Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy

Yulong Zhang; Omar Velasco; Xinli Zhang; Kang Ting; Chia Soo; Benjamin M Wu

doi:10.1016/j.biomaterials.2014.04.061

Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy

Biomaterials. 2014 Aug;35(24):6614-21. doi: 10.1016/j.biomaterials.2014.04.061. Epub 2014 May 10.

Authors

Yulong Zhang¹, Omar Velasco², Xinli Zhang², Kang Ting³, Chia Soo³, Benjamin M Wu⁴

Affiliations

¹ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Materials Science and Engineering, and Division of Advanced Prosthodontics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Materials Science and Engineering, and Division of Advanced Prosthodontics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Weintraub Center for Reconstructive Biotechnology, and Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: benwu@ucla.edu.

Abstract

Osteoporosis is a progressive bone disease due to low osteoblast activity and/or high osteoclast activity. NELL-1 is a potential therapy for osteoporosis because it specifically increases osteoblast differentiation. However, similar to other protein drugs, the bioavailability of NELL-1 may be limited by its in vivo half-life and rapid clearance from body. The purpose of the present study is to prolong NELL-1 circulation time in vivo by PEGylation with three monomeric PEG sizes (5, 20, 40 kDa). While linear PEG 5k yielded the most efficient PEGylation and the most thermally stable conjugate, linear PEG 20k resulted in the conjugate with the highest Mw and longest in vivo circulation. Compared to non-modified NELL-1, all three PEGylated conjugates showed enhanced thermal stability and each prolonged the in vivo circulation time significantly. Furthermore, PEGylated NELL-1 retained its osteoblastic activity without any appreciable cytotoxicity. These findings motivate further studies to evaluate the efficacy of PEGylated NELL-1 on the prevention and treatment of osteoporosis.

Keywords: Bioactivity; Characterization; Circulation time; NELL-1; PEGylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alkaline Phosphatase / metabolism
Animals
Biological Availability
Blood Vessels / cytology
Calcification, Physiologic / drug effects
Calcium-Binding Proteins / blood*
Calcium-Binding Proteins / metabolism
Calcium-Binding Proteins / therapeutic use*
Cell Death
Cell Line
Glycoproteins / blood*
Glycoproteins / metabolism
Glycoproteins / therapeutic use*
Humans
Mice
Osteoblasts / drug effects
Osteoblasts / metabolism
Osteoporosis / blood
Osteoporosis / drug therapy*
Polyethylene Glycols / chemical synthesis
Polyethylene Glycols / chemistry*
Polyethylene Glycols / toxicity
Protein Stability
Skull / cytology
Stem Cells / cytology
Stem Cells / metabolism
Temperature
Time Factors

Substances

Calcium-Binding Proteins
Glycoproteins
Nell1 protein, mouse
Polyethylene Glycols
Alkaline Phosphatase

Abstract

Publication types

MeSH terms

Substances

Grants and funding