ABSTRACT
Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix-metalloproteinase (MMP)-sensitive and arg-gly-asp-ser (RGDS) peptide functionalized poly (ethylene-glycol) (PEG) particles which are synthesized via visible-light-induced water-in-water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP-sensitive particles are cytocompatible and superior to promote TRAIL-induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC-loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC-loaded particles, but not QC or PEG-hydrogels alone, enhance apoptosis as is measured through expression of apoptosis-related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy.
Subject(s)
Glioblastoma/drug therapy , Hydrogels/chemistry , Matrix Metalloproteinase 2/metabolism , Polyethylene Glycols/chemistry , Quinacrine/therapeutic use , TNF-Related Apoptosis-Inducing Ligand/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Carriers , Drug Liberation , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Microscopy, Atomic Force , Peptides/pharmacology , Polymerization , Quinacrine/pharmacology , X-Ray DiffractionABSTRACT
As an efficient controlled release system for rhBMP-2, a functional nanoparticle-hydrogel complex, incorporated with matrix metalloproteinase( MMP) sensitive peptide cross-linker, was developed and used as a bone transplant. In vivo bone formation was evaluated by soft x-ray, histology, alkaline phosphatase(ALP) activity and mineral contents analysis, based on the rat calvarial critical size defect(8mm in diameter) model.Significantly, effective bone regeneration was achieved with the rhBMP-2 loaded MMP sensitive hyaluronic acid(HA) based hydrogel- Nanoparticles(NP) complex, as compared to only MMP HA, the MMP HA-NP without rhBMP-2, or even with the rhBMP-2. These improvements included the formation pattern of bone and functional marrow, the degree of calcium quantification, and the ALP activity. These results indicate that the MMP sensitive HA with nano-particle complex can be a promising candidate for a new bone defect replacement matrix, and an enhanced rhBMP-2 scaffold.
