Browsing by Subject "drug delivery"

The leading causes of vision loss in developed countries are related to the impairment of the posterior segment of the eye. The drug delivery to the posterior segment with topical or systemic methods is challenging due to the protective barriers of the eye. The conventional and effective technique to deliver therapeutic concentrations of drugs to the posterior segment is intravitreal injection. Since naked molecules usually have a rapid vitreal clearance, the invasive injections need repeated administration in chronic conditions, resulting to increased risk of complications and poor patient compliance. The growing field of research of drug delivery systems, such as implants, nano- and microparticles and liposomes emphasizes to answer these challenges by enhancing time-controlled and targeted drug release to retinal and choroidal tissues, enabling less frequent administration and reduced off-target side effects. Liposomal drug delivery systems have potential in delivering therapeutics to posterior eye tissues in sustained and targeted manner. The experimental part of the thesis focused on studying the cell uptake, content release and cytotoxicity of light triggered pH-sensitive gold nanoparticle liposomes in human retinal pigment epithelial (ARPE-19), human umbilical vein endothelial (HUVEC) and monkey choroidal endothelial (RF/6A) cell lines. To enhance the cell differentiation to resemble the in vivo morphology, ARPE-19 cells were also used as a filter-cultured model. HUVEC cells were cultured on an artificial basement membrane matrix and induced with vascular endothelial growth factor (VEGF) to form capillary like tube structures. The liposomes were not cytotoxic during 24-hour incubation. All cells internalized liposomes to some extent, but in HUVEC capillary tubes the uptake seemed to be negligible. The light induced calcein release was variable between the experiments, possibly due to the study setting related factors, such as difficulties in temperature control. The liposomal carrier system has promising attributes to posterior eye drug delivery. Liposome-encapsulation prolongs the half-live of a drug. Light triggered release and pH-sensitivity enables highly targeted intracellular drug release decreasing the off-target side effects. Optimization of the study arrangement and liposome production procedure is needed in order to get more reliable results and further assess the future potential of these liposomes in the treatment of posterior eye diseases.

Throughout the history, there has been a wide selection of drugs developed for therapy of cardiovascular diseases (CVD). Despite a broad spectrum of different therapeutic strategies to deaccelerate and try to reverse the progression of cardiovascular diseases has been achieved, only a modest amelioration of the health of the CVD patients was achieved, as the mortality remains high by being the cause of nearly one in every three deaths yearly, myocardial infarction being involved in majority of these cases. Novel solutions are being studied to overcome this problem, one of them being nanoparticles, which may provide potential solution by carrying drugs to the desired location. Microfluidics technique may further improve the properties of nanoparticles, being a platform that allows the production of homogenous and repeatable batches that are non-dependent by the operator using it. In this thesis, it is described how microfluidics-based preparation of spermine-functionalised acetalated dextran nanoparticles co-loaded with a trisubstituted isoxazole and curcumin perform in physicochemical and in vitro experiments, in order to evaluate their potential in the application of ischemic myocardial injury therapy.

The usage of polymer conjugation to modulate the biopharmaceutical behavior of both protein drugs as well as small molecule drugs is discussed. Emphasis has been given to polyethylene glycol (PEG) and poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) but also other polymers are looked into. Drug products on the market as well as drug candidates in clinical trials are used as examples when reviewing different polymers. The material is looked upon from a biopharmaceutical point of view. In the experimental part a polymer-drug conjugate for the treatment of ovarian cancer is synthesized and characterized. The conjugate has a HPMA polymer backbone with the anticancer drug gemcitabine attached through enzymatically labile Gly-Phe-Leu-Gly linkers. The conjugate is expected to target passively and actively to cancer tissue. The enhanced permeation and retention effect is responsible for the passive targeting, while Fab' fragments of OV-TL16 monoclonal antibodies provide the active targeting of the copolymer conjugate. In vitro cytotoxicity studies of a PHPMA-gemcitabine conjugate (without active targeting) was carried out on two ovarian cancer cell lines, A2780S and A2780AD. The IC50 values of the conjugate was shown to be 50.6 nM and 14.3 nM for A2780S and A2780AD, respectively. The corresponding IC50 values for free gemcitabine were 7.0 nM for the A2780S cell line and 3.9 nM for A2780AD cells. A preliminary in vivo efficacy study in mice with subcutaneous A2780AD tumor xenografts showed that a PHMA-gemcitabine conjugate given at a dose of 15 mg/kg (gemcitabine equivalence) was able to shrink the tumor volume by 50 % while only inducing minor body weight loss.