Lipid-nucleic acid nanoparticles of novel ionizable lipids for systemic BMP-9 gene delivery to bone-marrow mesenchymal stem cells for osteoinduction

被引：49

作者：

Vhora, Imran ^{[1
]}

Lalani, Rohan ^{[1
]}

Bhatt, Priyanka ^{[1
,2
]}

Patil, Sushilkumar ^{[1
]}

Misra, Ambikanandan ^{[1
]}

机构：

[1] Maharaja Sayajirao Univ Baroda, Fac Pharm, Dept Pharmaceut, Kalabhavan Campus, Vadodara 390001, Gujarat, India

[2] Univ S Florida, Coll Pharm, Dept Pharmaceut Sci, 12901 Bruce B Downs Blvd,MDC30, Tampa, FL 33612 USA

来源：

INTERNATIONAL JOURNAL OF PHARMACEUTICS | 2019年 / 563卷

关键词：

LNP; Lipid nanoparticles; Liposomes; Lipoplex; Ionizable lipid; Histidine; CATIONIC LIPIDS; DNA COMPLEXES; OSTEOPOROSIS; DEPOSITION; EFFICIENCY; IMIDAZOLE; LIPOSOMES; MECHANISM; VECTORS; PEPTIDE;

D O I：

10.1016/j.ijpharm.2019.04.006

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Rational design of novel ionizable lipids for development of lipid-nucleic acid nanoparticles (LNP) is required for safe and effective systemic gene delivery for osteoporosis. LNPs require suitable characteristics for intravenous administration and effective accumulation in bone marrow for enhanced transfection. Hence, lipids with C18 tail and ionizable headgroup (Boc-His-ODA/BHODA and His-ODA/HODA) were synthesized and characterized physicochemically. LNPs were prepared with bone morphogenetic protein-9 gene (BHODA-LNP, HODA-LNP, and bone-homing peptide targeted HODA-LNP - HODA-LNPT). Thorough physicochemical (electrolyte stability, DNase I and serum stability) and biological (hemolysis, ROS induction, cytotoxicity and transfection) characterization was carried out followed by acute toxicity studies and therapeutic performance studies in ovariectomized rat model. Lipids with pH dependent ionization were successfully synthesized. LNPs thereof were similar to 100 nm size with stability against electrolytes, DNase I and serum and exhibited low hemolytic potential demonstrating suitability for intravenous administration. LNPs exhibited minimal cytotoxicity, non-significant ROS induction and high transfection. In vivo studies demonstrated safety and improved bone regeneration in OVX rats with HODA-LNPT showing significantly better performance. Synthesized ionizable lipids offer safe and effective alternative for preparation of LNPs for gene delivery. Targeted BMP-9 LNP show potential for systemic osteoporosis treatment.

引用

页码：324 / 336

页数：13