TY  - JOUR
AB  - The pyrimidine analogue gemcitabine (dFdC) is frequently used in the treatment of patients with solid tumors. However, after i.v. application dFdC is rapidly inactivated by metabolization. Here, the potential of thermosensitive liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG(2)-TSL) were investigated as carrier and targeting system for delivery of dFdC in combination with local hyperthermia (HT). DPPG(2)-TSL were prepared by the lipid film hydration and extrusion method and characterized by dynamic light scattering, thin layer chromatography, phosphate assay and HPLC. In vivo experiments were performed in Brown Norway rats with a syngeneic soft tissue sarcoma. Local HT treatment was performed by light exposure. DPPG(2)-TSL were stable at 37A degrees C in serum and showed a temperature dependent dFdC release > 40A degrees C. Plasma half-life of dFdC was strongly increased from 0.07 h (non-liposomal) to 0.53 h (liposomal, vesicle size 105 nm) or 2.59 h (liposomal, 129 nm). Therapy of BN175 tumors with dFdC encapsulated in DPPG(2)-TSL + HT showed significant improvement in tumor growth delay compared to non-liposomal dFdC without HT (p < 0.05), non-liposomal dFdC with HT (p < 0.01), and liposomal dFdC without HT (p < 0.05), respectively. Gemcitabine encapsulated in DPPG(2)-TSL in combination with local HT is a promising tool for the treatment of solid tumors. Therefore, these encouraging results ask for further investigation and evaluation.
AU  - Limmer, S.
AU  - Hahn, J.*
AU  - Schmidt, R.*
AU  - Wachholz, K.*
AU  - Zengerle, A.*
AU  - Lechner, K.
AU  - Eibl, H.*
AU  - Issels, R.D.
AU  - Hossann, M.
AU  - Lindner, L.H.
C1  - 42758
C2  - 35325
CY  - New York
SP  - 2276-2286
TI  - Gemcitabine treatment of rat soft tissue sarcoma with phosphatidyldiglycerol-based thermosensitive liposomes.
JO  - Pharm. Res.
VL  - 31
IS  - 9
PB  - Springer/plenum Publishers
PY  - 2014
SN  - 0724-8741
ER  - 

TY  - JOUR
AB  - Gene delivery from biomaterials has become an important tool in tissue engineering. The purpose of this study was to generate a gene vector-doted fibrin glue as a versatile injectable implant to be used in gene therapy supported tissue regeneration. METHODS: Copolymer-protected polyethylenimine(PEI)-DNA vectors (COPROGs), naked DNA and PEI-DNA were formulated with the fibrinogen component of the fibrin glue TISSUCOL(R) and lyophilized. Clotting parameters upon rehydration and thrombin addition were measured, vector release from fibrin clots was determined. Structural characterizations were carried out by electron microscopy. Reporter and growth factor gene delivery to primary keratinocytes and chondrocytes in vitro was examined. Finally,chondrocyte colonized clots were tested for their potency in cartilage regeneration in a osteochondral defect model. RESULTS: The optimized glue is based on the fibrinogen component of TISSUCOL(R), a fibrin glue widely used in the clinics, co-lyophilized with copolymer-protected polyethylenimine(PEI)- DNA vectors (COPROGs). This material, when rehydrated, forms vector-containing clots in situ upon thrombin addition and is suitable to mediate growth factor gene delivery to primary keratinocytes and primary chondrocytes admixed before clotting. Unprotected PEI-DNA in the same setup was comparatively unsuitable for clot formation while naked DNA was ineffective in transfection. Naked DNA was released rapidly from fibrin clots (>70% within the first seven days) in contrast to COPROGs which remained tightly immobilized over extended periods of time (0.29% release per day). Electron microscopy of chondrocytecolonized COPROG-clots revealed avid endocytotic vector uptake. In situ BMP-2 gene transfection and subsequent expression in chondrocytes grown in COPROG clots resulted in the upregulation of alkaline phosphatase expression and increased extracellular matrix formation in vitro. COPROG-fibrinogen preparations with admixed autologous chondrocytes when clotted in situ in osteochondral defects in the patellar grooves of rabbit femura gave rise to luciferase reporter gene expression detectable for two weeks (n=3 animals per group). However, no significant improvement in cartilage formation in osteochondral defects filled with autologous chondrocytes in BMP-2-COPROG clots was achieved in comparison to controls (n=8 animals per group). CONCLUSIONS: COPROGs co-lyophilized with fibrinogen are a simple basis for an injectable fibrin gluebased gene-activated matrix. The preparation can be used is complete analogy to fibrin glue preparations that are used in the clinics. However, further improvements in transgene expression levels and persistence are required to yield cartilage regeneration in the osteochondral defect model chosen in this study.
AU  - Schillinger, U.*
AU  - Wexel, G.*
AU  - Hacker, C.*
AU  - Kullmer, M.*
AU  - Koch, C.*
AU  - Gerg, M.*
AU  - Vogt, S.*
AU  - Ueblacker, P.*
AU  - Tischer, T.*
AU  - Hensler, D.*
AU  - Wilisch, J.*
AU  - Aigner, J.*
AU  - Walch, A.K.
AU  - Stemberger, A.*
AU  - Plank, C.*
C1  - 2350
C2  - 25762
SP  - 2946-2962
TI  - A fibrin glue composition as carrier for nucleic acid vectors.
JO  - Pharm. Res.
VL  - 25
IS  - 12
PB  - Springer
PY  - 2008
SN  - 0724-8741
ER  -