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Microgels as drug delivery vehicles: loading and release of amphiphilic drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Pharmaceutical Physical Chemistry)
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polyelectrolyte microgels are used as delivery vehicles for amphiphilic drugs in, e.g., treatments of liver cancer by a method called trans-arterial chemoembolization. The thesis deals with fundamental properties of such delivery systems related to the self-assembling properties of the drug molecules and their interaction with the charged polymer network of the microgel. The main objective was to establish mechanistic models describing the loading and release of drugs under relevant conditions. For that purpose experimental techniques providing thermodynamic, compositional and microstructural information were used to elucidate how the kinetics depend on the stability of the drug self-assemblies and the volume response of the microgels. Micromanipulator-assisted microscopy studies showed that negatively charged microgels phase separated during loading and release of cationic amphiphilic drugs. At intermediate loading levels the drug aggregates and part of the network formed a collapsed phase coexisting with a swollen, drug-lean phase. In particular, during release in a medium of physiological ionic strength, the drug-lean phase formed a depletion layer (shell) surrounding a drug-rich core. Investigations of a series of drugs with different molecular architectures showed that the drug release rate was determined mainly by the stability of the drug aggregates in the core and the diffusive mass transport of drug molecules through the shell. Detailed studies of polyacrylate microgels interacting with amitriptyline hydrochloride showed that swelling of the shell network greatly influenced the release rate. Furthermore, experiments with a specially constructed microscopy cell was used to establish that the collapsed and swollen phases could coexist in equilibrium, and that the swelling of the network in the swollen phase depended on the proportion between them when present in the same microgel. The latter effect was related to the elastic coupling between the phases. Confocal Raman microscopy was employed to demonstrate, for the first time, the related elastic effect, that the concentration of amitriptyline in the swollen phase decreased with increasing proportion of the collapsed phase. Small-angle X-ray scattering showed that the collapsed phase had a disordered microstructure of drug micelles with ellipsoidal shape. The aggregation number increased with increasing concentration of drug in the microgel, most likely by incorporating the uncharged base form. By providing detailed information about thermodynamic properties and microstructures, the results of the thesis provide a basis for rational design of microgel drug delivery systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. , p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 312
Keywords [en]
microgel, amphiphilic drug, phase separation, micropipette, Raman microscopy, controlled release, drug delivery, SAXS
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-472818ISBN: 978-91-513-1502-7 (print)OAI: oai:DiVA.org:uu-472818DiVA, id: diva2:1652297
Public defence
2022-06-14, Room A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2022-05-17 Created: 2022-04-18 Last updated: 2022-06-15
List of papers
1. Single bead investigation of a clinical drug delivery system – a novel release mechanism
Open this publication in new window or tab >>Single bead investigation of a clinical drug delivery system – a novel release mechanism
Show others...
2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, p. 235-247Article in journal (Refereed) Published
Abstract [en]

Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

Keywords
Microgel, Drug delivery, Release mechanism
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-360988 (URN)10.1016/j.jconrel.2018.11.011 (DOI)000452348100019 ()30419268 (PubMedID)
Funder
Swedish Research Council, 521-2011-373
Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2022-04-18Bibliographically approved
2. Drug-Eluting Polyacrylate Microgels: Loading and Release of Amitriptyline
Open this publication in new window or tab >>Drug-Eluting Polyacrylate Microgels: Loading and Release of Amitriptyline
2020 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 124, no 11, p. 2289-2304Article in journal (Refereed) Published
Abstract [en]

We investigated the loading of an amphiphilic drug, amitriptyline hydrochloride (AMT), onto sodium polyacrylate hydrogels at low ionic strength and its release at high ionic strength. The purpose was to show how the self-assembling properties of the drug and the swelling of the gel network influenced the loading/release mechanisms and kinetics, important for the development of improved controlled-release systems for parenteral administration of amphiphilic drugs. Equilibrium studies showed that single microgels (similar to 100 mu m) in a large solution volume underwent a discrete transition between swollen and dense states at a critical drug concentration in the solution. For single macrogels in a small solution volume, the transition progressed gradually with increasing amount of added drug, with swollen and dense phases coexisting in the same gel; in a suspension of microgels, swollen and collapsed particles coexisted. Time-resolved micropipette-assisted microscopy studies showed that drug self-assemblies accumulated in a dense shell enclosing the swollen core during loading and that a dense core was surrounded by a swollen shell during release. The time evolution of the radius of single microgels was determined as functions of liquid flow rate, network size, and AMT concentration in the solution. Mass transport of AMT in the surrounding liquid, and in the dense shell, influenced the deswelling rate during loading. Mass transport in the swollen shell controlled the swelling rate during release. A steady-state kinetic model taking into account drug self-assembly, core-shell phase separation, and microgel volume changes was developed and found to be in semiquantitative agreement with the experimental loading and release data.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2020
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-410897 (URN)10.1021/acs.jpcb.0c00030 (DOI)000526862000026 ()32105083 (PubMedID)
Funder
Vinnova, Dnr 2017-02690
Available from: 2020-05-25 Created: 2020-05-25 Last updated: 2022-04-18Bibliographically approved
3. Drug-Induced Phase Separation in Polyelectrolyte Microgels
Open this publication in new window or tab >>Drug-Induced Phase Separation in Polyelectrolyte Microgels
2022 (English)In: Gels, E-ISSN 2310-2861, Vol. 8, no 1, article id 4Article in journal (Refereed) Published
Abstract [en]

Polyelectrolyte microgels may undergo volume phase transition upon loading and the release of amphiphilic molecules, a process important in drug delivery. The new phase is "born" in the outermost gel layers, whereby it grows inward as a shell with a sharp boundary to the "mother" phase (core). The swelling and collapse transitions have previously been studied with microgels in large solution volumes, where they go to completion. Our hypothesis is that the boundary between core and shell is stabilized by thermodynamic factors, and thus that collapsed and swollen phases should be able to also coexist at equilibrium. We investigated the interaction between sodium polyacrylate (PA) microgel networks (diameter: 400-850 mu m) and the amphiphilic drug amitriptyline hydrochloride (AMT) in the presence of NaCl/phosphate buffer of ionic strength (I) 10 and 155 mM. We used a specially constructed microscopy cell and micromanipulators to study the size and internal morphology of single microgels equilibrated in small liquid volumes of AMT solution. To probe the distribution of AMT micelles we used the fluorescent probe rhodamine B. The amount of AMT in the microgel was determined by a spectrophotometric technique. In separate experiments we studied the binding of AMT and the distribution between different microgels in a suspension. We found that collapsed, AMT-rich, and swollen AMT-lean phases coexisted in equilibrium or as long-lived metastable states at intermediate drug loading levels. In single microgels at I = 10 mM, the collapsed phase formed after loading deviated from the core-shell configuration by forming either discrete domains near the gel boundary or a calotte shaped domain. At I = 155 mM, single microgels, initially fully collapsed, displayed a swollen shell and a collapsed core after partial release of the AMT load. Suspensions displayed a bimodal distribution of swollen and collapsed microgels. The results support the hypothesis that the boundary between collapsed and swollen phases in the same microgel is stabilized by thermodynamic factors.

Place, publisher, year, edition, pages
MDPI AG, 2022
Keywords
microgel, drug, amphiphile, phase transition, phase separation, microscopy, micropipette, binding isotherm, swelling
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-469557 (URN)10.3390/gels8010004 (DOI)000757572900001 ()35049539 (PubMedID)
Available from: 2022-03-14 Created: 2022-03-14 Last updated: 2022-04-18Bibliographically approved
4. A small-angle X-ray scattering study of amphiphilic drug self-assemblies in polyacrylate microgels
Open this publication in new window or tab >>A small-angle X-ray scattering study of amphiphilic drug self-assemblies in polyacrylate microgels
2024 (English)In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 686, article id 133403Article in journal (Refereed) Published
Abstract [en]

Common ionisable amphiphilic drug molecules form micelles in aqueous solution. Loaded onto oppositely charged polyelectrolyte microgels they associate with the network chains to form dense complex phases. The self-assembling properties control the loading and release properties in drug delivery applications of microgel systems but little is known about the nature of the aggregates and the phase structure. In this paper, we investigated the size and organization of the self-assemblies formed by the hydrochloride salts of amitriptyline (AMT), chlorpromazine (CPZ), and doxepin (DXP) in sodium polyacrylate microgels. Small-angle X-ray scattering (SAXS) was used to determine the microstructure of drug loaded microgels in aqueous environment at ionic strengths relevant for drug loading (0.01 M) and release (0.15 M). The composition of drug loaded microgels was determined by means of a purpose built microscopy cell and UV spectroscopy measurements. Upon drug loading the microgels formed complex phases of low water content. SAXS experiments showed that the drugs formed oblate shaped or spherical micelles displaying local ordering but without long-range ordering even at very high micelle volume fractions. The local ordering resembled the packing of randomly packed hard oblates and spheres. The aggregation number of AMT varied between 10 and 49 depending on the composition. Incorporation of the uncharged base form of the drug caused a transformation of oblate shaped (aspect ratio ∼ 0.4) to spherical micelles, accompanied by an abrupt increase of the aggregation number. Variation of the ionic strength had minor effects on the aggregation number. CPZ formed oblate shape micelles (aspect ratios 0.3–0.4) with aggregation number between 9 and 30. DXP formed oblate shape micelles (aspect ratios 0.3–0.4) with aggregation numbers 10 − 11 at all studied compositions. The results provide a structural basis for, and justification of, previously assumed microstructures underlying mechanistic models of drug-microgel interactions and drug release.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Amphiphilic drug, Microgel, Self-assembly, Small-angle X-ray scattering, Ellipsoidal packing, Polyelectrolyte
National Category
Pharmaceutical Sciences Physical Chemistry
Research subject
Pharmaceutical Physical Chemistry; Pharmaceutical Science; Pharmaceutics
Identifiers
urn:nbn:se:uu:diva-472815 (URN)10.1016/j.colsurfa.2024.133403 (DOI)001184937500001 ()
Funder
Vinnova, 2019-00048
Available from: 2022-04-18 Created: 2022-04-18 Last updated: 2024-04-02Bibliographically approved
5. Elastic forces give rise to unusual phase transformations in polyelectrolyte gels: A Raman microscopy study
Open this publication in new window or tab >>Elastic forces give rise to unusual phase transformations in polyelectrolyte gels: A Raman microscopy study
(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry; Pharmaceutical Science; Pharmaceutics
Identifiers
urn:nbn:se:uu:diva-472817 (URN)
Available from: 2022-04-18 Created: 2022-04-18 Last updated: 2022-04-18

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