Mesenchymal Stem Cell Membrane Coating of Gelatin Nanospheres with Drug Release Ability for Inflammatory Tissue Targeting

Abstract

Improvements in drug delivery have been achieved using nanospheres to prolong drug efficacy, accelerate absorption, and target tissues with ongoing inflammation. Although nanospheres have numerous pharmacokinetic advantages their tissue-targeting ability is poor. In contrast, mesenchymal stem cells (MSC) accumulate in high numbers in inflammatory tissues via the interaction between CXC-chemokine receptor 4 (CXCR4) expressed on MSC and stromal cell-derived factor 1 (SDF-1) secreted during inflammation. Therefore, this study investigated coating gelatin nanospheres (GNS) with MSC membranes (MSC-GNS) by extrusion and ultrasonication methods to enhance their inflammatory tissue tropism. {zeta}-potential measurements, western blotting and single-particle analysis of MSC-GNS by flow cytometry demonstrated the GNS surface was successfully coated with MSC membranes. Dot blotting demonstrated the binding ability of CXCR4 for SDF-1 was retained by MSC-GNS but absent for MSC-membrane-free GNS. The blood clearance of MSC-GNS was examined by their intravenous injection into mice. Although MSC-GNS and GNS were retained during the early distribution phase, MSC-GNS had a higher retention than GNS during the later elimination phase. Finally, we investigated the tissue distribution of MSC-GNS by intravenous injection into a mouse model of liver fibrosis and their potential therapeutic effect on liver fibrosis. We found a higher accumulation of MSC-GNS in inflamed livers and higher blood retention compared with MSC-membrane-free GNS. Furthermore, MSC-GNS loaded with an anti-fibrotic agent (LSKL, a 4-amino acid peptide that inhibits fibrosis progression) had an enhanced therapeutic effect on liver fibrosis than uncoated nanoparticles. Therefore, MSC-GNS might be a drug carrier with inflammatory tissue targeting and controlled drug release abilities. Synopsis Table of Contents Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/657318v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@12331d8org.highwire.dtl.DTLVardef@19d7b43org.highwire.dtl.DTLVardef@79591org.highwire.dtl.DTLVardef@1ec805a_HPS_FORMAT_FIGEXP M_FIG C_FIG Mesenchymal stem cell membrane coated gelatin nanosphere as DDS nanocarrier