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Design of Functional Polymeric Nanoparticles for Biomedical Applications
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Coating Technology.ORCID iD: 0000-0001-8887-9141
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Most of the devastating diseases such as cancer are relatively incurable and have high risks of relapse. Therefore, persistent endeavors have been devoted to improve patient survival rate and quality of life. Drug delivery systems (DDS) based on polymeric nanoparticles (PNPs) have been demonstrated to increase the therapeutic index (efficacy/toxicity ratio) of chemotherapeutic agents. This thesis focuses on designing non-toxic and multifunctional biodegradable PNPs from preformed polymers for bioimaging and drug delivery applications. Multifunctional poly(lactide-co-glycolide) (PLGA) NPs were simultaneously loaded with imaging probes, superparamagnetic iron oxide nanoparticles (SPION) and manganese-doped zinc sulfide (Mn:ZnS) quantum dots (QDs), as well as an anti-cancer drug, busulfan (Bu), during the particle formation. The NPs were utilized to enhance magnetic resonance imaging (MRI) in vivo and controlled drug release in vitro (Paper I). Poly(ε-caprolactone) (PCL) was copolymerized with poly(ethylene glycol) (PEG) to achieve stealth property for in vivo purposes. Aluminum phthalocyanine, a photosensitizer and an anti-cancer drug, was encapsulated in the PEG-b-PCL NPs for photodynamic therapy during particle formation. The biodistribution of the prepared nanophotosensitizer showed targeted drug delivery toward lungs, liver and spleen as monitored by the intrinsic fluorescence of the photosensitizer (Paper II). The PEG-b-PCL NPs were loaded with SPION or surface functionalized with VivoTag 680XL fluorochrome and utilized for in vivo multimodal imaging, MRI and fluorescence imaging (Paper III). This thesis also presents stable and engineered PNPs obtained using reversible addition-fragmentation chain transfer (RAFT) mediated polymerization-induced self-assembly (PISA). Hydrophobic agents, nile red (NR) dye or doxorubicin (DOX) drug, were encapsulated in poly(N-[3- (dimethylamino) propyl] methacrylamide)-b-poly(methyl methacrylate) (PDMAPMA-b-PMMA) NPs via one-pot RAFT-mediated PISA in water (Paper IV). The PDMAPMA-b-PMMA NPs showed very monodisperse spheres and core-shell nanostructures. Stable and non-toxic poly(acrylic acid)-b-poly(butyl acrylate) (PAA-b-PBA) NPs, synthesized via RAFTmediated PISA in water, were surface engineered by allyl-functional groups prior to bio-conjugation for targeted drug delivery (Paper V). The engineered NPs retained their colloidal stability and size post-allyl functionalization. DOX was efficiently (90 %) encapsulated in the PAA-bPBA NPs during NPs formation. A controlled release pattern of DOX from PAA-b-PBA NPs was observed over 7 days.

Abstract [sv]

Aggressiva sjukdomar, såsom cancer, har ofta stor risk för återfall och är i många fall obotliga. Det gör att det finns en stark strävan efter att förbättra patienters livskvalitet och överlevnad. Nanopartikel-baserade system för att frisätta läkemedelbaserade på polymerer (PNPs) har visats vara lovande för att öka det terapeutiska indexet (effektivitet/toxicitet) för kemoterapeutiska medel. Denna avhandling fokuserar på att framställa icke-toxiska och multifunktionella biologiskt nedbrytbara PNPs för avbildning och läkemedelsadministrationsapplikationer från polymerer. Parallellt med partikelbildningen laddades multifunktionella poly(laktid-sam-glykolid) (PLGA) NPs med superparamagnetiska nanopartiklar av järnoxid (SPION) och kvantprickar (QDs) av mangandopad zinksulfid (Mn:ZnS), såväl som med ett anti-cancerläkemedel, busulfan (Bu). Dessa NPs användes sedan för att förbättra kontrasten i MRI in vivo och för kontrollerad läkemedelsfrisättning in vitro (Paper I). Polykaprolakton (PCL) sampolymeriserades med polyetylenglykol (PEG) för att uppnå partiklar med stealth-egenskaper. För fotodynamisk terapi inkapslades en fotosensibilisator av aluminiumftalocyanin som också är ett anticancerläkemedel i PEG-b-PCL NPs samtidigt som partiklarna bildades. Analys av dessas biodistribution med fluorescensmätningar visade en målsökande förmåga mot lunga, lever och mjälte, (Paper II). PEG-b-PCL NPs laddades också med SPION och ytfunktionaliserades med VivoTag 680XL fluorokrom och utvärderades med in vivo multimodal avbildning, MRI och fluorescensavbildning (Paper III). Denna avhandling presenterar också stabila och skräddarsydda PNPs syntetiserade med hjälp av reversibel addition-fragmenteringkedjeöverföring (RAFT) medierad polymerisation med inducerad självorganisation (PISA). Hydrofoba substanser, nile red (NR) färgämne eller doxorubicin (DOX) läkemedel, inkapslades i poly(N-[3- (dimetylamino)propyl] metakrylamid)-b-poly(metylmetakrylat) (PDMAPMA-b-PMMA) NPs via one-pot RAFT-medierad PISA (Paper IV). PDMAPMA-b-PMMA NPs påvisade mycket monodispersa sfärer och nanostrukturer med kärna-skal. Stabila och icke-toxiska NPs av poly(akrylsyra)-b-poly(butylakrylat) (PAA-b-PBA) ytmodifierades med allyl-grupper före biokonjugering för målsökande läkemedelsleverans (Paper V). De modifierade NPs behöll deras kolloidala stabilitet och storlek efter allyl-funktionalisering. DOX inkapslades effektivt (90 %) i PAA-bPBA NPs under partikelbildningen. Kontrollera frisättning av DOX från PAA-b-PBA NPs observerades under 7 dagar.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2020. Vol. 35, p. 65p. 3885-3894
Series
TRITA-CBH-FOU ; 2020:7
Keywords [en]
Biodegradable polymers, SPION, PISA, RAFT, nanoparticles, drug delivery, cytotoxicity, MRI, in vivo fluorescence imaging
National Category
Polymer Chemistry Nano Technology Pharmaceutical Chemistry
Research subject
Fibre and Polymer Science
Identifiers
URN: urn:nbn:se:kth:diva-263780ISBN: 978-91-7873-429-0 (electronic)OAI: oai:DiVA.org:kth-263780DiVA, id: diva2:1391469
Public defence
2020-03-06, sal F3, Lindstedtsvägen 26, KTH, 10:00 (English)
Opponent
Supervisors
Note

QC 2020-02-07

Available from: 2020-02-07 Created: 2020-02-04 Last updated: 2020-02-07Bibliographically approved
List of papers
1. Biodegradable polymeric vesicles containing magnetic nanoparticles,quantum dots and anticancer drugs for drug delivery and imaging
Open this publication in new window or tab >>Biodegradable polymeric vesicles containing magnetic nanoparticles,quantum dots and anticancer drugs for drug delivery and imaging
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2014 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, p. 3885-3894Article in journal (Refereed) Published
Abstract [en]

We have developed biodegradable polymeric vesicles as a nanocarrier system for multimodal bio-imaging and anticancer drug delivery. The poly(lactic-co-glycolic acid) (PLGA) vesicles were fabricated by encapsulating inorganic imaging agents of superparamagnetic iron oxide nanoparticles (SPION), manganese-doped zinc sulfide (Mn:ZnS) quantum dots (QDs) and the anticancer drug busulfan into PLGA nanoparticles via an emulsion-evaporation method. T2∗-weighted magnetic resonance imaging (MRI) of PLGA-SPION-Mn:ZnS phantoms exhibited enhanced negative contrast with r2∗ relaxivity of approximately 523 s(-1) mM(-1) Fe. Murine macrophage (J774A) cellular uptake of PLGA vesicles started fluorescence imaging at 2 h and reached maximum intensity at 24 h incubation. The drug delivery ability of PLGA vesicles was demonstrated in vitro by release of busulfan. PLGA vesicle degradation was studied in vitro, showing that approximately 32% was degraded into lactic and glycolic acid over a period of 5 weeks. The biodistribution of PLGA vesicles was investigated in vivo by MRI in a rat model. Change of contrast in the liver could be visualized by MRI after 7 min and maximal signal loss detected after 4 h post-injection of PLGA vesicles. Histological studies showed that the presence of PLGA vesicles in organs was shifted from the lungs to the liver and spleen over time.

Place, publisher, year, edition, pages
Elsevier: , 2014
Keywords
Anticancer drug delivery; Biodegradable polymer; Busulfan; Fluorescence imaging; Magnetic resonance imaging; Multifunctional nanoparticles
National Category
Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-266129 (URN)10.1016/j.biomaterials.2014.01.041 (DOI)000332431700017 ()24495486 (PubMedID)
Note

QC 20200102

Available from: 2019-12-23 Created: 2019-12-23 Last updated: 2020-02-19Bibliographically approved
2. Development and biodistribution of a theranostic aluminumphthalocyanine nanophotosensitizer
Open this publication in new window or tab >>Development and biodistribution of a theranostic aluminumphthalocyanine nanophotosensitizer
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2016 (English)In: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, E-ISSN 1873-1597, Vol. 13, p. 48-57Article in journal (Refereed) Published
National Category
Polymer Technologies Nano Technology
Identifiers
urn:nbn:se:kth:diva-267221 (URN)10.1016/j.pdpdt.2015.12.005 (DOI)000372376500009 ()
Note

QC 20200205

Available from: 2020-02-04 Created: 2020-02-04 Last updated: 2020-02-05Bibliographically approved
3. Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging
Open this publication in new window or tab >>Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging
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2016 (English)In: Journal of Nanobiotechnology, ISSN 1477-3155, Vol. 14, no 1, article id 82Article in journal (Refereed) Published
Abstract [en]

Background: Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging. Results: Busulphan entrapment efficiency was 83% while the drug release showed a sustained pattern over 10 h. SPION loaded-PEG-PCL micelles showed contrast enhancement in T-2*-weighted MRI with high r(2)* relaxivity. In vitro cellular uptake of PEG-PCL micelles labeled with fluorescein in J774A cells was found to be time-dependent. The maximum uptake was observed after 24 h of incubation. The biodistribution of PEG-PCL micelles functionalized with VivoTag 680XL was investigated in Balb/c mice over 48 h using in vivo fluorescence imaging. The results of real-time live imaging were then confirmed by ex vivo organ imaging and histological examination. Generally, PEG-PCL micelles were highly distributed into the lungs during the first 4 h post intravenous administration, then redistributed and accumulated in liver and spleen until 48 h post administration. No pathological impairment was found in the major organs studied. Conclusions: Thus, with loaded contrast agent and conjugated fluorochrome, PEG-PCL micelles as biodegradable and biocompatible nanocarriers are efficient multimodal imaging agents, offering high drug loading capacity, and sustained drug release. These might offer high treatment efficacy and real-time tracking of the drug delivery system in vivo, which is crucial for designing of an efficient drug delivery system.

Place, publisher, year, edition, pages
BioMed Central, 2016
Keywords
Biodegradable polymer, Drug delivery, Magnetic resonance imaging, In vivo fluorescence imaging, Biodistribution, Busulphan, Cancer
National Category
Microbiology
Identifiers
urn:nbn:se:kth:diva-200409 (URN)10.1186/s12951-016-0239-0 (DOI)000391072700002 ()2-s2.0-85006482286 (Scopus ID)
Funder
Swedish Cancer Society, CAN2014/759
Note

QC 20170127

Available from: 2017-01-27 Created: 2017-01-27 Last updated: 2020-02-04Bibliographically approved
4. In situ encapsulation of Nile red or Doxorubicin during RAFT-mediated emulsion polymerization via polymerization-induced self-assembly for biomedical applications
Open this publication in new window or tab >>In situ encapsulation of Nile red or Doxorubicin during RAFT-mediated emulsion polymerization via polymerization-induced self-assembly for biomedical applications
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2020 (English)In: Macromolecular Chemistry and Physics, ISSN 1022-1352, E-ISSN 1521-3935Article in journal (Refereed) In press
National Category
Polymer Technologies Nano Technology
Identifiers
urn:nbn:se:kth:diva-267222 (URN)
Note

QCR 20200205

Available from: 2020-02-04 Created: 2020-02-04 Last updated: 2020-02-05Bibliographically approved
5. Functional nano-carriers for drug delivery by surface engineering of polymeric nanoparticles post-PISA
Open this publication in new window or tab >>Functional nano-carriers for drug delivery by surface engineering of polymeric nanoparticles post-PISA
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Engineered polymeric nanoparticles (NPs) have been comprehensively explored as potential platforms for diagnosis and targeted therapy for several diseases including cancer. Herein, we designed functional poly(acrylic acid)-b-poly(butyl acrylate) (PAA-b-PBA) NPs using reversible addition-fragmentation chain-transfer (RAFT)-mediated emulsion polymerization via polymerization-induced self-assembly (PISA). The hydrophilic PAA-macroRAFT, forming a stabilizing shell (i.e. corona), was chain-extended using the hydrophobic monomer n-butyl acrylate (n-BA), resulting in stable, monodisperse and reproducible PAA-b-PBA NPs, typically having a diameter of 130 nm. Two approaches of surface engineering of the PAA-b-PBA NPs post-PISA were explored; a two-step and a one-step approach. In the two-step approach, the hydrophilic NP-shell corona was modified with allyl-groups under mild conditions using allylamine in water which resulted in stable allyl-functional NPs (allyl-NPs) suitable for further bio-conjugation. Their versatility was investigated by the subsequent conjugation of a thiol-functional fluorescent dye (BODIPY-SH) to the allyl-groups using click chemistry, in order to mimic the attachment of a thiol-functional target ligand. The average size and size distribution of the corresponding NPs did not change after BODIPY-conjugation. Neither the NPs nor allyl-NPs showed significant cytotoxicity towards RAW264.7 or MCF-7 cell lines, which indicates their desirable safety profile. A one-step approach to concurrently conjugate allyl-groups and a fluorescent dye (FITC) to the preformed PAA-b-PBA NPs was investigated. The cellular uptake of the FITC-NPs using J774A cells in vitro was found to be time- and concentration-dependent. The anti-cancer drug, doxorubicin, was efficiently (90%) encapsulated into the PAA-b-PBA NPs during NP formation. After a small burst release during the first two hours, a controlled release pattern over 7 days was observed. The present investigation demonstrates a potential method to functionalize polymeric NPs post-PISA to produce targeted drug delivery carriers.

Keywords
Nanoparticles (NPs), engineered-NPs, RAFT-mediated emulsion polymerization, post-PISA functionalization, drug delivery, doxorubicin (DOX).
National Category
Chemical Engineering Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-267219 (URN)
Note

QC 20200214

Available from: 2020-02-04 Created: 2020-02-04 Last updated: 2020-02-14Bibliographically approved

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34567896 of 14
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