title: Improved biological half-life and anti-tumor activity of TNF-related apoptosis-inducing ligand (TRAIL) using PEG-exposed nanoparticles.
abstract: TRAIL has received considerable attention as a potential anti-cancer agent due to its specific ability to target tumors. However, recombinant TRAIL has several limitations, such as, its short biological half-life, its inherent instability, and its potential hepatotoxicity. In this study, we developed a sustained release nanoparticle formulation of TRAIL and investigated its therapeutic effects in tumor-bearing mice. TRAIL-loaded nanoparticles (NPs) were prepared by mixing PEGylated heparin (PEG-HE), poly-L-lysine (PLL), and TRAIL. NPs prepared by the ionic interaction between polymer and TRAIL showed uniform spherical structures of diameter 213.3 ± 9.7 nm and a surface charge of 5.33 ± 1.2 mV. An in vitro study of the bioactivity of TRAIL in NPs showed that TRAIL-loaded PEG-HE/PLL NPs (TRAIL-PEG-NPs) were slightly less cytotoxic than TRAIL in vitro. To investigate pharmacokinetic parameters, TRAIL and TRAIL-PEG-NPs were intravenously injected into SD rats. The PEG-NP-based formulation demonstrated a 28.3 fold greater half-life than TRAIL alone. To evaluate the anti-tumor effect, TRAIL, TRAIL-loaded HE/PLL NPs (TRAIL-NPs), and TRAIL-PEG-NPs were intravenously injected into HCT-116 tumor-bearing BALB/c athymic mice. The TRAIL-PEG-NP formulation efficiently suppressed tumor growth (>70%), and histological findings confirmed that NPs induced significant tumor cell apoptosis without inducing liver toxicity. The PEG-exposed NP fabrication method applied in this study could be widely applied to protein and peptide delivery systems.
authors.affiliation: College of Pharmacy, SungKyunKwan University, Jangan-gu, Suwon, Republic of Korea.
authors.forename: Sung Mook
authors.initials: SM
authors.lastname: Lim
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Hai Hua
authors.initials: HH
authors.lastname: Jiang
authors.forename: Chan Woong
authors.initials: CW
authors.lastname: Park
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy; D045325:HCT116 Cells; D006493:Heparin / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; D011092:Polyethylene Glycols; D006493:Heparin