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Pharmaceutical Quality by Design Approach to Develop High-Performance Nanoparticles for Magnetic Hyperthermia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-3710-405X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
Department of Materials and Environmental Chemistry, Stockholm University, 10691 Stockholm, Sweden.ORCID iD: 0000-0002-0999-3569
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
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2024 (English)In: ACS Nano, ISSN 1936-0851, E-ISSN 1936-086X, Vol. 18, no 23, p. 15284-15302Article in journal (Refereed) Published
Abstract [en]

Magnetic hyperthermia holds significant therapeutic potential, yet its clinical adoption faces challenges. One obstacle is the large-scale synthesis of high-quality superparamagnetic iron oxide nanoparticles (SPIONs) required for inducing hyperthermia. Robust and scalable manufacturing would ensure control over the key quality attributes of SPIONs, and facilitate clinical translation and regulatory approval. Therefore, we implemented a risk-based pharmaceutical quality by design (QbD) approach for SPION production using flame spray pyrolysis (FSP), a scalable technique with excellent batch-to-batch consistency. A design of experiments method enabled precise size control during manufacturing. Subsequent modeling linked the SPION size (6–30 nm) and composition to intrinsic loss power (ILP), a measure of hyperthermia performance. FSP successfully fine-tuned the SPION composition with dopants (Zn, Mn, Mg), at various concentrations. Hyperthermia performance showed a strong nonlinear relationship with SPION size and composition. Moreover, the ILP demonstrated a stronger correlation to coercivity and remanence than to the saturation magnetization of SPIONs. The optimal operating space identified the midsized (15–18 nm) Mn0.25Fe2.75O4 as the most promising nanoparticle for hyperthermia. The production of these nanoparticles on a pilot scale showed the feasibility of large-scale manufacturing, and cytotoxicity investigations in multiple cell lines confirmed their biocompatibility. In vitro hyperthermia studies with Caco-2 cells revealed that Mn0.25Fe2.75O4 nanoparticles induced 80% greater cell death than undoped SPIONs. The systematic QbD approach developed here incorporates process robustness, scalability, and predictability, thus, supporting the clinical translation of high-performance SPIONs for magnetic hyperthermia.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024. Vol. 18, no 23, p. 15284-15302
Keywords [en]
quality by design, superparamagnetic nanoparticles, magnetic hyperthermia, design of experiments, flame spray pyrolysis, doped ferrites
National Category
Pharmaceutical Sciences Other Materials Engineering
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-527076DOI: 10.1021/acsnano.4c04685ISI: 001236198600001PubMedID: 38814737OAI: oai:DiVA.org:uu-527076DiVA, id: diva2:1853573
Funder
Science for Life Laboratory, SciLifeLabEU, Horizon 2020, 101002582
Note

Title in the list of papers of Shaquib Rahman Ansari's thesis: A pharmaceutical quality by design approach to develop high performance nanoparticles for magnetic hyperthermia

Available from: 2024-04-23 Created: 2024-04-23 Last updated: 2024-10-24Bibliographically approved
In thesis
1. From design to application: Iron oxide nanoparticles for imaging and therapeutics in inflammatory and infectious diseases
Open this publication in new window or tab >>From design to application: Iron oxide nanoparticles for imaging and therapeutics in inflammatory and infectious diseases
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Superparamagnetic iron oxide nanoparticles (SPIONs) are a promising advancement in nanomedicine, demonstrating remarkable potential in both diagnostic and therapeutic applications. They can be magnetized in a magnetic field and do not show permanent magnetization, allowing precise localization within the body. Under an alternating magnetic field, SPIONs generate heat, which can be used for magnetic hyperthermia therapy against cancer or to trigger drug release. Diagnostically, they are widely used as contrast agents for magnetic resonance imaging (MRI), while magnetic particle imaging (MPI) is an emerging preclinical diagnostic technique using SPIONs as tracers.

Despite these promising applications, the clinical utility of SPIONs is hindered by challenges related to scalable and reproducible manufacturing. Focused efforts are also needed to improve MPI resolution. Moreover, the application of magnetic hyperthermia for treating inflammatory and infectious conditions remains relatively underexplored. Therefore, the primary objective of this thesis was to develop SPIONs tailored for imaging and therapy of inflammatory and infectious diseases through scalable manufacturing techniques. 

The first part of the study involved a systematic review to examine the most pertinent research on use of SPIONs for diagnosing and treating chronic inflammatory diseases. MRI was identified as the predominant application of SPIONs. However, there was limited exploration of MPI and magnetic hyperthermia for imaging and treating inflammatory diseases, respectively.

In the second project, a risk-based pharmaceutical quality by design approach was used to optimize SPIONs for magnetic hyperthermia. The effect of nanoparticle properties on MPI performance was systematically investigated in the third project. Additionally, these projects established flame spray pyrolysis as a scalable and reproducible technique, for synthesizing nanoparticles with complex stoichiometry for magnetic hyperthermia and MPI.

In final part of the study, SPIONs were incorporated into composites by scalable techniques, to improve the treatment of inflammatory and infectious diseases. SPIONs were incorporated in tablets with an anti-inflammatory drug, celecoxib. The drug solubility improved significantly through magnetic hyperthermia-induced in situ amorphization. SPIONs were also incorporated into microfibers, and heat dissipation from magnetic microfibers was used with doxycycline against methicillin-resistant Staphylococcus aureus. This resulted in substantial reduction in bacterial growth compared to using the drug alone.

This thesis introduced systematic exploration of SPION properties and their functional performance, established a scalable synthesis technique for their production, and developed novel systems for wider adaptation of SPIONs in biomedical applications.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 74
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 352
Keywords
Iron oxide nanoparticles, magnetic hyperthermia, quality by design, magnetic particle imaging, inflammatory diseases, poorly water-soluble drugs, in situ amorphization, infectious diseases, magnetic microfibers
National Category
Pharmaceutical Sciences Nano Technology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-527079 (URN)978-91-513-2144-8 (ISBN)
Public defence
2024-06-14, room A1:111a, Biomedical Center, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2024-05-24 Created: 2024-04-23 Last updated: 2024-05-24

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Rahman Ansari, ShaquibSuárez-López, Yael del CarmenThersleff, ThomasHäggström, LennartEricsson, ToreKatsaros, IoannisÅhlén, MichelleKarlgren, MariaSvedlindh, PeterTeleki, Alexandra

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Rahman Ansari, ShaquibSuárez-López, Yael del CarmenThersleff, ThomasHäggström, LennartEricsson, ToreKatsaros, IoannisÅhlén, MichelleKarlgren, MariaSvedlindh, PeterTeleki, Alexandra
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