Pluronic and Pluronic-polysaccharide Blends for Sustained Drug Delivery and Osteogenic Efficiency

Abstract

Hydrogels represent a strategic role in controlled and /or sustained drug delivery. This polymeric system consists of three dimensional structures that can absorb large amount of water or biological fluids and thus can be modified for stimuli response release. In the present work novel hydrogels were prepared by combining various concentrations of 12, 14, 16, 18 and 20% (w/w) pluronic F127 (PF) with 4% (w/w) Methylcellulose (MC) to form injectable implant drug delivery systems. These blends formed gels at significantly lower concentrations of PF when compared to using PF alone. Furthermore, the gels exhibited cytocompatibility to both mouse preosteoblasts (MC3T3-E1) and mouse myoblast (C2C12) cell lines whereas the gels of 16 PF, 18 PF and 20 PF were cytotoxic to the cells. Etidronate sodium (EDS) was loaded at a concentration of 4 × 103 M into these blends for yielding an osteogenesis effect. EDS loaded PF/MC blends exhibited cytocompatibility to both the osteoblast (MC3T3-E1) and myoblast (C2C12) cell lines. The EDS loaded gels further exhibited significantly greater alkaline phosphatase (ALP) activities compared to the pure gels. The ALP activity was found to be greater with increasing time. These EDS loaded gels increased proliferation of both cell lines thus indicating a bone regeneration effect. In vitro release of EDS from PF/MC blends found to be extended for more than 28 days. The in vitro degradation test, showed that MC extensively improved the gel strength of the PF and delayed the degradation of the gels thus making them more functional for a sustained drug delivery for osteogenesis. With the aim of enhancing the sustainability of etidronate in these gel systems a simple and inexpensive approach for preparation of drug loaded nanoparticles by nanoprecipitation has been employed in the present work. Bisphosphonates are drugs used for treatment of bone disorders like Paget's disease and osteoporosis. These bisphosphonates have a very short half-life in circulation (0.5-2 hr) for which controlled release of bisphosphonates is essential for long term therapeutic efficacy. In this work Etidronate, a bisphosphonate, was selected as a model drug. Gelatin-etidronate nanoparticles were prepared by nanoprecipitation method. These nanoparticles were characterized by Zetasizer and TEM for their size and morphology, respectively. The prepared nanoparticles were in the size range of 100-260 nm. The zeta potential value was found to be +5.86mV. The drug loading efficiency was found to be 40%. In vitro drug release studies revealed control release of the drug from the polymer matrix. Further these nanoparticles exhibited dose dependent cytotoxicity on mouse C2C12 cells.