Zoledronic Acid-Loaded Hybrid Hyaluronic Acid/Polyethylene Glycol/Nano-Hydroxyapatite Nanoparticle: Novel Fabrication and Safety Verification.

Yan Xu,Hehui Wang,Wei Sun,Wu Zhong,Chengmei Sun,Hongwei Wu,Zheng Zhang

doi:10.3389/fbioe.2021.629928

Abstract

Osteosarcoma is a malignant tumor that often occurs in adolescents and children. Zoledronic acid, a new-generation bisphosphonate, has been widely used as an antitumor drug to inhibit bone metastasis. However, the rapid renal elimination results in low effective concentrations. Meanwhile, high-dose intravenous zoledronic acid administration leads to severe side effects. The present study fabricated an organic–inorganic hybrid nanoparticle as the carrier of zoledronic acid. The rod-like nanoparticle, which had 150-nm length and 40-nm cross-sectional diameter, consisted of a hyaluronic acid/polyethylene glycol (HA-PEG) polymer shell and a nano-hydroxyapatite (nHA) core, with zoledronic acid molecules loading on the surface of nHA and clearance of HA-PEG shell. The nanoparticle was characterized by microscopic analysis, in vitro release study, cytotoxicity analysis, and in vivo immune response examination. Results showed that the compact and stable structure could achieve high drug loading efficiency, sustained drug release, and great biocompatibility. In vitro and in vivo experiments revealed the low cytotoxicity and acceptable immune response under low-dose nanoparticle treatment, indicating its potential application for future osteosarcoma therapeutic strategies.

Highlights

Osteosarcoma is the most common bone malignancy, which usually occurs in adolescents and children (Moore and Luu, 2014)
The synthesis of hyaluronic acid/polyethylene glycol (HA-PEG)-nHA-Zoledronic acid (ZOL) nanoparticles consisted of three steps
Compared with traditional polymeric nanoparticles, the hybrid nanoparticle in this study had a much higher drug loading rate, which might be related to the high affinity between ZOL and nHA

Summary

Introduction

Osteosarcoma is the most common bone malignancy, which usually occurs in adolescents and children (Moore and Luu, 2014). Since it mostly occurs at the distal femur, proximal tibia, and humerus, it seriously affects the patient’s movement and survival (Bielack et al, 2002). Hybrid Zoledronic Acid Loaded Nano-Particle bisphosphonate, is widely used to inhibit osteosarcoma growth and bone metastasis (Poirier et al, 2003; Lipton, 2008). The low effective concentration and rapid elimination give rise to high-dose ZOL treatment, along with severe side effects including renal impairment and pyrexia (Black et al, 2007; Novartis Pharmaceuticals Corporation, 2016). Nanoparticle-targeted drug delivery is proposed as a potential method to achieve ZOL-mediated osteosarcoma therapy with low dose and high efficiency

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Discussion

Conclusion