywords: Anti-angiogenesis; Heparin conjugate; Protamine; Self-assembled nanocomplex