Synthesis of 6,12-disubstituted methanodibenzo[b,f ][1,5]dioxocins: Pyrrolidine catalyzed self-condensation of 2′-Hydroxyacetophenones

The preparation of unprecedented 6,12-disubstituted methanodibenzo[b,f ][1,5]dioxocins from pyrrolidine catalyzed self-condensation of 2′-hydroxyacetophenones is herein described. This method provides easy access to this highly bridged complex core, resulting in construction of two C-O and two C-C bonds, a methylene bridge and two quaternary centers in a single step. The intricate methanodibenzo[b,f ][1,5]dioxocin compounds were obtained in up to moderate yields after optimization of the reaction conditions concerning solvent, reaction times and the use of additives. Several halide substituted methanodibenzo[b,f ][1,5]dioxocins could be prepared from correspondent 2′-hydroxyacetophenones.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Materials Science and Environmental Engineering, Faculdade de Farmacia da Universidade de Lisboa, University of Jyvaskyla
Contributors: Assoah, B., Riihonen, V., Vale, J. R., Valkonen, A., Candeias, N. R.
Publication date: 2019
Peer-reviewed: Yes

Publication information

Journal: Molecules
Volume: 24
Issue number: 13
Article number: 2405
ISSN (Print): 1420-3049
Original language: English
ASJC Scopus subject areas: Analytical Chemistry, Chemistry (miscellaneous), Molecular Medicine, Pharmaceutical Science, Drug Discovery, Physical and Theoretical Chemistry, Organic Chemistry
Keywords: 1,5-dioxocin, 20-hydroxyacetophenone, Enamine, Self-condensation
Electronic versions: 

Bibliographical note

EXT="Valkonen, Arto"
INT=msee,"Riihonen, Vesa"
INT=msee,"Vale, João R."

Source: Scopus
Source ID: 85068362408

Research output: Contribution to journalArticleScientificpeer-review

Modulating sustained drug release from nanocellulose hydrogel by adjusting the inner geometry of implantable capsules

Nanocellulose hydrogel has been shown to be an excellent platform for drug delivery and it has been lately studied as an injectable drug carrier. 3D printing is an effective method for fast prototyping of pharmaceutical devices with unique shape and cavities enabling new types of controlled release. In this study, we combined the versatility of 3D printing capsules with controlled geometry and the drug release properties of nanocellulose hydrogel to accurately modulate its drug release properties. We first manufactured non-active capsules via 3D printing from biocompatible poly(lactic acid) (PLA) that limit the direction of drug diffusion. As a novel method, the capsules were filled with a drug dispersion composed of model compounds and anionic cellulose nanofiber (CNF) hydrogel. The main benefit of this device is that the release of any CNF-compatible drug can be modulated simply by modulating the inner geometry of the PLA capsule. In the study we optimized the size and shape of the capsules inner cavity and performed drug release tests with common beta blockers metoprolol and nadolol as the model compounds. The results demonstrate that the sustained release profiles provided by the CNF matrix can be accurately modulated via adjusting the geometry of the 3D printed PLA capsule, resulting in adjustable sustained release for the model compounds.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Materials Science and Environmental Engineering, Research group: Chemistry & Advanced Materials, BioMediTech, Research group: Micro and Nanosystems Research Group, University of Helsinki, Tampere University
Contributors: Auvinen, V. V., Virtanen, J., Merivaara, A., Virtanen, V., Laurén, P., Tuukkanen, S., Laaksonen, T.
Number of pages: 6
Publication date: 2020
Peer-reviewed: Yes

Publication information

Journal: JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
Volume: 57
Article number: 101625
ISSN (Print): 1773-2247
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: 3D printing, Hydrogel, Nanocellulose, Sustained drug release

Bibliographical note

INT=bmte,"Virtanen, Valtteri"

Source: Scopus
Source ID: 85081263628

Research output: Contribution to journalArticleScientificpeer-review

Multifunctional ultrasmall nanoplatforms for vascular-targeted interstitial photodynamic therapy of brain tumors guided by real-time MRI

Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. A number of studies show the major role of the vascular effect in the tumor eradication by PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting neuropilin-1 (NRP-1) peptide and encapsulated photosensitizer and magnetic resonance imaging (MRI) contrast agents, have been designed. Nanoplatforms confer photosensitivity to cells and demonstrate a molecular affinity to NRP-1. Intravenous injection into rats bearing intracranial glioma exhibited a dynamic contrast-enhanced MRI for angiogenic endothelial cells lining the neovessels mainly located in the peripheral tumor. By using MRI completed by NRP-1 protein expression of the tumor and brain adjacent to tumor tissues, we checked the selectivity of the nanoparticles. This study represents the first in vivo proof of concept of closed-head iPDT guided by real-time MRI using targeted ultrasmall nanoplatforms.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Frontier Photonics, Université de Lorraine, Lille University Hospital - CHRU, Marcilly-sur-Eure, CHU de Nancy, Claude Bernard-University
Contributors: Bechet, D., Auger, F., Couleaud, P., Marty, E., Ravasi, L., Durieux, N., Bonnet, C., Plénat, F., Frochot, C., Mordon, S., Tillement, O., Vanderesse, R., Lux, F., Perriat, P., Guillemin, F., Barberi-Heyob, M.
Number of pages: 14
Pages: 657-670
Publication date: 2015
Peer-reviewed: Yes

Publication information

Journal: NANOMEDICINE: NANOTECHNOLOGY BIOLOGY AND MEDICINE
Volume: 11
Issue number: 3
ISSN (Print): 1549-9634
Ratings: 
  • Scopus rating (2015): CiteScore 6.65 SJR 1.857 SNIP 1.684
Original language: English
ASJC Scopus subject areas: Molecular Medicine, Bioengineering, Biomedical Engineering, Materials Science(all), Medicine (miscellaneous), Pharmaceutical Science, Medicine(all)
Keywords: Brain tumor, iPDT, Multifunctional nanoplatforms, Real-time MRI, Targeting
Source: Scopus
Source ID: 84933510120

Research output: Contribution to journalArticleScientificpeer-review

Entangled and colloidally stable microcrystalline cellulose matrices in controlled drug release

Drug release from a new type of matrix material consisting of partially fibrillated microcrystalline cellulose was investigated. A mechanical treatment of novel AaltoCell™ cellulose microcrystals caused partial opening of the nanofibrillary structure of the cellulose particles and entanglement of individual particles led into formation of an elastic network of microcrystalline cellulose. The rheological properties of the stable hydrogel-like materials were characterised by shear rheometry. Model compounds metronidazole and lysozyme were successfully employed in drug release experiments carried out by delignified (bleached) and lignin-containing matrices. The viscosity as well as the lignin-content played a role in the release dynamics of the drugs. Microcrystalline AaltoCell™ was proven as high-performing material for diffusion controlled release of the chosen model compounds and can be seen as a safe and economical alternative for novel matrix materials such as nanocellulose or cellulose derivatives.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Research group: Chemistry & Advanced Materials, Chemistry and Bioengineering, Aalto University, University of Helsinki, Centre for Drug Research
Contributors: Dong, Y., Paukkonen, H., Fang, W., Kontturi, E., Laaksonen, T., Laaksonen, P.
Number of pages: 7
Pages: 113-119
Publication date: 5 Sep 2018
Peer-reviewed: Yes

Publication information

Journal: International Journal of Pharmaceutics
Volume: 548
Issue number: 1
ISSN (Print): 0378-5173
Ratings: 
  • Scopus rating (2018): CiteScore 4.35 SJR 1.135 SNIP 1.23
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Cellulose hydrogel, Controlled release, Diffusion-limited release, Microcrystalline cellulose
Electronic versions: 
URLs: 
Source: Scopus
Source ID: 85049349070

Research output: Contribution to journalArticleScientificpeer-review

Cell-based bioreporter assay coupled to HPLC micro-fractionation in the evaluation of antimicrobial properties of the basidiomycete fungus Pycnoporus cinnabarinus

Context Identification of bioactive components from complex natural product extracts can be a tedious process that aggravates the use of natural products in drug discovery campaigns. Objective This study presents a new approach for screening antimicrobial potential of natural product extracts by employing a bioreporter assay amenable to HPLC-based activity profiling. Materials and methods A library of 116 crude extracts was prepared from fungal culture filtrates by liquid–liquid extraction with ethyl acetate, lyophilised, and screened against Escherichia coli using TLC bioautography. Active extracts were studied further with a broth microdilution assay, which was, however, too insensitive for identifying the active microfractions after HPLC separation. Therefore, an assay based on bioluminescent E. coli K-12 (pTetLux1) strain was coupled with HPLC micro-fractionation. Results Preliminary screening yielded six fungal extracts with potential antimicrobial activity. A crude extract from a culture filtrate of the wood-rotting fungus, Pycnoporus cinnabarinus (Jacq.) P. Karst. (Polyporaceae), was selected for evaluating the functionality of the bioreporter assay in HPLC-based activity profiling. In the bioreporter assay, the IC50 value for the crude extract was 0.10 mg/mL. By integrating the bioreporter assay with HPLC micro-fractionation, the antimicrobial activity was linked to LC-UV peak of a compound in the chromatogram of the extract. This compound was isolated and identified as a fungal pigment phlebiarubrone. Discussion and conclusion HPLC-based activity profiling using the bioreporter-based approach is a valuable tool for identifying antimicrobial compound(s) from complex crude extracts, and offers improved sensitivity and speed compared with traditional antimicrobial assays, such as the turbidimetric measurement.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Department of Chemistry and Bioengineering, Research group: Industrial Bioengineering and Applied Organic Chemistry, University of Helsinki, Universite de Geneve
Contributors: Järvinen, P., Nybond, S., Marcourt, L., Ferreira Queiroz, E., Wolfender, J. L., Mettälä, A., Karp, M., Vuorela, H., Vuorela, P., Hatakka, A., Tammela, P.
Number of pages: 8
Pages: 1-8
Publication date: 21 Jan 2016
Peer-reviewed: Yes

Publication information

Journal: Pharmaceutical Biology
Volume: 54
Issue number: 6
ISSN (Print): 1388-0209
Ratings: 
  • Scopus rating (2016): CiteScore 1.88 SJR 0.575 SNIP 0.856
Original language: English
ASJC Scopus subject areas: Drug Discovery, Pharmacology, Pharmaceutical Science, Complementary and alternative medicine, Molecular Medicine
Keywords: Bioluminescent bacterial strain, Escherichia coli, Gram-negative bacteria, phlebiarubrone

Bibliographical note

OA kysytty 2.5.2016 / HO

Source: Scopus
Source ID: 84958036747

Research output: Contribution to journalArticleScientificpeer-review

His-tagged norovirus-like particles: A versatile platform for cellular delivery and surface display

In addition to vaccines, noninfectious virus-like particles (VLPs) that mimic the viral capsid show an attractive possibility of presenting immunogenic epitopes or targeting molecules on their surface. Here, functionalization of norovirus-derived VLPs by simple non-covalent conjugation of various molecules is shown. By using the affinity between a surface-exposed polyhistidine-tag and multivalent tris-nitrilotriacetic acid (trisNTA), fluorescent dye molecules and streptavidin-biotin conjugated to trisNTA are displayed on the VLPs to demonstrate the use of these VLPs as easily modifiable nanocarriers as well as a versatile vaccine platform. The VLPs are able to enter and deliver surface-displayed fluorescent dye into HEK293T cells via a surface-attached cell internalization peptide (VSV-G). The ease of manufacturing, the robust structure of these VLPs, and the straightforward conjugation provide a technology, which can be adapted to various applications in biomedicine.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: BioMediTech, Integrated Technologies for Tissue Engineering Research (ITTE), Multi-scaled biodata analysis and modelling (MultiBAM), Environmental Science/Nanoscience Center, University of Tampere, Medical School, Goethe-University Frankfurt, Fimlab Laboratories Ltd
Contributors: Koho, T., Ihalainen, T. O., Stark, M., Uusi-Kerttula, H., Wieneke, R., Rahikainen, R., Blazevic, V., Marjomäki, V., Tampé, R., Kulomaa, M. S., Hytönen, V. P.
Number of pages: 10
Pages: 22-31
Publication date: 21 Jul 2015
Peer-reviewed: Yes

Publication information

Journal: European Journal of Pharmaceutics and Biopharmaceutics
Volume: 96
ISSN (Print): 0939-6411
Ratings: 
  • Scopus rating (2015): CiteScore 4.37 SJR 1.437 SNIP 1.458
Original language: English
ASJC Scopus subject areas: Biotechnology, Pharmaceutical Science
Keywords: Bioconjugation, Cell entry peptide, Drug delivery, Molecular display, Targeting, Virus-like particle (VLP)
Source: Scopus
Source ID: 84937598228

Research output: Contribution to journalArticleScientificpeer-review

Expression of MUC5AC in ocular surface epithelial cells using cationized gelatin nanoparticles

Decreased production of the mucin MUC5AC in the eye is related to several pathological conditions, including dry eye syndrome. A specific strategy for increasing the ocular levels of MUC5AC is not yet available. Using a plasmid specially designed to encode human MUC5AC, we evaluated the ability of hybrid cationized gelatin nanoparticles (NPs) containing polyanions (chondroitin sulfate or dextran sulfate) to transfect ocular epithelial cells. NPs were developed using the ionic gelation technique and characterized by a small size (95%). MUC5AC mRNA and protein were detected in conjunctival cells after in vitro transfection of the NPs. The in vivo administration of the NPs resulted in significantly higher MUC5AC expression in the conjunctiva compared to untreated control and naked plasmid. These results provide a proof-of-concept that these NPs are effective vehicles for gene therapy and candidates for restoring the MUC5AC concentration in the ocular surface.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Integrated Technologies for Tissue Engineering Research (ITTE), University of Santiago de Compostela (USC), Biomaterials and Nanomedicine (CIBER BBN), Complejo Hospitalario Universitario de Santiago
Contributors: Konat Zorzi, G., Contreras-Ruiz, L., Párraga, J. E., López-García, A., Romero Bello, R., Diebold, Y., Seijo, B., Sánchez, A.
Number of pages: 6
Pages: 1783-1788
Publication date: 3 Oct 2011
Peer-reviewed: Yes

Publication information

Journal: Molecular Pharmaceutics
Volume: 8
Issue number: 5
ISSN (Print): 1543-8384
Ratings: 
  • Scopus rating (2011): CiteScore 5.62 SJR 2.351 SNIP 1.532
Original language: English
ASJC Scopus subject areas: Molecular Medicine, Pharmaceutical Science, Drug Discovery
Keywords: dry eye, gene therapy, MUC5AC, nanoparticle, ocular surface
Source: Scopus
Source ID: 80053545182

Research output: Contribution to journalArticleScientificpeer-review

Indocyanine Green-Loaded Liposomes for Light-Triggered Drug Release

Light-triggered drug delivery systems enable site-specific and time-controlled drug release. In previous work, we have achieved this with liposomes containing gold nanoparticles in the aqueous core. Gold nanoparticles absorb near-infrared light and release the energy as heat that increases the permeability of the liposomal bilayer, thus releasing the contents of the liposome. In this work, we replaced the gold nanoparticles with the clinically approved imaging agent indocyanine green (ICG). The ICG liposomes were stable at storage conditions (4-22 °C) and at body temperature, and fast near-infrared (IR) light-triggered drug release was achieved with optimized phospholipid composition and a 1:50 ICG-to-lipid molar ratio. Encapsulated small molecular calcein and FITC-dextran (up to 20 kDa) were completely released from the liposomes after light exposure for 15 s. Location of ICG in the PEG layer of the liposomes was simulated with molecular dynamics. ICG has important benefits as a light-triggering agent in liposomes: fast content release, improved stability, improved possibility of liposomal size control, regulatory approval to use in humans, and the possibility of imaging the in vivo location of the liposomes based on the fluorescence of ICG. Near-infrared light used as a triggering mechanism has good tissue penetration and safety. Thus, ICG liposomes are an attractive option for light-controlled and efficient delivery of small and large drug molecules.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Department of Physics, Department of Chemistry and Bioengineering
Contributors: Lajunen, T., Kontturi, L., Viitala, L., Manna, M., Cramariuc, O., Róg, T., Bunker, A., Laaksonen, T., Viitala, T., Murtomäki, L., Urtti, A.
Number of pages: 13
Pages: 2095-2107
Publication date: 6 Jun 2016
Peer-reviewed: Yes

Publication information

Journal: Molecular Pharmaceutics
Volume: 13
Issue number: 6
ISSN (Print): 1543-8384
Ratings: 
  • Scopus rating (2016): CiteScore 4.84 SJR 1.538 SNIP 1.216
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science, Molecular Medicine, Drug Discovery
Keywords: indocyanine green, light activation, liposome, macromolecules, molecular dynamics, triggered release
Source: Scopus
Source ID: 84973635764

Research output: Contribution to journalArticleScientificpeer-review

The effect of light sensitizer localization on the stability of indocyanine green liposomes

Light triggered drug delivery systems offer attractive possibilities for sophisticated therapy, providing both temporal and spatial control of drug release. We have developed light triggered liposomes with clinically approved indocyanine green (ICG) as the light sensitizing compound. Amphiphilic ICG can be localized in different compartments of the liposomes, but the effect of its presence, on both triggered release and long term stability, has not been studied. In this work, we report that ICG localization has a significant effect on the properties of the liposomes. Polyethylene glycol (PEG) coating of the liposomes leads to binding and stabilization of the ICG molecules on the surface of the lipid bilayer. This formulation showed both good storage stability in buffer solution (at +4–37 °C) and adequate stability in serum and vitreous (at +37 °C). The combination of ICG within the lipid bilayer and PEG coating lead to poor stability at elevated temperatures of +22 °C and + 37 °C. The mechanisms of the increased instability due to ICG insertion in the lipid bilayer was elucidated with molecular dynamics simulations. Significant PEG insertion into the bilayer was induced in the presence of ICG in the lipid bilayer. Finally, feasibility of freeze-drying as a long term storage method for the ICG liposomes was demonstrated. Overall, this is the first detailed study on the interactions of lipid bilayer, light sensitizer (ICG) and PEG coating on the liposome stability. The localization of the light triggering agent significantly alters the structure of the liposomes and it is important to consider these aspects in triggered drug delivery system design.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Physics, University of Helsinki, Utrecht University, University of Eastern Finland, School of Pharmacy
Contributors: Lajunen, T., Nurmi, R., Wilbie, D., Ruoslahti, T., Johansson, N. G., Korhonen, O., Rog, T., Bunker, A., Ruponen, M., Urtti, A.
Number of pages: 11
Pages: 213-223
Publication date: 28 Aug 2018
Peer-reviewed: Yes

Publication information

Journal: Journal of Controlled Release
Volume: 284
ISSN (Print): 0168-3659
Ratings: 
  • Scopus rating (2018): CiteScore 7.82 SJR 2.411 SNIP 1.717
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Drug delivery system, Indocyanine green, Liposome, Polyethylene glycol, Stability, Triggered release
Electronic versions: 
Source: Scopus
Source ID: 85049307558

Research output: Contribution to journalArticleScientificpeer-review

Pectin and Mucin Enhance the Bioadhesion of Drug Loaded Nanofibrillated Cellulose Films

Purpose: Bioadhesion is an important property of biological membranes, that can be utilized in pharmaceutical and biomedical applications. In this study, we have fabricated mucoadhesive drug releasing films with bio-based, non-toxic and biodegradable polymers that do not require chemical modifications. Methods: Nanofibrillar cellulose and anionic type nanofibrillar cellulose were used as film forming materials with known mucoadhesive components mucin, pectin and chitosan as functional bioadhesion enhancers. Different polymer combinations were investigated to study the adhesiveness, solid state characteristics, film morphology, swelling, mechanical properties, drug release with the model compound metronidazole and in vitro cytotoxicity using TR146 cells to model buccal epithelium. Results: SEM revealed lamellar structures within the films, which had a thickness ranging 40–240 μm depending on the film polymer composition. All bioadhesive components were non-toxic and showed high adhesiveness. Rapid drug release was observed, as 60–80% of the total amount of metronidazole was released in 30 min depending on the film formulation. Conclusions: The liquid molding used was a straightforward and simple method to produce drug releasing highly mucoadhesive films, which could be utilized in treating local oral diseases, such as periodontitis. All materials used were natural biodegradable polymers from renewable sources, which are generally regarded as safe.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, Research group: Chemistry & Advanced Materials, Aalto University, Universita degli Studi di Padova, Italy, University of Helsinki, University of Helsinki
Contributors: Laurén, P., Paukkonen, H., Lipiäinen, T., Dong, Y., Oksanen, T., Räikkönen, H., Ehlers, H., Laaksonen, P., Yliperttula, M., Laaksonen, T.
Publication date: 1 Jul 2018
Peer-reviewed: Yes

Publication information

Journal: Pharmaceutical Research
Volume: 35
Issue number: 7
Article number: 145
ISSN (Print): 0724-8741
Ratings: 
  • Scopus rating (2018): CiteScore 3.89 SJR 1.093 SNIP 1.108
Original language: English
ASJC Scopus subject areas: Biotechnology, Molecular Medicine, Pharmacology, Pharmaceutical Science, Organic Chemistry, Pharmacology (medical)
Keywords: bioadhesion, drug release, mucoadhesion, nanofibrillar cellulose, TR146
Electronic versions: 
URLs: 
Source: Scopus
Source ID: 85047448577

Research output: Contribution to journalArticleScientificpeer-review

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy

Purpose: To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods. Method: Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy. Results: Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage. Conclusions: SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Department of Chemistry and Bioengineering, University of Helsinki, Division of Biopharmaceutical Sciences, Biomedicum Imaging Unit, FIN-00014 University of Helsinki
Contributors: Mah, P. T., Novakovic, D., Saarinen, J., van Landeghem, S., Peltonen, L., Laaksonen, T., Isomäki, A., Strachan, C. J.
Number of pages: 14
Pages: 957-970
Publication date: May 2017
Peer-reviewed: Yes
Early online date: 13 Oct 2016

Publication information

Journal: Pharmaceutical Research
Volume: 34
Issue number: 5
ISSN (Print): 0724-8741
Ratings: 
  • Scopus rating (2017): CiteScore 3.3 SJR 1.077 SNIP 1.054
Original language: English
ASJC Scopus subject areas: Biotechnology, Molecular Medicine, Pharmacology, Pharmaceutical Science, Organic Chemistry, Pharmacology (medical)
Source: Scopus
Source ID: 84991051806

Research output: Contribution to journalArticleScientificpeer-review

Comparison of liposomal drug formulations for transdermal iontophoretic drug delivery

This study was aimed to evaluate the in vitro transdermal direct/pulsed current iontophoretic delivery of an amphiphilic model compound from various lipid vesicle-encapsulated formulations compared to free-drug formulation. Conventional, pegylated, ultradeformable liposomes (transfersomes) and ethosomes loaded with a negatively charged drug diclofenac sodium (DS) were prepared and characterized. All the liposomes possessed an average size of ≈ 100–150 nm and negative zeta potential. No changes in colloidal stability were detected after 8 h incubation of any vesicle formulation under constant or pulsed iontophoretic current. DS was released from all the liposome formulations with a similar, limited rate (≈ 50% in 24 h), leading therefore to significantly lower transdermal fluxes across full-thickness porcine skin compared to the respective free drug formulation. From the tested lipid vesicle formulations, the transfersomes resulted in the highest passive flux and the ethosomes in the highest iontophoretic flux under direct constant current treatment. Higher negative surface charge of the vesicle led to better transport efficiency due to the higher mobility of the drug carrier under electric field. Pulsed current iontophoresis had no advantage over constant current treatment in combination with any type of lipid vesicular nanocarriers, in contrast to what has been described earlier with drug-loaded polymeric nanocarriers.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, Research group: Chemistry & Advanced Materials, University of Helsinki, University of Navarra, Division of Pharmaceutical Chemistry and Technology
Contributors: Malinovskaja-Gomez, K., Espuelas, S., Garrido, M. J., Hirvonen, J., Laaksonen, T.
Number of pages: 8
Pages: 294-301
Publication date: 30 Aug 2017
Peer-reviewed: Yes

Publication information

Journal: European Journal of Pharmaceutical Sciences
Volume: 106
ISSN (Print): 0928-0987
Ratings: 
  • Scopus rating (2017): CiteScore 3.81 SJR 1.016 SNIP 1.317
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Diclofenac sodium, Iontophoresis, Liposome, NSAID delivery, Skin permeation, Transdermal drug delivery
Electronic versions: 
URLs: 
Source: Scopus
Source ID: 85020916069

Research output: Contribution to journalArticleScientificpeer-review

Molecular Communications Pulse-based Jamming Model for Bacterial Biofilm Suppression

Studies have recently shown that the bacteria survivability within biofilms is responsible for the emergence of superbugs. The combat of bacterial infections, without enhancing its resistance to antibiotics, includes the use of nanoparticles to quench the quorum sensing of these biofilm-forming bacteria. Several sequential and parallel multi-stage communication processes are involved in the formation of biofilms. In this paper, we use proteomic data from a wet lab experiment to identify the communication channels that are vital to these processes.We also identified the main proteins from each channel and propose the use of jamming signals from synthetically engineered bacteria to suppress the production of those proteins. This biocompatible technique is based on synthetic biology and enables the inhibition of biofilm formation. We analyse the communications performance of the jamming process, by evaluating the path loss for a number of conditions that include different engineered bacterial population sizes, distances between the populations and molecular signal power. Our results show that sufficient molecular pulsebased jamming signals are able to prevent the biofilm formation by creating lossy communications channels (almost -3 dB for certain scenarios). From these results, we define the main design parameters to develop a fully operational bacteria-based jamming system.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Electronics and Communications Engineering, Research group: Emerging Technologies for Nano-Bio-Info-Cogno, Waterford Institute of Technology, Kasetsart University
Contributors: Martins, D. P., Leetanasaksakul, K., Barros, M. T., Thamchaipenet, A., Donnelly, W., Balasubramaniam, S.
Number of pages: 12
Pages: 533-542
Publication date: Oct 2018
Peer-reviewed: Yes
Early online date: 19 Sep 2018

Publication information

Journal: IEEE Transactions on Nanobioscience
Volume: 17
Issue number: 4
ISSN (Print): 1536-1241
Ratings: 
  • Scopus rating (2018): CiteScore 2.23 SJR 0.541 SNIP 0.741
Original language: English
ASJC Scopus subject areas: Biotechnology, Bioengineering, Medicine (miscellaneous), Biomedical Engineering, Pharmaceutical Science, Computer Science Applications, Electrical and Electronic Engineering
Keywords: Biofilm suppression, Communications systems, Jamming, Synthetic logic circuits
Source: Scopus
Source ID: 85053611196

Research output: Contribution to journalArticleScientificpeer-review

Quality and Capacity Analysis of Molecular Communications in Bacterial Synthetic Logic Circuits

Synthetic logic circuits have been proposed as potential solutions for theranostics of biotechnological problems. One proposed model is the engineering of bacteria cells to create logic gates, and the communication between the bacteria populations will enable the circuit operation. In this paper, we analyse the quality of bacteria-based synthetic logic circuit through molecular communications that represent communication along a bus between three gates. In the bacteria-based synthetic logic circuit, the system receives environmental signals as molecular inputs and will process this information through a cascade of synthetic logic gates and free diffusion channels. We analyse the performance of this circuit by evaluating its quality and its relationship to the channel capacity of the molecular communications links that interconnect the bacteria populations. Our results show the effect of the molecular environmental delay and molecular amplitude differences over both the channel capacity and circuit quality. Furthermore, based on these metrics we also obtain an optimum region for the circuit operation resulting in an accuracy of 80% for specific conditions. These results show that the performance of synthetic biology circuits can be evaluated through molecular communications, and lays the groundwork for combined systems that can contribute to future biomedical and biotechnology applications.

General information

Publication status: Accepted/In press
MoE publication type: A1 Journal article-refereed
Organisations: Electrical Engineering, Waterford Institute of Technology
Contributors: Martins, D. P., Barros, M. T., Balasubramaniam, S.
Publication date: 2019
Peer-reviewed: Yes

Publication information

Journal: IEEE Transactions on Nanobioscience
ISSN (Print): 1536-1241
Original language: English
ASJC Scopus subject areas: Biotechnology, Bioengineering, Medicine (miscellaneous), Biomedical Engineering, Pharmaceutical Science, Computer Science Applications, Electrical and Electronic Engineering
Keywords: Engineered bacteria, Logic circuits, Logic gates, Microorganisms, Molecular communication (telecommunication), Molecular communications, Sensors, Sociology, Statistics, Synthetic logic circuits
Source: Scopus
Source ID: 85070392121

Research output: Contribution to journalArticleScientificpeer-review

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View

The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and ?-forms, the less reported metastable ?- and ?-forms were also observed, with the ?-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, Research group: Chemistry & Advanced Materials, University of Helsinki, University of Helsinki Faculty of Medicine, University of Otago
Contributors: Novakovic, D., Isomäki, A., Pleunis, B., Fraser-Miller, S. J., Peltonen, L., Laaksonen, T., Strachan, C. J.
Number of pages: 13
Pages: 5361-5373
Publication date: 5 Nov 2018
Peer-reviewed: Yes

Publication information

Journal: Molecular Pharmaceutics
Volume: 15
Issue number: 11
ISSN (Print): 1543-8384
Ratings: 
  • Scopus rating (2018): CiteScore 4.7 SJR 1.402 SNIP 1.165
Original language: English
ASJC Scopus subject areas: Molecular Medicine, Pharmaceutical Science, Drug Discovery
Keywords: amorphous, dissolution, indomethacin, nonlinear optics, polymorphism, surface crystallization
Electronic versions: 

Bibliographical note

EXT="Isomäki, Antti"

Source: Scopus
Source ID: 85054882971

Research output: Contribution to journalArticleScientificpeer-review

Surface Stabilization and Dissolution Rate Improvement of Amorphous Compacts with Thin Polymer Coatings: Can We Have It All?

The distinction between surface and bulk crystallization of amorphous pharmaceuticals, as well as the importance of surface crystallization for pharmaceutical performance, is becoming increasingly evident. An emerging strategy in stabilizing the amorphous drug form is to utilize thin coatings at the surface. While the physical stability of systems coated with pharmaceutical polymers has recently been studied, the effect on dissolution performance as a function of storage time, as a further necessary step toward the success of these formulations, has not been previously studied. Furthermore, the effect of coating thickness has not been elucidated. This study investigated the effect of these polymer-coating parameters on the interplay between amorphous surface crystallization and drug dissolution for the first time. The study utilized simple tablet-like coated dosage forms, comprising a continuous amorphous drug core and thin polymer coating (hundreds of nanometers to a micrometer thick). Monitoring included analysis of both the solid-state of the model drug (with SEM, XRD, and ATR FTIR spectroscopy) and dissolution performance (and associated morphology and solid-state changes) after different storage times. Stabilization of the amorphous form (dependent on the coating thickness) and maintenance of early-stage intrinsic dissolution rates characteristic for the unaged amorphous drug were achieved. However, dissolution in the latter stages was likely inhibited by the presence of a polymer at the surface. Overall, this study introduced a versatile coated system for studying the dissolution of thin-coated amorphous dosage forms suitable for different drugs and coating agents. It demonstrated the importance of multiple factors that need to be taken into consideration when aiming to achieve both physical stability and improved release during the shelf life of amorphous formulations.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Materials Science and Environmental Engineering, Research group: Chemistry & Advanced Materials, University of Helsinki, University of Otago, Danmarks Tekniske Universitet, DTU Informatik
Contributors: Novakovic, D., Peltonen, L., Isomäki, A., Fraser-Miller, S. J., Nielsen, L. H., Laaksonen, T., Strachan, C. J.
Number of pages: 13
Pages: 1248-1260
Publication date: 2020
Peer-reviewed: Yes

Publication information

Journal: Molecular Pharmaceutics
Volume: 17
Issue number: 4
ISSN (Print): 1543-8384
Original language: English
ASJC Scopus subject areas: Molecular Medicine, Pharmaceutical Science, Drug Discovery
Keywords: amorphous, dissolution, indomethacin, polymer coating, surface crystallization
Source: Scopus
Source ID: 85080145435

Research output: Contribution to journalArticleScientificpeer-review

Antimicrobial assay optimization and validation for HTS in 384-well format using a bioluminescent E. coli K-12 strain

This report describes the optimization and validation of an antimicrobial assay based on the genetically modified bacterial strain Escherichia coli K-12 (pTetlux1). The use of this particular strain enables an inducible cell-based bioluminescent assay for high-throughput screening (HTS) of antimicrobial agents, which shows a pronounced detection of compounds targeting transcriptional and translational events in protein synthesis. The optimizations in 96-well format led to several improvements in assay conditions, such as reduction of the pre-incubation time before luminescence induction by half. The threshold for DMSO tolerability was concluded to be up to 1%. Assay protocol was further miniaturized into 384- well format and the liquid handling was automated using a robotic workstation. The use of compound pre-plating into 384-well plates as a part of the process was evaluated, and the total assay volume was further downscaled from 50 μl to 30 μl. With this approach, the amount of test compound needed per well was reduced to nanoliter volumes. Using the miniaturized protocol a pilot screen of 2000 known drugs and bioactives was performed. The assay performance was evaluated by calculating known assay quality parameters, the Z′ factor having a mean value of 0.8 during the compound library screening indicated an excellent performance. Of the assay positives, 54 compounds showed high inhibitions (60-100%), of which the majority (89%) were known antibacterial agents. Of the actives showing >60% inhibition, 16 compounds were identified as known transcriptional and translational inhibitors. The screening results demonstrated that the miniaturized assay is well suited for identification of antimicrobial compounds in HT screening, and that the assay is specifically sensitive towards bacterial transcription and translation inhibitors. © 2013 Elsevier B.V.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Department of Chemistry and Bioengineering, Research group: Industrial Bioengineering and Applied Organic Chemistry, Tampere University of Technology, Urban circular bioeconomy (UrCirBio), Centre for Drug Research, Faculty of Pharmacy, Helsinki University
Contributors: Nybond, S., Karp, M., Tammela, P.
Number of pages: 8
Pages: 782-789
Publication date: 2013
Peer-reviewed: Yes

Publication information

Journal: European Journal of Pharmaceutical Sciences
Volume: 49
Issue number: 4
ISSN (Print): 0928-0987
Ratings: 
  • Scopus rating (2013): CiteScore 3.47 SJR 1.04 SNIP 1.256
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Bioluminescence, Cell-based assay, High-throughput screening, Miniaturization, Transcription, Translation

Bibliographical note

Contribution: organisation=keb,FACT1=1<br/>Portfolio EDEND: 2013-09-29<br/>Publisher name: Elsevier BV

Source: researchoutputwizard
Source ID: 3025

Research output: Contribution to journalArticleScientificpeer-review

In vitro characterization of arylhydrazones of active methylene derivatives

Arylhydrazones of active methylene compounds (AHAMCs) are potent chemotherapy agents for the cancer treatment. AHAMCs enhance the apoptotic cell death and antiproliferation properties in cancer cells. In this study, a series of AHAMCs, 13 compounds, was assayed for cytotoxicity, apoptosis, externalization of phosphatidylserine, heterogeneity and cellular calcium level changes. The in vitro cytotoxicity study against HEK293T cells suggests that AHAMCs have significant cytotoxic effect over the concentrations. Top 5 compounds, 5-(2-(2-hydroxyphenyl) hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione (5), 4-hydroxy-5-(2-(2,4,6-trioxo-tetrahydro-pyrimidin-5(6H) ylidene)hydrazinyl)benzene-1,3-disulfonic acid (6), 5-chloro-3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxybenzenesulfonic acid (8), 5-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-4-hydroxybenzene-1,3-disulfonic acid (9) and 2-(2-sulfophenylhydrazo)malononitrile (10) were chosen for the pharmacodynamics study. Among these, compound 5 exhibited the better cytotoxic effect with the IC50 of 50.86 ± 2.5 mM. DNA cleavage study revealed that 5 induces cell death through apoptosis and shows more effects after 24 and/or 48 h. Independent validation of apoptosis by following the externalization of phosphatidylserine using Annexin-V is also in agreement with the potential activity of 5. Single cell image analysis of Annexin-V bound cells confirms the presence of mixture of early, mid and late apoptotic cells in the population of the cells treated with 5 and a decreased trend in cell-to-cell variation over the phase was also identified. Additionally, intracellular calcium level measurements identified the Ca2+ up-regulation in compound treated cells. A brief inspection of the effect of the compound 5 against multiple human brain astrocytoma cells showed a better cell growth inhibitory effect at micro molar level. These systematic studies provide insights in the development of novel AHAMACs compounds as potential cell growth inhibitors for cancer treatment.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Faculty of Biomedical Sciences and Engineering, Research group: Computational Systems Biology, Peoples’ Friendship University of Russia, Baku State University, Centro de Quimica Estrutural at Instituto Superior Tecnico
Contributors: Palanivel, S., Zhurina, A., Doan, P., Chandraseelan, J. G., Khandelwal, V. K. M., Zubkov, F. I., Mahmudov, K. T., Pombeiro, A. J., Yli-Harja, O., Kandhavelu, M.
Pages: 430-436
Publication date: 2018
Peer-reviewed: Yes

Publication information

Journal: Saudi Pharmaceutical Journal
Volume: 26
Issue number: 3
ISSN (Print): 1319-0164
Ratings: 
  • Scopus rating (2018): CiteScore 3.48 SJR 0.67 SNIP 1.925
Original language: English
ASJC Scopus subject areas: Pharmacology, Pharmaceutical Science
Keywords: Apoptosis, Arylhydrazones of active methylene compounds, Chemotherapy, Cytotoxic effect, Glioma, Immortal cells, Single cell analysis
Electronic versions: 
Source: Scopus
Source ID: 85039901326

Research output: Contribution to journalArticleScientificpeer-review

Anticancer activity of THMPP: Downregulation of PI3K/ S6K1 in breast cancer cell line

Breast cancer is the most common cancer that majorly affects female. The present study is focused on exploring the potential anticancer activity of 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), against human breast cancer. The mechanism of action, activation of specific signaling pathways, structural activity relationship and drug-likeness properties of THMPP remains elusive. Cell proliferation and viability assay, caspase enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR, QSAR and ADME analysis were executed to understand the mode of action of the drug. The effect of THMPP on multiple breast cancer cell lines (MCF-7 and SkBr3), and non-tumorigenic cell line (H9C2) was assessed by MTT assay. THMPP at IC50 concentration of 83.23 μM and 113.94 μM, induced cell death in MCF-7 and SkBr3 cells, respectively. Increased level of caspase-3 and -9, fragmentation of DNA, translocation of phosphatidylserine membrane and morphological changes in the cells confirmed the effect of THMPP in inducing the apoptosis. Gene expression analysis has shown that THMPP was able to downregulate the expression of PI3K/S6K1 genes, possibly via EGFR signaling pathway in both the cell lines, MCF-7 and SkBr3. Further, molecular docking also confirms the potential binding of THMPP with EGFR. QSAR and ADME analysis proved THMPP as an effective anti-breast cancer drug, exhibiting important pharmacological properties. Overall, the results suggest that THMPP induced cell death might be regulated by EGFR signaling pathway which augments THMPP being developed as a potential candidate for treating breast cancer.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: BioMediTech, Research group: Molecular Signaling Lab, Institute of Biosciences and Medical Technology, Department of Biotechnology, Lady Doak College, Institute for Systems Biology, Seattle, Washington, USA
Contributors: Palanivel, S., Murugesan, A., Yli-Harja, O., Kandhavelu, M.
Number of pages: 9
Pages: 495-503
Publication date: 1 Apr 2020
Peer-reviewed: Yes

Publication information

Journal: Saudi Pharmaceutical Journal
Volume: 28
Issue number: 4
ISSN (Print): 1319-0164
Original language: English
ASJC Scopus subject areas: Pharmacology, Pharmaceutical Science
Keywords: ADME, Apoptosis, Docking, EGFR, Gene expression, QSAR, Tetrahydroquinoline
Source: Scopus
Source ID: 85082417780

Research output: Contribution to journalArticleScientificpeer-review

Nanoparticles based on naturally-occurring biopolymers as versatile delivery platforms for delicate bioactive molecules: An application for ocular gene silencing

Nanoparticles based on naturally-occurring biopolymers, most of them endogenous macromolecules, were designed as a versatile generation of delivery platforms for delicate bioactive molecules. The design of these nanosystems was specifically based on our recent finding about the ability of endogenous polyamine spermine (SPM) to interact with anionic biopolymers (ABs) generating ionically cross-linked nanosystems. The initial first generation of these delivery platforms, based on glycosaminoglycans and other polysaccharides, showed a very high association capacity for some delicate bioactive proteins such as growth factors, but a limited capacity to associate negatively charged molecules, such as pDNA and siRNA. However, the versatility of these nanosystems in terms of composition allowed us to customise the association of active ingredients and their physicochemical characteristics. Concretely, we prepared and incorporated gelatine cationized with spermine (CGsp) to their composition. The resulting modified formulations were characterised by a nanometric size (150-340 nm) and offer the possibility to modulate their zeta potential (from -35 to 28 mV), providing an efficient association of nucleic acids. The biological evaluation of these optimised nanosystems revealed that they are able to be internalised in vivo into corneal and conjunctival tissues and also to provide a significant siRNA gene silencing effect.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Integrated Technologies for Tissue Engineering Research (ITTE), University of Santiago de Compostela (USC), Federal University of Rio Grande do Sul, University of Valladolid, University Clinical Hospital of Santiago de Compostela (IDIS)
Contributors: Parraga, J. E., Zorzi, G. K., Diebold, Y., Seijo, B., Sanchez, A.
Number of pages: 9
Pages: 12-20
Publication date: 30 Dec 2014
Peer-reviewed: Yes

Publication information

Journal: International Journal of Pharmaceutics
Volume: 477
Issue number: 1
ISSN (Print): 0378-5173
Ratings: 
  • Scopus rating (2014): CiteScore 4.13 SJR 1.347 SNIP 1.532
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Cationized gelatine, Nanoparticles, Polyanionic biopolymers, siRNAGene therapy, Spermine
Source: Scopus
Source ID: 84908396404

Research output: Contribution to journalArticleScientificpeer-review

Design of cholesterol arabinogalactan anchored liposomes for asialoglycoprotein receptor mediated targeting to hepatocellular carcinoma: In silico modeling, in vitro and in vivo evaluation

We have developed active targeting liposomes to deliver anticancer agents to ASGPR which will contribute to effective treatment of hepatocellular carcinoma. Active targeting is achieved through polymeric ligands on the liposome surface. The liposomes were prepared using reverse phase evaporation method and doxorubicin hydrocholoride, a model drug, was loaded using the ammonium sulphate gradient method. Liposomes loaded with DOX were found to have a particle size of 200 nm with more than 90% entrapment efficiency. Systems were observed to release the drug in a sustained manner in acidic pH in vitro. Liposomes containing targeting ligands possessed greater and selective toxicity to ASGPR positive HepG2 cell lines due to specific ligand receptor interaction. Bio-distribution studies revealed that liposomes were concentrated in the liver even after 3 h of administration, thus providing conclusive evidence of targeting potential for formulated nanosystems. Tumor regression studies indicated greater tumor suppression with targeted liposomes thereby establishing superiority of the liposomal system. In this work, we used a novel methodology to guide the determination of the optimal composition of the targeting liposomes: molecular dynamics (MD) simulation that aided our understanding of the behaviour of the ligand within the bilayer. This can be seen as a demonstration of the utility of this methodology as a rational design tool for active targeting liposome formulation.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Department of Physics, Research area: Computational Physics, Bombay College of Pharmacy, University of Helsinki, Council of Scientific and Industrial Research-Centre for Cellular and Molecular Biology (CSIR-CCMB), Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Friedrich-Schiller-University Jena
Contributors: Pathak, P., Dhawan, V., Magarkar, A., Danne, R., Govindarajan, S., Ghosh, S., Steiniger, F., Chaudhari, P., Gopal, V., Bunker, A., Róg, T., Fahr, A., Nagarsenker, M.
Number of pages: 10
Pages: 149-158
Publication date: 25 Jul 2016
Peer-reviewed: Yes

Publication information

Journal: International Journal of Pharmaceutics
Volume: 509
Issue number: 1-2
ISSN (Print): 0378-5173
Ratings: 
  • Scopus rating (2016): CiteScore 4.24 SJR 1.323 SNIP 1.386
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Arabinogalactan, Asialoglycoprotein receptor, Cholesterol, Hepatocellular carcinoma, Liposomes, Simulations, Targeting
Source: Scopus
Source ID: 84974593689

Research output: Contribution to journalArticleScientificpeer-review

Hydrophobin-nanofibrillated cellulose stabilized emulsions for encapsulation and release of BCS class II drugs

The purpose of this study was to construct biopolymer-based oil-in-water emulsion formulations for encapsulation and release of poorly water soluble model compounds naproxen and ibuprofen. Class II hydrophobin protein HFBII from Trichoderma reesei was used as a surfactant to stabilize the oil/water interfaces of the emulsion droplets in the continuous aqueous phase. Nanofibrillated cellulose (NFC) was used as a viscosity modifier to further stabilize the emulsions and encapsulate protein coated oil droplets in NFC fiber network. The potential of both native and oxidized NFC were studied for this purpose. Various emulsion formulations were prepared and the abilities of different formulations to control the drug release rate of naproxen and ibuprofen, used as model compounds, were evaluated. The optimal formulation for sustained drug release consisted of 0.01% of drug, 0.1% HFBII, 0.15% oxidized NFC, 10% soybean oil and 90% water phase. By comparison, the use of native NFC in combination with HFBII resulted in an immediate drug release for both of the compounds. The results indicate that these NFC originated biopolymers are suitable for pharmaceutical emulsion formulations. The native and oxidized NFC grades can be used as emulsion stabilizers in sustained and immediate drug release applications. Furthermore, stabilization of the emulsions was achieved with low concentrations of both HFBII and NFC, which may be an advantage when compared to surfactant concentrations of conventional excipients traditionally used in pharmaceutical emulsion formulations.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, University of Helsinki, VTT Technical Research Centre of Finland, Universita degli Studi di Padova, Italy, Division of Biopharmaceutical Sciences
Contributors: Paukkonen, H., Ukkonen, A., Szilvay, G., Yliperttula, M., Laaksonen, T.
Number of pages: 11
Pages: 238-248
Publication date: 30 Mar 2017
Peer-reviewed: Yes

Publication information

Journal: European Journal of Pharmaceutical Sciences
Volume: 100
ISSN (Print): 0928-0987
Ratings: 
  • Scopus rating (2017): CiteScore 3.81 SJR 1.016 SNIP 1.317
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Drug release, Emulsions, Hydrophobin, Ibuprofen, Nanofibrillated cellulose, Naproxen
Electronic versions: 
URLs: 
Source: Scopus
Source ID: 85011004558

Research output: Contribution to journalArticleScientificpeer-review

Nanofibrillar cellulose hydrogels and reconstructed hydrogels as matrices for controlled drug release

Concentrated 3% and 6.5% anionic nanofibrillar cellulose (ANFC) hydrogels were introduced as matrix reservoirs for controlled delivery applications of small molecules and proteins. A further aim was to study how the freeze-drying and subsequent rehydration of ANFC hydrogel affects the rheological properties and drug release of selected model compounds from the reconstructed hydrogels. It was demonstrated that the 3% and 6.5% ANFC hydrogels can be freeze-dried with suitable excipients into highly porous aerogel structures and redispersed back into the hydrogel form without significant change in the rheological properties. Freeze-drying did not affect the drug release properties from redispersed ANFC hydrogels, indicating that these systems could be stored in the dry form and only redispersed when needed. For large molecules, the diffusion coefficients were significantly smaller when higher ANFC fiber content was used, indicating that the amount of ANFC fibers in the hydrogel can be used to control the release rate. The release of small molecules was controlled with the ANFC fiber content only to a moderate extent. The results indicate that ANFC hydrogel can be used for controlled delivery of several types of molecules and that the hydrogel can be successfully freeze-dried and redispersed.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, Research group: Chemistry & Advanced Materials, University of Helsinki, Centre for Drug Research, Universita degli Studi di Padova, Italy
Contributors: Paukkonen, H., Kunnari, M., Laurén, P., Hakkarainen, T., Auvinen, V., Oksanen, T., Koivuniemi, R., Yliperttula, M., Laaksonen, T.
Number of pages: 12
Pages: 269-280
Publication date: 30 Oct 2017
Peer-reviewed: Yes

Publication information

Journal: International Journal of Pharmaceutics
Volume: 532
Issue number: 1
ISSN (Print): 0378-5173
Ratings: 
  • Scopus rating (2017): CiteScore 4.06 SJR 1.172 SNIP 1.302
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Aerogel, Diffusion, Drug release, Freeze-drying, Hydrogel, Nanofibrillar cellulose, Rheology
Electronic versions: 
URLs: 
Source: Scopus
Source ID: 85029371925

Research output: Contribution to journalArticleScientificpeer-review

Reversible biofunctionalization of surfaces with a switchable mutant of avidin

Label-free biosensors detect binding of prey molecules (″ analytes″) to immobile bait molecules on the sensing surface. Numerous methods are available for immobilization of bait molecules. A convenient option is binding of biotinylated bait molecules to streptavidin-functionalized surfaces, or to biotinylated surfaces via biotin-avidin-biotin bridges. The goal of this study was to find a rapid method for reversible immobilization of biotinylated bait molecules on biotinylated sensor chips. The task was to establish a biotin-avidin-biotin bridge which was easily cleaved when desired, yet perfectly stable under a wide range of measurement conditions. The problem was solved with the avidin mutant M96H which contains extra histidine residues at the subunit-subunit interfaces. This mutant was bound to a mixed self-assembled monolayer (SAM) containing biotin residues on 20% of the oligo(ethylene glycol)-terminated SAM components. Various biotinylated bait molecules were bound on top of the immobilized avidin mutant. The biotin-avidin-biotin bridge was stable at pH ≥3, and it was insensitive to sodium dodecyl sulfate (SDS) at neutral pH. Only the combination of citric acid (2.5%, pH 2) and SDS (0.25%) caused instantaneous cleavage of the biotin-avidin-biotin bridge. As a consequence, the biotinylated bait molecules could be immobilized and removed as often as desired, the only limit being the time span for reproducible chip function when kept in buffer (2-3 weeks at 25 C). As expected, the high isolectric pH (pI) of the avidin mutant caused nonspecific adsorption of proteins. This problem was solved by acetylation of avidin (to pI <5), or by optimization of SAM formation and passivation with biotin-BSA and BSA.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Multi-scaled biodata analysis and modelling (MultiBAM), Johannes Kepler University, Fimlab Laboratories Ltd, University of Salzburg, University of Basel, University of South Bohemia, Goethe-University Frankfurt
Contributors: Pollheimer, P., Taskinen, B., Scherfler, A., Gusenkov, S., Creus, M., Wiesauer, P., Zauner, D., Schöfberger, W., Schwarzinger, C., Ebner, A., Tampé, R., Stutz, H., Hytönen, V. P., Gruber, H. J.
Number of pages: 13
Pages: 1656-1668
Publication date: 16 Oct 2013
Peer-reviewed: Yes

Publication information

Journal: Bioconjugate Chemistry
Volume: 24
Issue number: 10
ISSN (Print): 1043-1802
Ratings: 
  • Scopus rating (2013): CiteScore 5.12 SJR 2.02 SNIP 1.201
Original language: English
ASJC Scopus subject areas: Biotechnology, Bioengineering, Organic Chemistry, Pharmaceutical Science, Biomedical Engineering, Pharmacology
Source: Scopus
Source ID: 84886070072

Research output: Contribution to journalArticleScientificpeer-review

Crystallization Kinetics of an Amorphous Pharmaceutical Compound Using Fluorescence-Lifetime-Imaging Microscopy

Pharmaceutical scientists are increasingly interested in amorphous drug formulations especially because of their higher dissolution rates. Consequently, the thorough characterization and analysis of these formulations are becoming more and more important for the pharmaceutical industry. Here, fluorescence-lifetime-imaging microscopy (FLIM) was used to monitor the crystallization of an amorphous pharmaceutical compound, indomethacin. Initially, we identified different solid indomethacin forms, amorphous and γ- and α-crystalline, on the basis of their time-resolved fluorescence. All of the studied indomethacin forms showed biexponential decays with characteristic fluorescence lifetimes and amplitudes. Using this information, the crystallization of amorphous indomethacin upon storage in 60 °C was monitored for 10 days with FLIM. The progress of crystallization was detected as lifetime changes both in the FLIM images and in the fluorescence-decay curves extracted from the images. The fluorescence-lifetime amplitudes were used for quantitative analysis of the crystallization process. We also demonstrated that the fluorescence-lifetime distribution of the sample changed during crystallization, and when the sample was not moved between measuring times, the lifetime distribution could also be used for the analysis of the reaction kinetics. Our results clearly show that FLIM is a sensitive and nondestructive method for monitoring solid-state transformations on the surfaces of fluorescent samples.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, Research group: Chemistry & Advanced Materials
Contributors: Rautaniemi, K., Vuorimaa-Laukkanen, E., Strachan, C. J., Laaksonen, T.
Number of pages: 8
Pages: 1964-1971
Publication date: 7 May 2018
Peer-reviewed: Yes

Publication information

Journal: Molecular Pharmaceutics
Volume: 15
Issue number: 5
ISSN (Print): 1543-8384
Ratings: 
  • Scopus rating (2018): CiteScore 4.7 SJR 1.402 SNIP 1.165
Original language: English
ASJC Scopus subject areas: Molecular Medicine, Pharmaceutical Science, Drug Discovery
Keywords: amorphous materials, crystal growth, fluorescence, fluorescence lifetime, kinetics
Electronic versions: 
Source: Scopus
Source ID: 85046674658

Research output: Contribution to journalArticleScientificpeer-review

FLIM reveals alternative EV-mediated cellular up-take pathways of paclitaxel

In response to physiological and artificial stimuli, cells generate nano-scale extracellular vesicles (EVs) by encapsulating biomolecules in plasma membrane-derived phospholipid envelopes. These vesicles are released to bodily fluids, hence acting as powerful endogenous mediators in intercellular signaling. EVs provide a compelling alternative for biomarker discovery and targeted drug delivery, but their kinetics and dynamics while interacting with living cells are poorly understood. Here we introduce a novel method, fluorescence lifetime imaging microscopy (FLIM) to investigate these interaction attributes. By FLIM, we show distinct cellular uptake mechanisms of different EV subtypes, exosomes and microvesicles, loaded with anti-cancer agent, paclitaxel. We demonstrate differences in intracellular behavior and drug release profiles of paclitaxel-containing EVs. Exosomes seem to deliver the drug mostly by endocytosis while microvesicles enter the cells by both endocytosis and fusion with cell membrane. This research offers a new real-time method to investigate EV kinetics with living cells, and it is a potential advancement to complement the existing techniques. The findings of this study improve the current knowledge in exploiting EVs as next-generation targeted drug delivery systems.

General information

Publication status: Published
MoE publication type: A2 Review article in a scientific journal
Organisations: Chemistry and Bioengineering, Research group: Chemistry & Advanced Materials, Faculty of Pharmacy, University of Helsinki, UC Davis, Orion Corporation, Universita degli Studi di Padova, Italy
Contributors: Saari, H., Lisitsyna, E., Rautaniemi, K., Rojalin, T., Niemi, L., Nivaro, O., Laaksonen, T., Yliperttula, M., Vuorimaa-Laukkanen, E.
Number of pages: 11
Pages: 133-143
Publication date: 28 Aug 2018
Peer-reviewed: Yes

Publication information

Journal: Journal of Controlled Release
Volume: 284
ISSN (Print): 0168-3659
Ratings: 
  • Scopus rating (2018): CiteScore 7.82 SJR 2.411 SNIP 1.717
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Cancer, Drug delivery, Exosomes, Extracellular vesicles, Fluorescence lifetime imaging microscopy, Microvesicles, Paclitaxel, Prostate
Electronic versions: 
Source: Scopus
Source ID: 85048776358

Research output: Contribution to journalReview ArticleScientificpeer-review

Pharmacokinetics of an injectable modified-release 2-hydroxyflutamide formulation in the human prostate gland using a semiphysiologically based biopharmaceutical model

The local distribution of 2-hydroxyflutamide (2-HOF) in prostate tissue after a single intraprostatic injection of a novel parenteral modified-release (MR) formulation in patients with localized prostate cancer was estimated using a semiphysiologically based biopharmaceutical model. Plasma concentration-time profiles for 2-HOF were acquired from a phase II study in 24 patients and the dissolution of the MR formulation was investigated in vitro. Human physiological values and the specific physicochemical properties of 2-HOF were obtained from the literature or calculated via established algorithms. A compartmental modeling approach was adopted for tissue and blood in the prostate gland, where the compartments were modeled as a series of concentric spherical shells contouring the centrally positioned depot formulation. Discrete fluid connections between the blood compartments were described by the representative flow of blood, whereas the mass transport of drug from tissue to tissue and tissue to blood was described by a one-dimensional diffusion approximation. An empirical dissolution approach was adopted for the release of 2-HOF from the formulation. The model adequately described the plasma concentration-time profiles of 2-HOF. Predictive simulations indicated that the local tissue concentration of 2-HOF within a distance of 5 mm from the depot formulation was approximately 40 times higher than that of unbound 2-HOF in plasma. The simulations also indicated that spreading the formulation throughout the prostate gland would expose more of the gland and increase the overall release rate of 2-HOF from the given dose. The increased release rate would initially increase the tissue and plasma concentrations but would also reduce the terminal half-life of 2-HOF in plasma. Finally, an in vitro-in vivo correlation of the release of 2-HOF from the parenteral MR formulation was established. This study shows that intraprostatic 2-HOF concentrations are significantly higher than systemic plasma concentrations and that increased distribution of 2-HOF throughout the gland, using strategic imaging-guided administration, is possible. This novel parenteral MR formulation, thus, facilitates good pharmacological effect while minimizing the risk of side effects.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Prostate cancer research center (PCRC), Uppsala University, Tampere University Hospital, University of Gothenburg, Helsinki University Central Hospital, Päijät-Häme Central Hospital, LIDDS AB
Contributors: Sjögren, E., Tammela, T. L., Lennernäs, B., Taari, K., Isotalo, T., Malmsten, L. Å., Axén, N., Lennernäs, H.
Number of pages: 15
Pages: 3097-3111
Publication date: 2 Sep 2014
Peer-reviewed: Yes

Publication information

Journal: Molecular Pharmaceutics
Volume: 11
Issue number: 9
ISSN (Print): 1543-8384
Ratings: 
  • Scopus rating (2014): CiteScore 4.92 SJR 1.641 SNIP 1.291
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science, Molecular Medicine, Drug Discovery, Medicine(all)
Keywords: 2-hydroxyflutamide, drug delivery, Liproca Depot, physiological modeling, prostate cancer
Source: Scopus
Source ID: 84906915553

Research output: Contribution to journalArticleScientificpeer-review

Switchavidin: Reversible biotin-avidin-biotin bridges with high affinity and specificity

Switchavidin is a chicken avidin mutant displaying reversible binding to biotin, an improved binding affinity toward conjugated biotin, and low nonspecific binding due to reduced surface charge. These properties make switchavidin an optimal tool in biosensor applications for the reversible immobilization of biotinylated proteins on biotinylated sensor surfaces. Furthermore, switchavidin opens novel possibilities for patterning, purification, and labeling. (Graph Presented).

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Integrated Technologies for Tissue Engineering Research (ITTE), Multi-scaled biodata analysis and modelling (MultiBAM), Fimlab Laboratories Ltd, Johannes Kepler University, Tampere University Hospital
Contributors: Taskinen, B., Zauner, D., Lehtonen, S. I., Koskinen, M., Thomson, C., Kähkönen, N., Kukkurainen, S., Määttä, J. A. E., Ihalainen, T. O., Kulomaa, M. S., Gruber, H. J., Hytönen, V. P.
Number of pages: 11
Pages: 2233-2243
Publication date: 17 Dec 2014
Peer-reviewed: Yes

Publication information

Journal: Bioconjugate Chemistry
Volume: 25
Issue number: 12
ISSN (Print): 1043-1802
Ratings: 
  • Scopus rating (2014): CiteScore 4.85 SJR 1.711 SNIP 1.164
Original language: English
ASJC Scopus subject areas: Biotechnology, Bioengineering, Organic Chemistry, Pharmaceutical Science, Biomedical Engineering, Pharmacology, Medicine(all)
Source: Scopus
Source ID: 84918539954

Research output: Contribution to journalArticleScientificpeer-review

Modification of olivomycin A at the side chain of the aglycon yields the derivative with perspective antitumor characteristics

A novel way of chemical modification of the antibiotic olivomycin A (1) at the side chain of the aglycon moiety was developed. Interaction of olivomycin A with the sodium periodate produced the key acid derivative olivomycin SA (2) in 86% yield. This acid was used in the reactions with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate (PyBOP) or diphenylphosphoryl azide (DPPA) to give corresponding amides. Whereas olivomycin SA was two orders of magnitude less cytotoxic than the parent antibiotic, the amides of 2 demonstrated a higher cytotoxicity. In particular, N,N-dimethylaminoethylamide of olivomycin SA showed a pronounced antitumor effect against transplanted experimental lymphoma and melanoma and a remarkably high binding constant to double stranded DNA. The therapeutic effects of this derivative were achievable at tolerable concentrations, suggesting that modifications of the aglycon's side chain, namely, its shortening to methoxyacetic residue and blocking of free carboxyl group, are straightforward for the design of therapeutically applicable derivatives of olivomycin A.

General information

Publication status: Published
MoE publication type: A2 Review article in a scientific journal
Organisations: Frontier Photonics, Russian Academy of Medical Sciences, N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Emanuel’ Institute of Biochemical Physics, Russian Academy of Sciences
Contributors: Tevyashova, A. N., Shtil, A. A., Olsufyeva, E. N., Luzikov, Y. N., Reznikova, M. I., Dezhenkova, L. G., Isakova, E. B., Bukhman, V. M., Durandin, N. A., Vinogradov, A. M., Kuzmin, V. A., Preobrazhenskaya, M. N.
Number of pages: 7
Pages: 7387-7393
Publication date: 15 Dec 2011
Peer-reviewed: Yes

Publication information

Journal: BIOORGANIC AND MEDICINAL CHEMISTRY
Volume: 19
Issue number: 24
ISSN (Print): 0968-0896
Ratings: 
  • Scopus rating (2011): CiteScore 3.09 SJR 1.137 SNIP 1.254
Original language: English
ASJC Scopus subject areas: Biochemistry, Molecular Medicine, Molecular Biology, Pharmaceutical Science, Drug Discovery, Clinical Biochemistry, Organic Chemistry
Keywords: Antibiotics, Antitumor activity, Aureolic acid, Chemical modifications, Drug-DNA complexes, Olivomycin A, Olivomycin SA
Source: Scopus
Source ID: 82255193979

Research output: Contribution to journalReview ArticleScientificpeer-review

Metabolic profiling of water-soluble compounds from the extracts of dark septate endophytic fungi (DSE) isolated from scots pine (Pinus sylvestris L.) seedlings using UPLC–orbitrap–MS

Endophytes are microorganisms living inside plant hosts and are known to be beneficial for the host plant vitality. In this study, we isolated three endophytic fungus species from the roots of Scots pine seedlings growing on Finnish drained peatland setting. The isolated fungi belonged to dark septate endophytes (DSE). The metabolic profiles of the hot water extracts of the fungi were investigated using Ultrahigh Performance Liquid Chromatography with Diode Array Detection and Electron Spray Ionization source Mass Spectrometry with Orbitrap analyzer (UPLC–DAD–ESI–MS–Orbitrap). Out of 318 metabolites, we were able to identify 220, of which a majority was amino acids and peptides. Additionally, opine amino acids, amino acid quinones, Amadori compounds, cholines, nucleobases, nucleosides, nucleotides, siderophores, sugars, sugar alcohols and disaccharides were found, as well as other previously reported metabolites from plants or endophytes. Some differences of the metabolic profiles, regarding the amount and identity of the found metabolites, were observed even though the fungi were isolated from the same host. Many of the discovered metabolites have been described possessing biological activities and properties, which may make a favorable contribution to the host plant nutrient availability or abiotic and biotic stress tolerance.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Materials Science and Environmental Engineering, Research group: Bio- and Circular Economy, Natural Resources Institute Finland (Luke), Turku University of Applied Science, University of Helsinki, School of Chemical Engineering, Aalto University
Contributors: Tienaho, J., Karonen, M., Muilu–Mäkelä, R., Wähälä, K., Denegri, E. L., Franzén, R., Karp, M., Santala, V., Sarjala, T.
Publication date: 2019
Peer-reviewed: Yes

Publication information

Journal: Molecules
Volume: 24
Issue number: 12
Article number: 2330
ISSN (Print): 1420-3049
Original language: English
ASJC Scopus subject areas: Analytical Chemistry, Chemistry (miscellaneous), Molecular Medicine, Pharmaceutical Science, Drug Discovery, Physical and Theoretical Chemistry, Organic Chemistry
Keywords: Acephala applanata, Coniochaeta mutabilis, Endophytes, Endophytic fungi, Humicolopsis cephalosporioides, Metabolites, Peptides, Phialocephala fortinii, Scots pine, UPLC–MS
Electronic versions: 

Bibliographical note

EXT="Franzén, Robert"

Source: Scopus
Source ID: 85068104207

Research output: Contribution to journalArticleScientificpeer-review

Human Neural Tissues from Neural Stem Cells Using Conductive Biogel and Printed Polymer Microelectrode Arrays for 3D Electrical Stimulation

Electricity is important in the physiology and development of human tissues such as embryonic and fetal development, and tissue regeneration for wound healing. Accordingly, electrical stimulation (ES) is increasingly being applied to influence cell behavior and function for a biomimetic approach to in vitro cell culture and tissue engineering. Here, the application of conductive polymer (CP) poly(3,4-ethylenedioxythiophene)-polystyrenesulfonate (PEDOT:PSS) pillars is described, direct-write printed in an array format, for 3D ES of maturing neural tissues that are derived from human neural stem cells (NSCs). NSCs are initially encapsulated within a conductive polysaccharide-based biogel interfaced with the CP pillar microelectrode arrays (MEAs), followed by differentiation in situ to neurons and supporting neuroglia during stimulation. Electrochemical properties of the pillar electrodes and the biogel support their electrical performance. Remarkably, stimulated constructs are characterized by widespread tracts of high-density mature neurons and enhanced maturation of functional neural networks. Formation of tissues using the 3D MEAs substantiates the platform for advanced clinically relevant neural tissue induction, with the system likely amendable to diverse cell types to create other neural and non-neural tissues. The platform may be useful for both research and translation, including modeling tissue development, function and dysfunction, electroceuticals, drug screening, and regenerative medicine.

General information

Publication status: E-pub ahead of print
MoE publication type: A1 Journal article-refereed
Organisations: Research group: Computational Biophysics and Imaging Group, BioMediTech, University of Wollongong, The University of Auckland, Department of Chemistry and Bioengineering, MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Melbourne
Contributors: Tomaskovic-Crook, E., Zhang, P., Ahtiainen, A., Kaisvuo, H., Lee, C. Y., Beirne, S., Aqrawe, Z., Svirskis, D., Hyttinen, J., Wallace, G. G., Travas-Sejdic, J., Crook, J. M.
Publication date: 2019
Peer-reviewed: Yes

Publication information

Journal: ADVANCED HEALTHCARE MATERIALS
Article number: 1900425
ISSN (Print): 2192-2640
Original language: English
ASJC Scopus subject areas: Biomaterials, Biomedical Engineering, Pharmaceutical Science
Keywords: 3D electrical stimulation, conductive biogels, human neural tissue, printed conducting polymer electrodes, stem cells
Source: Scopus
Source ID: 85067695878

Research output: Contribution to journalArticleScientificpeer-review

Antimicrobial activity and molecular analysis of azoderivatives of β-diketones

The emergence and increase in the number of multidrug resistant microorganisms have highly increased the need of therapeutic trials, necessitating a deep exploration on novel antimicrobial response tactics. This study is intended to screen and analyze the activity of a novel set of azoderivatives of β-diketones and their known analogs for antimicrobial properties. The compounds were analyzed to determine their minimum inhibitory concentration. Hit compounds 5-(2-(2-hydroxyphenyl)hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione (C5), 5-chloro-3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxybenzenesulfonic acid (C8), 2-(2-carboxyphenylhydrazo)malononitrile (C11) were then considered in evaluating their effect on transcription, translation and cellular oxidation impact. All three compounds were found to have in vitro inhibitory action on E. coli cell growth. The study also revealed that those compounds have a notable impact on cellular activities. It is determined that the newly synthesized azoderivative of barbituric acid (C8) have maximum growth inhibitory activity among the three compounds considered, characterized by a MIC50 of 0.42 mg/ml. The MS2 reporter system was used to detect the transcriptional response of the bacteria to the treatment with the selected drugs. All three compounds are found to down regulate the transcriptional pathway. The novel compound, C8, showed maximum inhibition of transcription mechanism, followed by C5 and C11. The effect of the compounds on translation was analyzed using a Yellow Fluorescent protein reporter system. All the compounds displayed reductive impact on translation of which C8 was found to the best, exhibiting 8.5-fold repression followed by C5 and C11, respectively. Fluctuations of the Reactive Oxygen Species (ROS) concentrations were investigated upon incubation in hit compounds using ROS sensor protein. All the three compounds were found to contribute to oxidative pathway. C8 is found to have the best oxidative effect than C5 and C11. All experiments were repeated at least twice, the results being verified to be significant using statistical analysis.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Prostate cancer research center (PCRC), Department of Signal Processing, Research group: Computational Systems Biology, Research group: Molecular Signaling Lab, Institute for Systems Biology, Seattle, Washington, USA
Contributors: Viswanathan, A., Sala, A., Yli-Harja, O., Kandhavelu, M.
Number of pages: 7
Pages: 83-89
Publication date: 23 Jan 2015
Peer-reviewed: Yes

Publication information

Journal: European Journal of Pharmaceutical Sciences
Volume: 66
ISSN (Print): 0928-0987
Ratings: 
  • Scopus rating (2015): CiteScore 4.04 SJR 1.167 SNIP 1.422
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Antimicrobial activity, Azoderivatives of β-diketones, Oxidation, Single cell, Transcription, Translation
Source: Scopus
Source ID: 84908389333

Research output: Contribution to journalArticleScientificpeer-review

Difference in the core-shell dynamics of polyethyleneimine and poly(l-lysine) DNA polyplexes

Electrostatic polymer-DNA complexes (polyplexes) have been widely investigated for DNA delivery, and remarkable differences in transfection efficacy have been seen among the materials. For example, polyethyleneimine (PEI) mediates DNA transfection more effectively than poly(l-lysine) (PLL). Biophysical properties of the polyplexes may explain their different properties in gene delivery. We investigated the structural dynamics in DNA polyplexes, especially the material exchange between the core and shell regions of the PEI and PLL polyplexes. Steady-state fluorescence spectroscopy and double labeling based fluorescence resonance energy transfer (FRET) techniques were used to study the DNA polyplexes. According to our results there is a clear difference between these two polymers: core exchange takes place in PEI but not in PLL polyplexes. Such differences in structural dynamics of polyplexes explain, at least partly, the differences in DNA release and transfection efficacy at cellular level.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Chemistry and Bioengineering, Research group: Supramolecular photochemistry, University of Helsinki, Ita-Suomen yliopisto, Universita degli Studi di Padova, Italy
Contributors: Vuorimaa-Laukkanen, E., Lisitsyna, E. S., Ketola, T., Morin-Pickardat, E., Liang, H., Hanzlíková, M., Yliperttula, M.
Pages: 122-127
Publication date: 2017
Peer-reviewed: Yes
Early online date: 2017

Publication information

Journal: European Journal of Pharmaceutical Sciences
Volume: 103
ISSN (Print): 0928-0987
Ratings: 
  • Scopus rating (2017): CiteScore 3.81 SJR 1.016 SNIP 1.317
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: DNA complexation, Fluorescence spectroscopy, Non-viral gene delivery, Poly-l-lysine, Polyethylene imine, Polyplex
Source: Scopus
Source ID: 85017349792

Research output: Contribution to journalArticleScientificpeer-review

Fluorescence spectroscopy "knife" for polyplex "cakes": taste the filling

General information

Publication status: Published
Organisations: Chemistry and Bioengineering, Research group: Supramolecular photochemistry, Research group: Chemistry & Advanced Materials, Univ Helsinki, University of Helsinki, Ctr Drug Res, Div Pharmaceut Biosci, Univ Eastern Finland, University of Eastern Finland, Sch Pharm, Univ Helsinki, University of Helsinki, Fac Pharm, Ctr Drug Res, Div Biopharmaceut Sci, Division of Biopharmaceutical Sciences, Faculty of Pharmacy, Helsinki University
Contributors: Vuorimaa-Laukkanen, E., Lisitsyna, E. S., Ketola, T., Morin-Pickardat, E., Liang, H., Hanzlikova, M., Urtti, A., Yliperttula, M. L., Lisitsyna, E., Laaksonen, T.
Publication date: 2017
Peer-reviewed: Unknown
Event: Paper presented at 30 Years of Drug Delivery Research, Kuopio, Finland.
ASJC Scopus subject areas: Chemistry(all), Pharmaceutical Science

Research output: Other conference contributionPaper, poster or abstractScientific

Effect of piroxicam on lipid membranes: Drug encapsulation and gastric toxicity aspects

Uptake of piroxicam, a non-steroidal anti-inflammatory drug, from the intestines after oral intake is limited due to its low solubility and its wide use is associated with several side effects related to the gastrointestinal tract. In this study, all-atom molecular dynamics (MD) simulations and fluorescent spectroscopy were employed to investigate the interaction of piroxicam in neutral, zwitterionic, and cationic forms with lipid bilayers composed of phosphatidylcholine, cholesterol, and PEGylated lipids. Our study was aimed to assess the potential for encapsulation of piroxicam in liposomal carriers and to shed more light on the process of gastrointestinal tract injury by the drug. Through both the MD simulations and laser scanning confocal microscopy, we have demonstrated that all forms of piroxicam can associate with the lipid bilayers and locate close to the water-membrane interface. Conventional liposomes used in drug delivery are usually stabilized by the addition of cholesterol and have their bloodstream lifetime extended through the inclusion of PEGylated lipids in the formulation to create a protective polymer corona. For this reason, we tested the effect of these two modifications on the behavior of piroxicam in the membrane. When the bilayer was PEGylated, piroxicam localize to the PEG layer and within the lipid headgroup region. This suggests that PEGylated liposomes are capable of carrying a larger quantity of piroxicam than the conventional ones.

General information

Publication status: Published
MoE publication type: A1 Journal article-refereed
Organisations: Physics, Research area: Computational Physics, Uniwersytet Jagiellonski w Krakowie, University of Helsinki
Contributors: Wilkosz, N., Rissanen, S., Cyza, M., Szybka, R., Nowakowska, M., Bunker, A., Róg, T., Kepczynski, M.
Number of pages: 10
Pages: 116-125
Publication date: 30 Mar 2017
Peer-reviewed: Yes

Publication information

Journal: European Journal of Pharmaceutical Sciences
Volume: 100
ISSN (Print): 0928-0987
Ratings: 
  • Scopus rating (2017): CiteScore 3.81 SJR 1.016 SNIP 1.317
Original language: English
ASJC Scopus subject areas: Pharmaceutical Science
Keywords: Gastric toxicity, Lipid bilayer, MD simulations, NSAIDs, PEGylated liposomes, Piroxicam
Source: Scopus
Source ID: 85009919657

Research output: Contribution to journalArticleScientificpeer-review