Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting

In spite of the success of current therapies and preventive strategies in reducing cardiovascular risk, cardiovascular diseases (CVD) continue to be the leading cause of death globally. Inflammation is the underlying pathological process of atherosclerosis, the major cause of most CVD, but has not b...

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Main Author: Darwitan, Anastasia
Other Authors: Subbu S. Venkatraman
Format: Thesis-Doctor of Philosophy
Language:English
Published: Nanyang Technological University 2020
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Online Access:https://hdl.handle.net/10356/137197
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spelling sg-ntu-dr.10356-1371972020-11-01T05:03:24Z Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting Darwitan, Anastasia Subbu S. Venkatraman Interdisciplinary Graduate School (IGS) subbu@nus.edu.sg Engineering::Nanotechnology In spite of the success of current therapies and preventive strategies in reducing cardiovascular risk, cardiovascular diseases (CVD) continue to be the leading cause of death globally. Inflammation is the underlying pathological process of atherosclerosis, the major cause of most CVD, but has not been adequately addressed. Additionally, the increasing age trend of general population will present increasing incidence with individual’s unique and complex coronary anatomy with high-risk comorbidities. Thus, there is a need for novel therapies that are effective. Anti-inflammatory agents, such as glucocorticoids (GC), when administered systemically for long duration, are associated with systemic adverse effect. One strategy to circumvent this is by utilizing a nanocarrier to encapsulate the active agents, thereby preventing off-target interaction and enabling targeted and sustained delivery of the active compounds at the diseased site; hence, enhancement of benefit/risk ratio of the therapeutic agents. In this report, both passive and active targeting strategies were explored using nanoliposomes as the nanocarrier. In passive strategy, nanoliposomes circulate in the bloodstream and preferentially accumulate at the sites of inflammation, which are characterized by dysfunctional endothelium and enhanced vascular leakiness, through ‘Enhanced Permeability and Retention’ (EPR) effect. Passive liposomes encapsulating fluocinolone acetonide (FA) were developed and reported in this thesis. Encapsulation efficiency of around 90% was achieved with final drug/lipid molar ratio of around 0.11. Release was sustained up to 30 days in vitro and the formulation was stable for at least 3 months. In active strategy, active ligands were decorated on nanoliposomal surface for enhancement of cell internalization. In this report, it was demonstrated that foam cells expressed high number of targetable cell surface folate receptors. Optimum cell uptake enhancement was achieved with 0.5 mol% folate (FOL) with polyethylene glycol (PEG) 2000 spacer. Subsequently, ligand-free PEG was incorporated on active liposomes with PEG 2000 (0.5% FOL) and cell uptake was evaluated after pre-incubation of liposomes in 80% serum in order to mimic the presence of high level of serum in vivo. It was demonstrated that the active targeting effect of active targeting nanoliposomes progressively decreased and eventually be lost as PEG-to-ligand ratio is increased. However, the value of PEG-to-ligand ratio at which the targeting effect was lost depended on PEG length (>2 for PEG 750; >0.5 for PEG 2000; <0.5 for PEG 5000). The novel anti-inflammatory therapy developed in this PhD work could be envisioned for treatment after an acute clinical event or as adjunct therapy for prevention of in-stent restenosis in patients receiving bare metal stents. Individually, the passive liposomal formulation developed represents novel anti-inflammatory therapeutic option for atherosclerosis. It can also be considered for other inflammatory conditions, such as diabetic macular edema. The active liposome formulation developed could potentially enhance therapeutic efficacy of liposomal anti-inflammatory nanotherapy. The knowledge from active liposome studies could contribute in development of other active nanocarriers utilizing PEG and ligand-PEG. Doctor of Philosophy 2020-03-06T02:13:53Z 2020-03-06T02:13:53Z 2020 Thesis-Doctor of Philosophy Darwitan, A. (2020). Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting. Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/137197 10.32657/10356/137197 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Engineering::Nanotechnology
spellingShingle Engineering::Nanotechnology
Darwitan, Anastasia
Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
description In spite of the success of current therapies and preventive strategies in reducing cardiovascular risk, cardiovascular diseases (CVD) continue to be the leading cause of death globally. Inflammation is the underlying pathological process of atherosclerosis, the major cause of most CVD, but has not been adequately addressed. Additionally, the increasing age trend of general population will present increasing incidence with individual’s unique and complex coronary anatomy with high-risk comorbidities. Thus, there is a need for novel therapies that are effective. Anti-inflammatory agents, such as glucocorticoids (GC), when administered systemically for long duration, are associated with systemic adverse effect. One strategy to circumvent this is by utilizing a nanocarrier to encapsulate the active agents, thereby preventing off-target interaction and enabling targeted and sustained delivery of the active compounds at the diseased site; hence, enhancement of benefit/risk ratio of the therapeutic agents. In this report, both passive and active targeting strategies were explored using nanoliposomes as the nanocarrier. In passive strategy, nanoliposomes circulate in the bloodstream and preferentially accumulate at the sites of inflammation, which are characterized by dysfunctional endothelium and enhanced vascular leakiness, through ‘Enhanced Permeability and Retention’ (EPR) effect. Passive liposomes encapsulating fluocinolone acetonide (FA) were developed and reported in this thesis. Encapsulation efficiency of around 90% was achieved with final drug/lipid molar ratio of around 0.11. Release was sustained up to 30 days in vitro and the formulation was stable for at least 3 months. In active strategy, active ligands were decorated on nanoliposomal surface for enhancement of cell internalization. In this report, it was demonstrated that foam cells expressed high number of targetable cell surface folate receptors. Optimum cell uptake enhancement was achieved with 0.5 mol% folate (FOL) with polyethylene glycol (PEG) 2000 spacer. Subsequently, ligand-free PEG was incorporated on active liposomes with PEG 2000 (0.5% FOL) and cell uptake was evaluated after pre-incubation of liposomes in 80% serum in order to mimic the presence of high level of serum in vivo. It was demonstrated that the active targeting effect of active targeting nanoliposomes progressively decreased and eventually be lost as PEG-to-ligand ratio is increased. However, the value of PEG-to-ligand ratio at which the targeting effect was lost depended on PEG length (>2 for PEG 750; >0.5 for PEG 2000; <0.5 for PEG 5000). The novel anti-inflammatory therapy developed in this PhD work could be envisioned for treatment after an acute clinical event or as adjunct therapy for prevention of in-stent restenosis in patients receiving bare metal stents. Individually, the passive liposomal formulation developed represents novel anti-inflammatory therapeutic option for atherosclerosis. It can also be considered for other inflammatory conditions, such as diabetic macular edema. The active liposome formulation developed could potentially enhance therapeutic efficacy of liposomal anti-inflammatory nanotherapy. The knowledge from active liposome studies could contribute in development of other active nanocarriers utilizing PEG and ligand-PEG.
author2 Subbu S. Venkatraman
author_facet Subbu S. Venkatraman
Darwitan, Anastasia
format Thesis-Doctor of Philosophy
author Darwitan, Anastasia
author_sort Darwitan, Anastasia
title Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
title_short Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
title_full Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
title_fullStr Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
title_full_unstemmed Liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
title_sort liposomal nanotherapy for treatment of atherosclerosis : passive versus active targeting
publisher Nanyang Technological University
publishDate 2020
url https://hdl.handle.net/10356/137197
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