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Identifier | 000452711 | ||||||
Title | 1. Biodegradable diblock and triblock copolymers for use in drug delivery 2. Polymeric drug carrier for ocular drug delivery | ||||||
Alternative Title | 1.Βιοαποικοδομήσιμα δισυσταδικά και τρισυσταδικά συμπολυμερή για χρήση σε μεταφορά φαρμάκων 2. Πολυμερικοί φορείς φαρμάκου για μεταφορά φαρμάκου στο μάτι | ||||||
Author | Φεργάδης, Γεώργιος Δημήτριος | ||||||
Thesis advisor | Βαμβακάκη, Μαρία | ||||||
Reviewer |
Τσιλιμπάρης, Μιλτιάδης
Χαραλαμπόπουλος, Ιωάννης |
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Abstract |
1st. Efficient drug delivery to the ocular tissues faces several challenges due to the presence of several dynamic and static barriers, such as the blood–ocular barrier, tear formation and the low permeability of the cornea. Several nanomedicines have been formulated and evaluated for ocular drug delivery over the years, among which are polymeric micelles, liposomes, hydrosizes, polymer-drug and protein-drug conjugates [1]. However, to the best of our knowledge, there are no examples of biodegradable systems, comprising materials which are approved by the Food and Drug Administration (FDA), being also capable of slowing down the release profile of drug, reported in the literature. Hence, the development of drug delivery systems that can ensure a suitable drug concentration for a prolonged time in different ocular tissues is certainly of great importance. In the present thesis, we aimed to develop polymeric nanocarriers for the encapsulation and delivery of Flurbiprofen, a nonsteroidal anti-inflammatory drug. Flurbiprofen is used before an ocular surgery in order to reduce or prevent miosis and it’s also used orally for the symptomatic treatment of arthritis. In the first part of this thesis, amphiphilic poly(ethylene glycol)-block-poly(L-lactide) (PEG-b-PLLA) diblock and PLLA-b-PEG-b-PLLA triblock copolymers were synthesized. For the polymer synthesis, the ring-opening polymerization of the hydrophobic monomer L-lactide was used [2]. Ring-opening polymerization (ROP) is a type of chain-growth polymerization in which the terminus of the polymer chain attacks the cyclic monomer to form longer polymer chains. The polymerization was carried out in the presence of stannous octoate (Sn(Oct)2) as the catalyst. The successful synthesis of the polymers was verified by size exclusion chromatography (SEC) whereas their composition was determined by proton nuclear magnetic resonance (1H NMR) spectroscopy. In the second part of this thesis, the amphiphilic copolymers were self-assembled in water to form micellar structures, able to encapsulate small hydrophobic molecules [3]. The nanocarriers were prepared by dissolution of the polymer in an organic solvent followed by the dropwise addition of the aqueous phase. The size of the nanocarriers was determined by dynamic light scattering (DLS). The shape and the morphology of the nanocarriers was confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), respectively. Next, the release profile of Flurbiprofen from the polymeric nanocarriers was studied. Polymeric micelles from the diblock copolymer showed a release rate of 100% in four days of 8μg of Flurbiprofen, while micelles from the triblock copolymer had a release of 100% of 2.5μg of the drug at the same time. The more complex mixed micelles released 50% of the load in 6 hours and reached 100% release in 7 days, demonstrating a slower release rate compared to the diblock and triblock micelles. 2nd. The presence of many dynamic and static obstacles in the ocular tissues, such as the blood-ocular barrier, tear production, and the cornea's limited permeability, renders the effective ocular drug delivery a challenging task. Polymeric micelles, liposomes, hydrogels, polymer-drug, and protein-drug conjugates are examples of the modalities developed and tested, throughout the years, for ocular drug delivery [1]. However, to the best of our knowledge, there are no reports on biodegradable systems, which include FDA-approved materials, that are also capable of slowing down the drug release profiles, documented in the literature so far. As a result, the development of drug delivery systems that can maintain an appropriate drug concentration in various ocular tissues for an extended period of time is of great importance. In the present thesis, we have developed polymeric nanocarriers for the encapsulation and delivery of Flurbiprofen, a nonsteroidal anti-inflammatory drug, used in ocular therapy. Next, hydrogels comprising a oxidized, natural polysaccharide, dextran, were used as a matrix to incorporate these nanocarriers, as it has been shown that hydrogels can prolong the release of the drug molecules into the medium [2]. In the first part of this thesis, amphiphilic poly(ethylene glycol)-block-poly(L-lactide) (PEG-b-PLLA) diblock and PLLA-b-PEG-b-PLLA triblock copolymers were synthesized. For the synthesis of the diblock and triblock copolymers, ring-opening polymerization of the hydrophobic monomer, L-lactide, was carried out using monohydroxy and dihydroxy PEG as the macroinitiator, respectively [3]. Size exclusion chromatography (SEC) was employed to confirm the successful synthesis of the copolymers and proton nuclear magnetic resonance (1H NMR) spectroscopy was used to ascertain their composition. Next, the amphiphilic copolymers were self-assembled into micellar structures in water, which entrapped small hydrophobic drug molecules within their micellar cores [4]. Micelles were prepared from both the diblock and triblock copolymers, as well as from a mixture of the two copolymers in order to form more complex structures. Dynamic light scattering (DLS) was used to determine the hydrodynamic size of the nanocarriers. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were employed to confirm the morphology of the nanocarriers. Next, the release profile of flurbiprofen from the polymeric nanostructures was studied. All the micellar structures released the drug within 4 days reaching 100% of release. Thus, the different chemical composition of the copolymers was not able to slow down sufficiently the release kinetics of the drug. In the second part of this work, to further slow-down the release profile of flurbiprofen from the polymer carriers, we developed biodegradable hydrogels and incorporated the drug loaded micellar structures within their porous structures. The hydrogels were prepared through the reaction of oxidized dextran (Ald-Dex), which bears aldehyde groups, with adipic acid dihydrazide (AAD), to form acylhydrazone bonds. The crosslinker, adipic acid dihydrazide, ranged between 10 and 30 wt% with respect to the polymer. The synthesized hydrogels were characterized in terms of their chemical composition and morphology by Fourier Transform infrared spectroscopy (FTIR) and SEM, respectively. Next, the flurbiprofen loaded polymeric nanocarriers were incorporated within the hydrogels and the release profile of the drug molecules was studied. The hydrogels were found to release 100% of the payload within 7 days, exhibiting a delay in the drug release profile compared to the micellar system alone. |
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Language | English, Greek | ||||||
Subject | Polymer | ||||||
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Μάτι | |||||||
Πολυμερή | |||||||
Φάρμακα | |||||||
Issue date | 2022-12-09 | ||||||
Collection | School/Department--School of Medicine--Department of Medicine--Post-graduate theses | ||||||
Type of Work--Post-graduate theses | |||||||
Permanent Link |
https://elocus.lib.uoc.gr//dlib/5/9/c/metadata-dlib-1673426729-807498-9043.tkl![]() ![]() |
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Biodegradable diblock and triblock copolymers for use in drug delivery Download document |
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Polymeric drug carrier for ocular drug delivery Download document |