Browsing by Subject "drug delivery"

Sort by: Order: Results:

Now showing items 1-20 of 26
  • Wannasarit, Saowanee; Wang, Shiqi; Figueiredo, Patricia; Trujillo Olvera, Claudia Ximenia; Eburnea, Francesca; Simón-Gracia, Lorena; Correia, Alexandra; Ding, Yaping; Teesalu, Tambet; Liu, Dongfei; Wiwattanapatapee, Ruedeekorn; Santos, Hélder A.; Li, Wei (2019)
    Achieving cellular internalization and endosomal escape remains a major challenge for many antitumor therapeutics, especially macromolecular drugs. Viral drug carriers are reported for efficient intracellular delivery, but with limited choices of payloads. In this study, a novel polymeric nanoparticle (ADMAP) is developed, resembling the structure and functional features of a virus. ADMAP is synthesized by grafting endosomolytic poly(lauryl methacrylate‐co‐methacrylic acid) on acetalated dextran. The endosomolytic polymer mimics the capsid protein for endosomal escape, and acetalated dextran resembles the viral core for accommodating payloads. After polymer synthesis, the subsequent controlled nanoprecipitation on a microfluidic device yields uniform nanoparticles with high encapsulation efficiency. At late endosomal pH (5.0), the ADMAP particles successfully destabilize endosomal membranes and release the drug payloads synergistically, resulting in a greater therapeutic efficacy compared with that of free anticancer drugs. Further conjugation of a tumor‐penetrating peptide enhances the antitumor efficacy toward 3D spheroids and finally leads to spheroid disintegration. The unique structure along with the synergistic endosomal escape and drug release make ADMAP nanoparticles favorable for intracellular delivery of antitumor therapeutics.
  • Matovic, Jelena; Järvinen, Juulia; Bland, Helena C.; Sokka, Iris K.; Imlimthan, Surachet; Ferrando, Ruth Mateu; Huttunen, Kristiina M.; Timonen, Juri; Peräniemi, Sirpa; Aitio, Olli; Airaksinen, Anu J.; Sarparanta, Mirkka; Johansson, Mikael P.; Rautio, Jarkko; Ekholm, Filip S. (2020)
    Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.
  • Tavaststjerna, Miisa (Helsingin yliopisto, 2020)
    Further proof of the unique morphologies of water-soluble poly(2-isopropyl-2-oxazoline)-block-poly(DL-lactide) and poly(2-isopropyl-2-oxazoline)-block-poly(L-lactide) (PiPOx-b-PDLLA and PiPOx-b-PLLA) nanoparticles was obtained via Fluorescence Spectroscopy. Additionally, loading and release studies were carried out with hydrophobic curcumin molecules to outline the potential of the amphiphilic block copolymers in drug delivery applications. To study the morphology of the nanoparticles, absorption and emission spectra of pyrene were measured in water dispersions of the nanoparticles at several concentrations. The obtained I1/I3, I337/I333.5 and partitioning constant (Kv) values were compared to corresponding data from a control core/shell nanoparticle poly(ethylene glycol)-block-poly(DL-lactide) (PEG-b-PDLLA). Of the three different amphiphilic polymers, PEG-b-PDLLA showed the smallest and PiPOx-b-PDLLA the highest Kv value. This indicates, that PiPOx-b-PDLLA core is less hydrophobic and looser compared to the dense cores of PEG-b-PDLLA and PiPOx-b-PLLA, making it capable of encapsulating the greatest amount of pyrene. In the loading and release studies, the nanoparticles were loaded with curcumin and placed in dialysis against PBS Tween® 80 solution. Curcumin content of the samples was monitored over a week by measuring the emission spectra of curcumin. PiPOx-b-PDLLA showed greater potential as a drug delivery agent: It formed more stable nanoparticles, showed higher loading capacities, higher encapsulation efficiencies and slower release rates. Flash nanoprecipitation method (FNP) was also used to prepare the same nanoparticles with and without encapsulated curcumin. In addition to the encapsulation efficiencies, sizes of the nanoparticles were determined via dynamic light scattering (DLS). PiPOx-b-PLLA forms the smallest nanoparticles with lowest encapsulation efficiencies, thus agreeing well with the higher density of PLLA core. All three investigated amphiphilic copolymers formed stable nanoparticles in water at room temperature. On the contrary, stability of the nanoparticles was found to be poor in saline solutions at body temperature. Mixing PEG-b-PDLLA with PiPOx-b-PLA in a ratio of 20:80 w-% increased the stability of the nanoparticles in physiological conditions simultaneously uncovering the thermoresponsive character of the PiPOx-blocks. Turbidity measurements of PEG-b-PDLLA mixed with PiPOx-b-PDLLA in ratio of 20:80 w-% showed slight decrease in transmittance at the 30 °C, which corresponds to the cloud point of PiPOx-b-PDLLA in PBS solution. However, it remains unclear, whether the increased stability is due to the PEG-b-PDLLA mixing in the same micelles with PiPOx-b-PDLLA, thus hindering the aggregation of the nanoparticles upon the cloud point of the PiPOx-blocks.
  • Paukkonen, Heli (Helsingfors universitet, 2013)
    Casein based formulations are promising materials for controlled drug release. Caseins are the major milk proteins, and their biocompatibility, low toxicity and natural metabolism in physiological systems make caseins extremely suitable materials for pharmaceutical formulations. Polyelectrolyte complex nanoparticles can be prepared under very mild conditions, and they are stable in the gastrointestinal tract, which makes them suitable carrier materials for oral delivery and controlled release of peptide and protein drugs. Aim of this work was to synthesize casein-poly(acrylic acid) polyelectrolyte complex nanoparticles in different mass ratios, and to study the release profile of a model compound rhodamine 6G from these nanoparticles. The casein shell of the nanoparticles was crosslinked with two different crosslinkers, because the objective was to study the effect of surface modification on size of nanoparticles as well as on the release profile of the model compound. The goal was to achieve controlled release of the model compound by modifying the thickness and the density of the casein shell structure. Size and size distribution of nanoparticles was studied by dynamic light scattering. Surface charge was studied by electrophoretic mobility measurements. Morphology was characterized with electron microscopy, and the effect of the casein shell thickness on the release of rhodamine 6G was studied with dialysis method. The synthesized nanoparticles had spherical morphology, but the size distribution was wide. The release of rhodamine 6G was slower from the nanoparticles when compared to the release of reference free rhodamine 6G, but the effect of casein shell thickness on the release of loaded rhodamine 6G remained partially unclear. However, it seems possible to achieve controlled release of encapsulated compounds from casein-poly(acrylic acid) nanoparticles with optimal surface modification in the future.
  • Qi, Shengcai; Zhang, Pengfei; Ma, Ming; Yao, Minghua; Wu, Jinjin; Mäkilä, Ermei; Salonen, Jarno; Ruskoaho, Heikki; Xu, Yuanzhi; Santos, Helder A.; Zhang, Hongbo (2019)
    Nanotechnology employs multifunctional engineered materials in the nanoscale range that provides many opportunities for translational stem cell research and therapy. Here, a cell-penetrating peptide (virus-1 transactivator of transcription)-conjugated, porous silicon nanoparticle (TPSi NP) loaded with the Wnt3a protein to increase both the cell survival rate and the delivery precision of stem cell transplantation via a combinational theranostic strategy is presented. The TPSi NP with a pore size of 10.7 nm and inorganic framework enables high-efficiency loading of Wnt3a, prolongs Wnt3a release, and increases antioxidative stress activity in the labeled mesenchymal stem cells (MSCs), which are highly beneficial properties for cell protection in stem cell therapy for myocardial infarction. It is confirmed that the intracellular aggregation of TPSi NPs can highly amplify the acoustic scattering of the labeled MSCs, resulting in a 2.3-fold increase in the ultrasound (US) signal compared with that of unlabeled MSCs. The translational potential of the designed nanoagent for real-time US imaging-guided stem cell transplantation is confirmed via intramyocardial injection of labeled MSCs in a nude mouse model. It is proposed that the intracellular aggregation of protein drug-loaded TPSi NPs could be a simple but robust strategy for improving the therapeutic effect of stem cell therapy.
  • Pérez, Alejandro Garcia; Nieminen, Heikki J.; Finnilä, Mikko; Salmi, Ari; Pritzker, Kenneth P. H.; Lampsijärvi, Eetu; Paulin, Tor; Airaksinen, Anu J.; Saarakkala, Simo; Haeggström, Edward (2018)
    Localized delivery of drugs into articular cartilage (AC) may facilitate the development of novel therapies to treat osteoarthritis (OA). We investigated the potential of spark-gap-generated sound to deliver a drug surrogate, i.e., methylene blue (MB), into AC. In vitro experiments exposed bovine AC samples to either simultaneous sonication and immersion in MB (Treatment 1; n = 10), immersion in MB after sonication (Control 1; n = 10), solely immersion in MB (Control 2; n = 10), or neither sonication nor immersion in MB (Control 3; n = 10). The sonication protocol consisted of 1,000 spark-gap -generated pulses. Delivery of MB into AC was estimated from optical absorbance in transmission light microscopy. Optical absorbance was significantly greater in the treatment group up to 900 mu m depth from AC surface as compared to all controls. Field emission scanning electron microscopy (FESEM), histological analysis, and digital densitometry (DD) of sonicated (n = 6) and non-sonicated (n = 6) samples showed no evidence of sonication-induced changes in proteoglycan content or collagen structure. Consequently, spark-gap -generated sound may offer a solution for localized drug delivery into AC in a non-destructive fashion. Further research on this method may contribute to OA drug therapies.
  • Kosma, Oona (Helsingfors universitet, 2016)
    The leading causes of vision loss in developed countries are related to the impairment of the posterior segment of the eye. The drug delivery to the posterior segment with topical or systemic methods is challenging due to the protective barriers of the eye. The conventional and effective technique to deliver therapeutic concentrations of drugs to the posterior segment is intravitreal injection. Since naked molecules usually have a rapid vitreal clearance, the invasive injections need repeated administration in chronic conditions, resulting to increased risk of complications and poor patient compliance. The growing field of research of drug delivery systems, such as implants, nano- and microparticles and liposomes emphasizes to answer these challenges by enhancing time-controlled and targeted drug release to retinal and choroidal tissues, enabling less frequent administration and reduced off-target side effects. Liposomal drug delivery systems have potential in delivering therapeutics to posterior eye tissues in sustained and targeted manner. The experimental part of the thesis focused on studying the cell uptake, content release and cytotoxicity of light triggered pH-sensitive gold nanoparticle liposomes in human retinal pigment epithelial (ARPE-19), human umbilical vein endothelial (HUVEC) and monkey choroidal endothelial (RF/6A) cell lines. To enhance the cell differentiation to resemble the in vivo morphology, ARPE-19 cells were also used as a filter-cultured model. HUVEC cells were cultured on an artificial basement membrane matrix and induced with vascular endothelial growth factor (VEGF) to form capillary like tube structures. The liposomes were not cytotoxic during 24-hour incubation. All cells internalized liposomes to some extent, but in HUVEC capillary tubes the uptake seemed to be negligible. The light induced calcein release was variable between the experiments, possibly due to the study setting related factors, such as difficulties in temperature control. The liposomal carrier system has promising attributes to posterior eye drug delivery. Liposome-encapsulation prolongs the half-live of a drug. Light triggered release and pH-sensitivity enables highly targeted intracellular drug release decreasing the off-target side effects. Optimization of the study arrangement and liposome production procedure is needed in order to get more reliable results and further assess the future potential of these liposomes in the treatment of posterior eye diseases.
  • Li, Wei; Zheng, Kai; Petrikaite, Vilma (2021)
  • Ding, Yaping; Li, Wei; Zhang, Feng; Liu, Zehua; Ezazi, Nazanin Zanjanizadeh; Liu, Dongfei; Santos, Helder A. (2019)
    The versatile electrospinning technique is recognized as an efficient strategy to deliver active pharmaceutical ingredients and has gained tremendous progress in drug delivery, tissue engineering, cancer therapy, and disease diagnosis. Numerous drug delivery systems fabricated through electrospinning regarding the carrier compositions, drug incorporation techniques, release kinetics, and the subsequent therapeutic efficacy are presented herein. Targeting for distinct applications, the composition of drug carriers vary from natural/synthetic polymers/blends, inorganic materials, and even hybrids. Various drug incorporation approaches through electrospinning are thoroughly discussed with respect to the principles, benefits, and limitations. To meet the various requirements in actual sophisticated in vivo environments and to overcome the limitations of a single carrier system, feasible combinations of multiple drug-inclusion processes via electrospinning could be employed to achieve programmed, multi-staged, or stimuli-triggered release of multiple drugs. The therapeutic efficacy of the designed electrospun drug-eluting systems is further verified in multiple biomedical applications and is comprehensively overviewed, demonstrating promising potential to address a variety of clinical challenges.
  • Wang, Shiqi; Wannasarit, Saowanee; Figueiredo, Patricia; Molinaro, Giuseppina; Ding, Yaping; Correia, Alexandra; Casettari, Luca; Wiwattanapatapee, Ruedeekorn; Hirvonen, Jouni; Liu, Dongfei; Li, Wei; Santos, Hélder A. (2021)
    In this study, a rationally designed nanocomposite (BUDPDA@MAP) composed of polydopamine (PDA) nanoparticle and anti‐inflammatory drug budesonide (BUD) encapsulated in a pH‐responsive endosomolytic polymer (poly(butyl methacrylate‐co‐methacrylic acid) grafted acetalated dextran, denoted by MAP), is proposed. The uniform nanocomposite is prepared using a microfluidic device. At low endosomal pH (5.5), MAP destabilizes the endosomal membranes for the cytoplasmic delivery of PDA, and releases BUD simultaneously, resulting in a greater reactive oxygen species scavenging capability than both the free drug and PDA alone. The combined therapeutic efficacy from PDA and BUD also leads to a successful macrophage phenotype switch from pro‐inflammatory M1 to anti‐inflammatory M2.
  • Junnuthula, Vijayabhaskarreddy; Sadeghi Boroujeni, Amir; Cao, Shoupeng; Tavakoli, Shirin; Ridolfo, Roxane; Toropainen, Elisa; Ruponen, Marika; van Hest, Jan C. M.; Urtti, Arto (2021)
    Posterior eye tissues, such as retina, are affected in many serious eye diseases, but drug delivery to these targets is challenging due to various anatomical eye barriers. Intravitreal injections are widely used, but the intervals between invasive injections should be prolonged. We synthesized and characterized (H-1 NMR, gel permeation chromatography) block copolymers of poly(ethylene glycol), poly(caprolactone), and trimethylene carbonate. These polymers self-assembled to polymersomes and polymeric micelles. The mean diameters of polymersomes and polymeric micelles, about 100 nm and 30-50 nm, respectively, were obtained with dynamic light scattering. Based on single particle tracking and asymmetric flow field-flow fractionation, the polymeric micelles and polymersomes were stable and diffusible in the vitreous. The materials did not show cellular toxicity in cultured human umbilical vein endothelial cells in the Alamar Blue Assay. Pharmacokinetics of the intravitreal nanocarriers in the rabbits were evaluated using in vivo fluorophotometry. The half-lives of the polymersomes (100 nm) and the micelles (30 nm) were 11.4-32.7 days and 4.3-9.5 days. The intravitreal clearance values were 1.7-8.7 mu L/h and 3.6-5.4 mu L/h for polymersomes and polymeric micelles, respectively. Apparent volumes of distribution of the particles in the rabbit vitreous were 0.6-1.3 mL for polymeric micelles and 1.9-3.4 mL for polymersomes. Polymersomes were found in the vitreous for at least 92 days post-dosing. Furthermore, fundus imaging revealed that the polymersomes accumulated near the optic nerve and retained there even at 111 days post-injection. Polymersomes represent a promising technology for controlled and site-specific drug delivery in the posterior eye segment.
  • Carvalho, Tiago; Guedes, Gabriela; Sousa, Filipa L.; Freire, Carmen S. R.; Santos, Hélder A. (2019)
    Bacterial cellulose (BC) is a nanocellulose form produced by some nonpathogenic bacteria. BC presents unique physical, chemical, and biological properties that make it a very versatile material and has found application in several fields, namely in food industry, cosmetics, and biomedicine. This review overviews the latest state-of-the-art usage of BC on three important areas of the biomedical field, namely delivery systems, wound dressing and healing materials, and tissue engineering for regenerative medicine. BC will be reviewed as a promising biopolymer for the design and development of innovative materials for the mentioned applications. Overall, BC is shown to be an effective and versatile carrier for delivery systems, a safe and multicustomizable patch or graft for wound dressing and healing applications, and a material that can be further tuned to better adjust for each tissue engineering application, by using different methods.
  • Medina, Tuula Penate; Gerle, Mirko; Humbert, Jana; Chu, Hanwen; Koepnick, Anna-Lena; Barkmann, Reinhard; Garamus, Vasil M.; Sanz, Beatriz; Purcz, Nicolai; Will, Olga; Appold, Lia; Damm, Timo; Suojanen, Juho; Arnold, Philipp; Lucius, Ralph; Willumeit-Roemer, Regina; Acil, Yahya; Wiltfang, Joerg; Goya, Gerardo F.; Glueer, Claus C.; Medina, Oula Penate (2020)
    Simple Summary A novel active release system magnetic sphingomyelin-containing liposome encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin was evaluated. The liposomal sphingomyelin is a target for the sphingomyelinase enzyme, which is released by stressed cells. Thus, sphingomyelin containing liposomes behave as a sensitizer for biological stress situations. In addition, the liposomes were engineered by adding paramagnetic beads to act as a receiver of outside given magnetic energy. The enzymatic activity towards liposomes and destruction caused by the applied magnetic field caused the release of the content from the liposomes. By using these novel liposomes, we could improve the drug release feature of liposomes. The improved targeting and drug-release were shown in vitro and the orthotopic tongue cancer model in mice optical imaging. The increased delivery of cisplatin prolonged the survival of the targeted delivery group versus free cisplatin. Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.
  • Tahir, Nayab; Madni, Asadullah; Correia, Alexandra; Rehman, Mubashar; Balasubramanian, Vimalkumar; Khan, Muhammad Muzamil; Santos, Hélder A. (2019)
    Background: Lipid polymer hybrid nanoparticles (LPHNPs) for the controlled delivery of hydrophilic doxorubicin hydrochloride (DOX.HCl) and lipophilic DOX base have been fabricated by the single step modified nanoprecipitation method. Materials and methods: Poly (D, L-lactide-co-glicolide) (PLGA), lecithin, and 1,2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000 (DSPE-PEG 2000) were selected as structural components. Results: The mean particle size was 173–208 nm, with an encapsulation efficiency of 17.8±1.9 to 43.8±4.4% and 40.3±0.6 to 59. 8±1.4% for DOX.HCl and DOX base, respectively. The drug release profile was in the range 33–57% in 24 hours and followed the Higuchi model (R2,=0.9867–0.9450) and Fickian diffusion (n<0.5). However, the release of DOX base was slower than DOX.HCl. The in vitro cytotoxicity studies and confocal imaging showed safety, good biocompatibility, and a higher degree of particle internalization. The higher internalization of DOX base was attributed to higher permeability of lipophilic component and better hydrophobic interaction of particles with cell membranes. Compared to the free DOX, the DOX.HCl and DOX base loaded LPHNPs showed higher antiproliferation effects in MDA-MB231 and PC3 cells. Conclusion: Therefore, LPHNPs have provided a potential drug delivery strategy for safe, controlled delivery of both hydrophilic and lipophilic form of DOX in cancer cells
  • Bunker, Alex; Rog, Tomasz (2020)
    In this review, we outline the growing role that molecular dynamics simulation is able to play as a design tool in drug delivery. We cover both the pharmaceutical and computational backgrounds, in a pedagogical fashion, as this review is designed to be equally accessible to pharmaceutical researchers interested in what this new computational tool is capable of and experts in molecular modeling who wish to pursue pharmaceutical applications as a context for their research. The field has become too broad for us to concisely describe all work that has been carried out; many comprehensive reviews on subtopics of this area are cited. We discuss the insight molecular dynamics modeling has provided in dissolution and solubility, however, the majority of the discussion is focused on nanomedicine: the development of nanoscale drug delivery vehicles. Here we focus on three areas where molecular dynamics modeling has had a particularly strong impact: (1) behavior in the bloodstream and protective polymer corona, (2) Drug loading and controlled release, and (3) Nanoparticle interaction with both model and biological membranes. We conclude with some thoughts on the role that molecular dynamics simulation can grow to play in the development of new drug delivery systems.
  • Pessi, Jenni (Helsingfors universitet, 2013)
    Polymer microspheres hold great potential as oral drug delivery system for therapeutic proteins. Microspheres prepared with biocompatible and biodegredable polymers have been extensively studied, since the oral delivery of therapeutic proteins is challenging due to the conditions in the GI-tract. The aims of this research were to apply microfluidics on polymeric microsphere preparation process, to determine what kind of formulations are suitable for this technology, to establish a controlled preparation process that produces advanced particles and to create a template for oral protein drug delivery. With microfluidic fabrication it is possible to gain control over the process and content of each droplet. However, finding suitable formulations for microfluidics is demanding. In this study, biphasic flow was employed to successfully produce double (W/O/W) emulsion droplets with ultra thin shells. Once the process and formulation variables were optimized constant droplet production was achieved. Flow rates used were 500 µl/h in the inner and in the middle phase and 2500 µl/h in the outer phase, respectively. Two formulations were selected for further characterization: 5 % poly(vinyl alcohol) in water in the outer phase, 3 % polycaprolactone in ethyl acetate in the middle phase and either 10 % or 20 % poly(vinyl alcohol) and polyethylenglycol (1:4) in water in the inner phase. All the particles were found to be intact and contain the inner phase, as verified by confocal microscopy. Further, the particles were monodisperse and non-porous, as observed by scanning electron microscopy. Particle size was found to be around 20-40 µm, variation in the particle size within one batch was small and the particles were stable up to 4 weeks. The encapsulation efficiency of the particles was remarkable; as high as 85 % loading of the model compound, bovine serum albumin. Particles released 30 % of their content within 48 hours. In conlusion, developing functional formulations for micfoluidic technology was possible, the microparticles encapsulated the model protein extremely well and all in all microfluidic technology had a lot of potential for droplet manufacturing for pharmaceutical applications.
  • Liu, Zehua; Fontana, Flavia; Python, Andre; Hirvonen, Jouni T.; Santos, Helder A. (2020)
    In the past two decades, microfluidics-based particle production is widely applied for multiple biological usages. Compared to conventional bulk methods, microfluidic-assisted particle production shows significant advantages, such as narrower particle size distribution, higher reproducibility, improved encapsulation efficiency, and enhanced scaling-up potency. Herein, an overview of the recent progress of the microfluidics technology for nano-, microparticles or droplet fabrication, and their biological applications is provided. For both nano-, microparticles/droplets, the previously established mechanisms behind particle production via microfluidics and some typical examples during the past five years are discussed. The emerging interdisciplinary technologies based on microfluidics that have produced microparticles or droplets for cellular analysis and artificial cells fabrication are summarized. The potential drawbacks and future perspectives are also briefly discussed.
  • Lifländer, Rami (Helsingin yliopisto, 2020)
    Throughout the history, there has been a wide selection of drugs developed for therapy of cardiovascular diseases (CVD). Despite a broad spectrum of different therapeutic strategies to deaccelerate and try to reverse the progression of cardiovascular diseases has been achieved, only a modest amelioration of the health of the CVD patients was achieved, as the mortality remains high by being the cause of nearly one in every three deaths yearly, myocardial infarction being involved in majority of these cases. Novel solutions are being studied to overcome this problem, one of them being nanoparticles, which may provide potential solution by carrying drugs to the desired location. Microfluidics technique may further improve the properties of nanoparticles, being a platform that allows the production of homogenous and repeatable batches that are non-dependent by the operator using it. In this thesis, it is described how microfluidics-based preparation of spermine-functionalised acetalated dextran nanoparticles co-loaded with a trisubstituted isoxazole and curcumin perform in physicochemical and in vitro experiments, in order to evaluate their potential in the application of ischemic myocardial injury therapy.
  • Hellinen, Laura; Bahrpeyma, Sina; Rimpela, Anna-Kaisa; Hagstrom, Marja; Reinisalo, Mika; Urtti, Arto (2020)
    Interactions between drugs and melanin pigment may have major impacts on pharmacokinetics. Therefore, melanin binding can modify the efficacy and toxicity of medications in ophthalmic and other disease of pigmented tissues, such as melanoma. As melanin is present in many pigmented tissues in the human body, investigation of pigment binding is relevant in drug discovery and development. Conventionally, melanin binding assays have been performed using an equilibrium binding study followed by chemical analytics, such as LC/MS. This approach is laborious, relatively slow, and limited to facilities with high performance quantitation instrumentation. We present here a screening of melanin binding with label-free microscale thermophoresis (MST) that utilizes the natural autofluorescence of melanin. We determined equilibrium dissociation constants (K-d) of 11 model compounds with melanin nanoparticles. MST categorized the compounds into extreme (chloroquine, penicillin G), high (papaverine, levofloxacin, terazosin), intermediate (timolol, nadolol, quinidine, propranolol), and low melanin binders (atropine, methotrexate, diclofenac) and displayed good correlation with binding parameter values obtained with the conventional binding study and LC/MS analytics. Further, correlation was seen between predicted melanin binding in human retinal pigment epithelium and choroid (RPE-choroid) and K(d)values obtained with MST. This method represents a useful and fast approach for classification of compounds regarding melanin binding. Thus, the method can be utilized in various fields, including drug discovery, pharmacokinetics, and toxicology.
  • Kari, Otto K. (Helsingfors universitet, 2018)
    Nanolääkkeiden pinnalle elimistössä muodostuva biomolekyylikerros eli proteiinikorona vaikuttaa muun muassa jakautumiseen, toksisuuteen ja soluvuorovaikutuksiin. Koronan ominaisuuksien tuntemus jakautumisen eri vaiheissa on siten edellytys tehokkaampien ja turvallisempien nanolääkkeiden kehittämiselle, mutta kehitystyötä on hidastanut soveltuvien menetelmien puute. Turvallisuuden ja tehon ennakoinnin osalta on korostettu leimavapaiden in vitro -menetelmien tarvetta. Tutkielmassa kehitettiin multiparametriseen pintaplasmoniresonanssilaitteistoon ja laskennalliseen mallinnukseen perustuva menetelmä liposomien koronan tiheyden ja paksuuden määrittämiseen. Toisin kuin koronan tutkimiseen yleisesti käytetyt menetelmät, valoon perustuva kajoamaton ja leimavapaa menetelmä ei vaikuta koronan rakenteeseen. Näin voidaan tutkia myös löyhemmin sitoutuneista proteiineista muodostunutta pintakerrosta, mikä vastaa keskeisimpään kirjallisuuskatsauksessa todettuun menetelmäpuutteeseen. Menetelmää sovellettiin neljän biosensorille immobilisoidun liposomiformulaation pinnalle ihmisen seerumissa muodostuvan koronan tutkimiseen. Sen avulla oli mahdollista määrittää ensimmäistä kertaa tiiviin ja löyhän koronan tiheys ja paksuus laimentamattomassa seerumissa. Tulokset tukevat käsitystä ns. erotteluhypoteesin kuvaamasta erillisestä löyhästä proteiinikerroksesta ja avaavat uusia mahdollisuuksia sen biologisen merkityksen arviointiin. Lisäksi voitiin määrittää ensi kerran opsoniinimolekyylien sitoutumiskinetiikka liposomien pinnalle, minkä avulla voidaan arvioida nanolääkkeiden taipumusta poistua verenkierrosta ja aktivoida sisäsyntyinen immuunipuolustus. Menetelmä soveltuu siten liposomien koostumuksen ja pinta-arkkitehtuurin optimointiin prekliinisessä lääkekehitysvaiheessa.