Preparation and optimization of matrix metalloproteinase-1-loaded poly(lactide-co-glycolide-co-caprolactone) nanoparticles with rotatable central composite design and response surface methodology

Ping Sun,Hua Song,Mousheng Xu,Hongquan Geng,Daxiang Cui,Jun Qi

doi:10.1186/1556-276x-7-359

Abstract

Matrix metalloproteases are key regulatory molecules in the breakdown of extracellular matrix and in inflammatory processes. Matrix metalloproteinase-1 (MMP-1) can significantly enhance muscle regeneration by promoting the formation of myofibers and degenerating the fibrous tissue. Herein, we prepared novel MMP-1-loaded poly(lactide-co-glycolide-co-caprolactone) (PLGA-PCL) nanoparticles (NPs) capable of sustained release of MMP-1. We established quadratic equations as mathematical models and employed rotatable central composite design and response surface methodology to optimize the preparation procedure of the NPs. Then, characterization of the optimized NPs with respect to particle size distribution, particle morphology, drug encapsulation efficiency, MMP-1 activity assay and in vitro release of MMP-1 from NPs was carried out. The results of mathematical modeling show that the optimal conditions for the preparation of MMP-1-loaded NPs were as follows: 7 min for the duration time of homogenization, 4.5 krpm for the agitation speed of homogenization and 0.4 for the volume ratio of organic solvent phase to external aqueous phase. The entrapment efficiency and the average particle size of the NPs were 38.75 ± 4.74% and 322.7 ± 18.1 nm, respectively. Further scanning electron microscopy image shows that the NPs have a smooth and spherical surface, with mean particle size around 300 nm. The MMP-1 activity assay and in vitro drug release profile of NPs indicated that the bioactivity of the enzyme can be reserved where the encapsulation allows prolonged release of MMP-1 over 60 days. Taken together, we reported here novel PLGA-PCL NPs for sustained release of MMP-1, which may provide an ideal MMP-1 delivery approach for tissue reconstruction therapy.

Highlights

Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading extracellular matrix proteins [1]
Matrix metalloproteinase-1 (MMP-1) enzyme-linked immunosorbent assay (ELISA) kit was from Fengxiang Biotech Co., Ltd. (Shanghai, China)
20 mg of PLGA-PCL was dissolved in an appropriate amount of dichloromethane and poured into 100 μL of phosphate buffer saline (PBS; pH 7.4) as the inner aqueous phase (W1) containing MMP-1

Summary

Introduction

Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading extracellular matrix proteins [1]. A number of artificial polymers have been investigated extensively to formulate the biodegradable nano-drug delivery carriers, such as polylactide, poly-L-lactic acid (PLLA), polycaprolactone (PCL) and poly(lactide-co-glycolide) (PLGA) [6,7] Even though they are biocompatible and biodegradable polymers approved by FDA as safe biomaterials for clinical application, the application of polymer nanoparticles (NPs) is still limited because of polymer crystallization, poor flexible property or low biodegradation rate. Poly(lactide-co-glycolide-co-caprolactone) (PLGA-PCL), a novel biodegradable block copolymer, has attracted much attention because it colligates the advantages of PLGA and PCL Characteristics such as excellent biocompatibility, suitable degradable rate, low glass transition temperature (Tg), good miscibility and great permeability make PLGA-PCL an ideal candidate for sustained drug release delivery systems [10]

Methods

Results

Conclusion