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Abstract
Optic neuropathies, such as glaucoma and diabetic retinal neuropathy, are a leading cause of acquired blindness. A common pathology of optic neuropathies is the loss of, non-regenerative retinal neurons, retinal ganglion cells (RGC). Drug delivery to the retina is an enormous challenge due to ocular uptake barriers.
In the clinic, injecting therapeutics directly into the vitreous body has become the preferred way of circumventing the ocular uptake barriers and enhancing the retinal drug bioavailability. Fast clearance rates of intravitreally injected drugs, unfortunately, poses the need for frequent injections increasing the risks for adverse effects and compromising patient compliance.
Loading drugs into nano-sized carriers, e.g. liposomes, hold the promise of enhancing the drug retention time in the eye. The vitreous is a hydrogel structure that has been proposed to act as a barrier to nano-carriers, depending on the specific surface characteristics of the carrier.
In this thesis, the diffusive behaviour and distribution of differently charged PEGylated liposomes in the ex vivo porcine eye was investigated using fluorescence correlation spectroscopy (FCS). The distribution of the liposomes after intravitreal injection was described by microscopy of cryosections of ex vivo porcine eyes. Negatively and neutrally charged liposomes were observed to diffuse faster in the vitreous than positively charged liposomes. PEGylated liposomes of all different surface charges were distributed evenly throughout the eye, negatively and neutrally charged liposomes 1 h post injection, positively charged liposomes 2 h after injection.
Having shown that liposomes can diffuse and distribute after intravitreal injection two liposome-based drug delivery systems, loaded with multiple pathway regulators for the cell survival and cell growth promoting pathways, Lip A and Lip B, were formulated and characterised. The multi-payload liposomes showed up-regulation of phosphorylated Akt in HEK293T cells and cellular uptake in 3Dinduced optic cup cell cultures ofmouse embryonic stem cells (mESC).
Efficacy of the multi-payload liposome was investigated in C57BL/6J mice with NMDA induced RGCloss. Lip A preserved RGCs and b-wave in electroretinograms
(ERG) significantly better than empty control liposomes,while Lip B showed significant preservation of stoscopic threshold response (STR), and trends of preserved b-wave and surviving RGCs 4 weeks post-treatment. The liposomes were also tested in combination with transplantation of Thy-1+ progenitor cells. Lib B showed a substantial amount of tumorigenesis when in conjunction with cell transplantation.
Lip A showed no significant effect on the survival of the transplanted cell when compared to empty control liposomes. The combination therapy did not show improvement of retinal function or RGC survival compared to the liposomes alone.
In the clinic, injecting therapeutics directly into the vitreous body has become the preferred way of circumventing the ocular uptake barriers and enhancing the retinal drug bioavailability. Fast clearance rates of intravitreally injected drugs, unfortunately, poses the need for frequent injections increasing the risks for adverse effects and compromising patient compliance.
Loading drugs into nano-sized carriers, e.g. liposomes, hold the promise of enhancing the drug retention time in the eye. The vitreous is a hydrogel structure that has been proposed to act as a barrier to nano-carriers, depending on the specific surface characteristics of the carrier.
In this thesis, the diffusive behaviour and distribution of differently charged PEGylated liposomes in the ex vivo porcine eye was investigated using fluorescence correlation spectroscopy (FCS). The distribution of the liposomes after intravitreal injection was described by microscopy of cryosections of ex vivo porcine eyes. Negatively and neutrally charged liposomes were observed to diffuse faster in the vitreous than positively charged liposomes. PEGylated liposomes of all different surface charges were distributed evenly throughout the eye, negatively and neutrally charged liposomes 1 h post injection, positively charged liposomes 2 h after injection.
Having shown that liposomes can diffuse and distribute after intravitreal injection two liposome-based drug delivery systems, loaded with multiple pathway regulators for the cell survival and cell growth promoting pathways, Lip A and Lip B, were formulated and characterised. The multi-payload liposomes showed up-regulation of phosphorylated Akt in HEK293T cells and cellular uptake in 3Dinduced optic cup cell cultures ofmouse embryonic stem cells (mESC).
Efficacy of the multi-payload liposome was investigated in C57BL/6J mice with NMDA induced RGCloss. Lip A preserved RGCs and b-wave in electroretinograms
(ERG) significantly better than empty control liposomes,while Lip B showed significant preservation of stoscopic threshold response (STR), and trends of preserved b-wave and surviving RGCs 4 weeks post-treatment. The liposomes were also tested in combination with transplantation of Thy-1+ progenitor cells. Lib B showed a substantial amount of tumorigenesis when in conjunction with cell transplantation.
Lip A showed no significant effect on the survival of the transplanted cell when compared to empty control liposomes. The combination therapy did not show improvement of retinal function or RGC survival compared to the liposomes alone.
Original language | English |
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Publisher | DTU Nanotech |
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Number of pages | 134 |
Publication status | Published - 2018 |
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Dive into the research topics of 'Novel Nanomedicines for the Treatment of Optic Neuropathy'. Together they form a unique fingerprint.Projects
- 1 Finished
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New nanomedicines for the treatment of diabetic retinopathy
Eriksen, A. Z. (PhD Student), Urquhart, A. (Main Supervisor), Kamaly, N. (Examiner), Wilson, C. G. (Examiner), Jensen, H. (Examiner) & Andresen, T. L. (Supervisor)
Technical University of Denmark
01/09/2014 → 07/03/2018
Project: PhD