In Situ, In Vitro and In Vivo evaluation of effectiveness of new treatment approaches involving controlled drug delivery systems in cartilage degenerations

Aydın, Özlem
Osteoarthritis (OA) is a degenerative joint disease which has yet no complete treatment with medication. Doxycycline, a well-known antibiotic, has been shown to prevent matrixmetallopreoteinases-MMPs, indicating potency on OA treatment. However, long term systemic use can cause side effects on other tissues. This study aimed to develop controlled drug delivery systems of doxycycline/doxycycline-chondroitin sulfate (D/D-CS) in the form of PCL microspheres for providing a better and new treatment approach via local application. After optimization studies for size, loading efficiency, surface/structure and release properties, microspheres of low Mw PCL (14 kDa) was decided to be more suitable than those of high Mw (65 kDa). The release profile of former was also more compatible with diffusion model than that of latter. The bio-effectiveness of the microspheres was evaluated with three-dimensional in vitro model; osteoarthritic-rabbit chondrocytes embedded in agarose and subjected to interleukin-1β throughout incubations. In vitro treatments with D/D-CS microspheres showed significant reduction in MMP-13 activity compared with untreated OA controls for 15 and 24-day incubations. Although collagen and GAG analysis results showed no enhancement of synthesis with MS treatments, significant decrease in GAG and collagen release from D/D-CS MS treated groups and from D MS treated ones respectively. Overall evaluations of the efficacy using in vivo rabbit OA model showed better radiographic scores and histological outcomes for D/D-CS MS groups compared to only hyaluronan injected and/or untreated controls in 8 weeks. The ex-vivo biomechanical properties of cartilages demonstrated improved hardness with values comparable to healthy group upon application of D-CS MS.


In vitro and in vivo evaluation of doxycycline-chondroitin sulfate/PCLmicrospheres for intraarticular treatment of osteoarthritis
AYDIN, Ozlem; KORKUSUZ, FEZA; KORKUSUZ, PETEK; Tezcaner, Ayşen; BİLGİÇ, ELİF; Yaprakci, Volkan; Keskin, Dilek (2015-08-01)
Osteoarthritis (OA) is a degenerative joint disease, which has no complete treatment with medication yet. Intraarticular hyaluronan (HA) injection can decrease pain and modify the natural course of OA. This study was designed to provide long term delivery of an MMP (matrix-metalloproteinase) inhibitor agent-doxycycline, together with matrix regenerative agent-chondroitin sulfate for treating OA which progress with matrix degenerations. Doxycycline (D) and doxycycline-chondroitin sulfate (D-CS) loaded poly--...
In vitro evaluation of effects of sustained anti-TNF release from MPEG-PCL-MPEG and PCL microspheres on human rheumatoid arthritis synoviocytes
Erdemli, Ozge; Özen, Seza; Keskin, Dilek; Usanmaz, Ali; Batu, Ezgi Deniz; Atilla, Bülent; Tezcaner, Ayşen (2014-10-01)
Anti-tumor necrosis factor (TNF) drugs such as etanercept (ETN) have been mostly used in systemic treatment of rheumatoid arthritis. To eliminate the side effects in long-term treatments and to achieve a local sustained anti-inflammatory effect, a controlled drug delivery system is needed for anti-TNF drugs. This study aims to develop novel injectable microcarriers of ETN that can provide long-term controlled release of this protein drug upon intra-articular application. In this study, poly(epsilon-caprolac...
Synthesis and characterization of fatty acid based hyperbranched polymers for anti-cancer drug delivery
Güç, Esra; Gündüz, Ufuk; Department of Biology (2008)
Conventional methods of chemotherapy requires novel therapy systems due to serious side effects and inefficiency of drug administration. In recent years many studies are carried out to improve drug delivery systems. Polymers are one of the most important elements for drug delivery research due to their versatility. By the discovery of dendritic polymers, drug delivery studies gained a new vision. Highly branched monodisperse structure, multiple sites of attachment, well-defined size and controllable physica...
Targeted co-delivery of doxorubicin and TPGS to breast cancer cells by PLGA coated magnetic nanoparticles
Metin, Esra; Gündüz, Ufuk; Mutlu, Pelin; Department of Biotechnology (2017)
Although conventional chemotherapy is the most common method for cancer treatment, it has several side effects such as neuropathy, alopecia and cardiotoxicity. Since the drugs are given to body systemically, normal cells also effect as cancer cells. However, in recent years, targeted drug delivery has been developed to overcome these drawbacks.The targeting strategy can be changed depending on carrier types, but magnetic nanoparticles are commonly preferred due to their easy targetable features by using ext...
Danışık, Nurseda; Acar, Ahmet; Özen, Can; Department of Biotechnology (2022-10-31)
The development of drug resistance in tumor cells is one of the biggest problems currently in the clinic. As the pace of drug discovery slows and each new drug becomes increasingly expensive to bring to market, it is becoming clearer that better model systems and an understanding of drug resistance mechanisms are needed for second-line therapies. The overall aim of this project is to investigate the clonal evolution and drug resistance in colorectal cancer cell lines Caco-2 and HT-29 by using cellular barco...
Citation Formats
Ö. Aydın, “In Situ, In Vitro and In Vivo evaluation of effectiveness of new treatment approaches involving controlled drug delivery systems in cartilage degenerations,” Ph.D. - Doctoral Program, Middle East Technical University, 2011.