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A small-angle X-ray scattering study of amphiphilic drug self-assemblies in polyacrylate microgels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Pharmaceutical Physical Chemistry)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. (Pharmaceutical Physical Chemistry)ORCID iD: 0000-0002-0895-1180
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. Vol. 686, article id 133403
Keywords [en]
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: urn:nbn:se:uu:diva-472815DOI: 10.1016/j.colsurfa.2024.133403ISI: 001184937500001OAI: oai:DiVA.org:uu-472815DiVA, id: diva2:1652292
Part of project
The Swedish Drug Delivery Center (SweDeliver), Vinnova
Funder
Vinnova, 2019-00048Available from: 2022-04-18 Created: 2022-04-18 Last updated: 2024-04-02Bibliographically approved
In thesis
1. Microgels as drug delivery vehicles: loading and release of amphiphilic drugs
Open this publication in new window or tab >>Microgels as drug delivery vehicles: loading and release of amphiphilic drugs
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
microgel, amphiphilic drug, phase separation, micropipette, Raman microscopy, controlled release, drug delivery, SAXS
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-472818 (URN)978-91-513-1502-7 (ISBN)
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

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Al-Tikriti, YassirHansson, Per

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