Publications by authors named "Diti Desai"

17 Publications

  • Page 1 of 1

A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships.

AAPS J 2020 03 2;22(2):53. Epub 2020 Mar 2.

Pharmacokinetics, Dynamics, & Metabolism, Pfizer Worldwide Research and Development, Pfizer Inc., 10646 Science Center Drive, San Diego, California, 92121, USA.

Static in vitro cell culture studies cannot capture the dynamic concentration profiles of drugs, nutrients, and other factors that cells experience in physiological systems. This limits the confidence in the translational relevance of in vitro experiments and increases the reliance on empirical testing of exposure-response relationships and dose optimization in animal models during preclinical drug development, introducing additional challenges owing to species-specific differences in drug pharmacokinetics (PK) and pharmacodynamics (PD). Here, we describe the development of a microfluidic cell culture device that enables perfusion of cells under 2D or 3D culture conditions with temporally programmable concentration profiles. Proof-of-concept studies using doxorubicin and gemcitabine demonstrated the ability of the microfluidic PK-PD device to examine dose- and time-dependent effects of doxorubicin as well as schedule-dependent effects of doxorubicin and gemcitabine combination therapy on cell viability using both step-wise drug concentration profiles and species-specific (i.e., mouse, human) drug PK profiles. The results demonstrate the importance of including physiologically relevant dynamic drug exposure profiles during in vitro drug testing to more accurately mimic in vivo drug effects, thereby improving translatability across nonclinical studies and reducing the reliance on animal models during drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1208/s12248-020-0430-yDOI Listing
March 2020

Comparison of Polydopamine-Coated Mesoporous Silica Nanorods and Spheres for the Delivery of Hydrophilic and Hydrophobic Anticancer Drugs.

Int J Mol Sci 2019 Jul 11;20(14). Epub 2019 Jul 11.

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, BioCity (3rd floor), Tykistökatu 6A, FI 20520 Turku, Finland.

Mesoporous silica nanoparticles (MSNs) have been widely studied as drug delivery systems in nanomedicine. Surface coating of MSNs have enabled them to perform efficiently in terms of bioavailability, biocompatibility, therapeutic efficacy and targeting capability. Recent studies have suggested the use of polydopamine (PDA) as a facilitative coating for MSNs that provides sustained and pH-responsive drug release, owing to the adhesive "molecular-glue" function of PDA. This further endows these hybrid MSN@PDA particles with the ability to carry large amounts of hydrophilic drugs. In this study, we expand the feasibility of this platform in terms of exploring its ability to also deliver hydrophobic drugs, as well as investigate the effect of particle shape on intracellular delivery of both a hydrophilic and hydrophobic anticancer drug. MSN@PDA loaded with doxorubicin (hydrophilic) and fingolimod (hydrophobic) was studied via a systematic in vitro approach (cellular internalization, intracellular drug distribution and cytotoxicity). To promote the cellular uptake of the MSN@PDA particles, they were further coated with a polyethylene imine (PEI)-polyethylene glycol (PEG) copolymer. Drug-loaded, copolymer-coated MSN@PDA showed effective cellular uptake, intracellular release and an amplified cytotoxic effect with both doxorubicin and fingolimod. Additionally, rods exhibited delayed intracellular drug release and superior intracellular uptake compared to spheres. Hence, the study provides an example of how the choice and design of drug delivery systems can be tuned by the need for performance, and confirms the PDA coating of MSNs as a useful drug delivery platform beyond hydrophilic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20143408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679059PMC
July 2019

Quantitative bioimage analytics enables measurement of targeted cellular stress response induced by celastrol-loaded nanoparticles.

Cell Stress Chaperones 2019 07 11;24(4):735-748. Epub 2019 May 11.

Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.

The cellular stress response, which provides protection against proteotoxic stresses, is characterized by the activation of heat shock factor 1 and the formation of nuclear stress bodies (nSBs). In this study, we developed a computerized method to quantify the formation and size distribution of nSBs, as stress response induction is of interest in cancer research, neurodegenerative diseases, and in other pathophysiological processes. We employed an advanced bioimaging and analytics workflow to enable quantitative detailed subcellular analysis of cell populations even down to single-cell level. This type of detailed analysis requires automated single cell analysis to allow for detection of both size and distribution of nSBs. For specific induction of nSB we used mesoporous silica nanoparticles (MSNs) loaded with celastrol, a plant-derived triterpene with the ability to activate the stress response. To enable specific targeting, we employed folic acid functionalized nanoparticles, which yields targeting to folate receptor expressing cancer cells. In this way, we could assess the ability to quantitatively detect directed and spatio-temporal nSB induction using 2D and 3D confocal imaging. Our results demonstrate successful implementation of an imaging and analytics workflow based on a freely available, general-purpose software platform, BioImageXD, also compatible with other imaging modalities due to full 3D/4D and high-throughput batch processing support. The developed quantitative imaging analytics workflow opens possibilities for detailed stress response examination in cell populations, with significant potential in the analysis of targeted drug delivery systems related to cell stress and other cytoprotective cellular processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12192-019-00999-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629742PMC
July 2019

Factors Affecting Intracellular Delivery and Release of Hydrophilic Versus Hydrophobic Cargo from Mesoporous Silica Nanoparticles on 2D and 3D Cell Cultures.

Pharmaceutics 2018 Nov 17;10(4). Epub 2018 Nov 17.

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, 20521 Turku, Finland.

Intracellular drug delivery by mesoporous silica nanoparticles (MSNs) carrying hydrophilic and hydrophobic fluorophores as model drug cargo is demonstrated on 2D cellular and 3D tumor organoid level. Two different MSN designs, chosen on the basis of the characteristics of the loaded cargo, were used: MSNs with a surface-grown poly(ethylene imine), PEI, coating only for hydrophobic cargo and MSNs with lipid bilayers covalently coupled to the PEI layer as a diffusion barrier for hydrophilic cargo. First, the effect of hydrophobicity corresponding to loading degree (hydrophobic cargo) as well as surface charge (hydrophilic cargo) on intracellular drug release was studied on the cellular level. All incorporated agents were able to release to varying degrees from the endosomes into the cytoplasm in a loading degree (hydrophobic) or surface charge (hydrophilic) dependent manner as detected by live cell imaging. When administered to organotypic 3D tumor models, the hydrophilic versus hydrophobic cargo-carrying MSNs showed remarkable differences in labeling efficiency, which in this case also corresponds to drug delivery efficacy in 3D. The obtained results could thus indicate design aspects to be taken into account for the development of efficacious intracellular drug delivery systems, especially in the translation from standard 2D culture to more biologically relevant organotypic 3D cultures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics10040237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320991PMC
November 2018

Targeting Somatostatin Receptors By Functionalized Mesoporous Silica Nanoparticles - Are We Striking Home?

Nanotheranostics 2018 12;2(4):320-346. Epub 2018 Jul 12.

Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Finland.

The concept of delivering nanoformulations to desired tissues by means of targeting membrane receptors of high local abundance by ligands anchored to the nanocarrier has gained a lot of attention over the last decade. Currently, there is no unanimous opinion on whether surface functionalization of nanocarriers by targeting ligands translates into any real benefit in terms of pharmacokinetics or treatment outcomes. Having examined the published nanocarriers designed to engage with somatostatin receptors, we realized that in the majority of cases targetability claims were not supported by solid evidence of targeting ligand-targeted receptor coupling, which is the very crux of a targetability concept. Here, we present an approach to characterize targetability of mesoporous silica-based nanocarriers functionalized with ligands of somatostatin receptors. The targetability proof in our case comes from a functional assay based on a genetically-encoded cAMP probe, which allows for real-time capture of receptor activation in living cells, triggered by targeting ligands on nanoparticles. We elaborate on the development and validation of the assay, highlighting the power of proper functional tests in the characterization pipeline of targeted nanoformulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ntno.23826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107779PMC
July 2018

Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles-A Platform for Drug Development.

Molecules 2017 Nov 21;22(11). Epub 2017 Nov 21.

Pharmaceutical Sciences Laboratory, Åbo Akademi University, FI-20520 Turku, Finland.

Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI) surface functionalized MSNs, as well as drug-free and drug-loaded MSN-PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules22112020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150386PMC
November 2017

Lipid Bilayer-Gated Mesoporous Silica Nanocarriers for Tumor-Targeted Delivery of Zoledronic Acid in Vivo.

Mol Pharm 2017 09 10;14(9):3218-3227. Epub 2017 Aug 10.

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University , Turku 20520, Finland.

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate used for the treatment of bone diseases and calcium metabolism. Anticancer activity of ZOL has been established, but its extraskeletal effects are limited due to its rapid uptake and accumulation to bone hydroxyapatite. In this work, we report on the development of tethered lipid bilayer-gated mesoporous silica nanocarriers (MSNs) for the incorporation, retention, and intracellular delivery of ZOL. The in vitro anticancer activity of ZOL-loaded nanocarriers was evaluated by cell viability assay and live-cell imaging. For in vivo delivery, the nanocarriers were tagged with folic acid to boost the affinity for breast cancer cells. Histological examination of the liver revealed no adverse off-target effects stemming from the nanocarriers. Importantly, nonspecific accumulation of ZOL within bone was not observed, which indicated in vivo stability of the tethered lipid bilayers. Further, the intravenously administered ZOL-loaded nanocarriers showed tumor growth suppression in breast cancer xenograft-bearing mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.7b00519DOI Listing
September 2017

Application of a handheld NIR spectrometer in prediction of drug content in inkjet printed orodispersible formulations containing prednisolone and levothyroxine.

Int J Pharm 2017 May 7;524(1-2):414-423. Epub 2017 Apr 7.

Pharmaceutical Sciences Laboratory, Åbo Akademi University, Tykistökatu 6A, FI-20540, Turku, Finland.

Quality control tools to assess the quality of printable orodispersible formulations are yet to be defined. Four different orodispersible dosage forms containing two poorly soluble drugs, levothyroxine and prednisolone, were produced on two different edible substrates by piezoelectric inkjet printing. Square shaped units of 4cm were printed in different resolutions to achieve an escalating drug dose by highly accurate and uniform displacement of droplets in picoliter range from the printhead onto the substrates. In addition, the stability of drug inks in a course of 24h as well as the mechanical properties and disintegration behavior of the printed units were examined. A compact handheld near-infrared (NIR) spectral device in the range of 1550-1950nm was used for quantitative estimation of the drug amount in printed formulations. The spectral data was treated with mean centering, Savitzky-Golay filtering and a third derivative approach. Principal component analysis (PCA) and orthogonal partial least squares (OPLS) regression were applied to build predictive models for quality control of the printed dosage forms. The accurate tuning of the dose in each formulation was confirmed by UV spectrophotometry for prednisolone (0.43-1.95mg with R=0.999) and high performance liquid chromatography for levothyroxine (0.15-0.86mg with R=0.997). It was verified that the models were capable of clustering and predicting the drug dose in the formulations with both Q and RY values between 0.94-0.99.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2017.04.014DOI Listing
May 2017

Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery.

Int J Nanomedicine 2016;11:6591-6608. Epub 2016 Dec 8.

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University.

Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with the challenge being to deliver it in a sustained manner. The combination of mesoporous silica nanoparticles (MSNs) and polycations in the confined pore space allows for incorporation and controlled release of therapeutic siRNA payloads. We hereby constructed MSNs with expanded mesopores and pore-surface-hyperbranched poly(ethyleneimine) (PEI) tethered with redox-cleavable linkers that could carry a high payload of siRNA (120 mg·g). The developed nanocarriers were efficiently taken up by cancer cells and were subsequently able to escape to the cytoplasm from the endosomes, most likely owing to the integrated PEI. Triggered by the intracellular redox conditions, the siRNA was sustainably released inside the cells over a period of several days. Functionality of siRNAs was demonstrated by using cell-killing siRNA as cargo. Despite not being the aim of the developed system, in vitro experiments using cell-killing siRNAs showed that the efficacy of siRNA transfection was comparable to the commercial in vitro transfection agent Lipofectamine. Consequently, the developed MSN-based delivery system offers a potential approach to hybrid nanocarriers for more efficient and long-term siRNA delivery and, in a longer perspective, in vivo gene silencing for RNA interference (RNAi) therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S120611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154729PMC
February 2017

Real-Time Label-Free Monitoring of Nanoparticle Cell Uptake.

Small 2016 Dec 30;12(45):6289-6300. Epub 2016 Sep 30.

Centre for Drug Research at the Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.

The surface plasmon resonance technique in combination with whole cell sensing is used for the first time for real-time label-free monitoring of nanoparticle cell uptake. The uptake kinetics of several types of nanoparticles relevant to drug delivery applications into HeLa cells is determined. The cell uptake of the nanoparticles is confirmed by confocal microscopy. The cell uptake of silica nanoparticles and polyethylenimine-plasmid DNA polyplexes is studied as a function of temperature, and the uptake energies are determined by Arrhenius plots. The phase transition temperature of the HeLa cell membrane is detected when monitoring cell uptake of silica nanoparticles at different temperatures. The HeLa cell uptake of the mesoporous silica nanoparticles is energy-independent at temperatures slightly higher than the phase transition temperature of the HeLa cell membrane, while the uptake of polyethylenimine-DNA polyplexes is energy-dependent and linear as a function of temperature with an activation energy of Ea = 62 ± 7 kJ mol = 15 ± 2 kcal mol . The HeLa cell uptake of red blood cell derived extracellular vesicles is also studied as a function of the extracellular vesicle concentration. The results show a concentration dependent behavior reaching a saturation level of the extracellular vesicle uptake by HeLa cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201601815DOI Listing
December 2016

Modulation of the structural properties of mesoporous silica nanoparticles to enhance the T-weighted MR imaging capability.

J Mater Chem B 2016 Mar 12;4(9):1720-1732. Epub 2016 Feb 12.

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland.

In this study, we have investigated the contrast enhancement of Gd(iii) incorporated nanoparticle-based contrast agents (CA) by the modulation of the synthesis and structural parameters of the mesoporous silica nanoparticle (MSN) matrix. In the optimisation process, the structure of the MSN matrix, post-synthesis treatment protocols, as well as the source and incorporation routes of paramagnetic gadolinium centers were considered, with the aim to shorten the T weighted relaxation time. After preliminary evaluation of the prepared MSNs as nanoparticulate T/positive contrast agents based on relaxivity, the structure of the MSN matrix was affirmed as the most decisive property to enhance the r relaxivity value, alongside the incorporation route of paramagnetic Gd(iii) centers. Based on these findings, the most promising Gd(iii) incorporated MSN-based CA candidate was further evaluated for its cytocompatibility and intensity enhancement by in vitro phantom MR-imaging of labeled cells. Furthermore, pre-labeled tumors grown on a chick embryo chorioallantoic membrane (CAM) were imaged as an in vivo model on a 3T clinical MRI scanner. Our findings show that the optimized MSN-based CA design enables proper access of water to Gd-centers in the selected MSN matrices, and simultaneously decreases the required amount of Gd(iii) content per mass when evaluated against the other MSNs. Consequently, the required Gd amount on a per-dose basis is significantly decreased with regard to clinically used Gd-based CAs for T-weighted MR imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5tb02371hDOI Listing
March 2016

Inhibiting Notch Activity in Breast Cancer Stem Cells by Glucose Functionalized Nanoparticles Carrying γ-secretase Inhibitors.

Mol Ther 2016 05 26;24(5):926-36. Epub 2016 Feb 26.

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.

Cancer stem cells (CSCs) are a challenge in cancer treatment due to their therapy resistance. We demonstrated that enhanced Notch signaling in breast cancer promotes self-renewal of CSCs that display high glycolytic activity and aggressive hormone-independent tumor growth in vivo. We took advantage of the glycolytic phenotype and the dependence on Notch activity of the CSCs and designed nanoparticles to target the CSCs. Mesoporous silica nanoparticles were functionalized with glucose moieties and loaded with a γ-secretase inhibitor, a potent interceptor of Notch signaling. Cancer cells and CSCs in vitro and in vivo efficiently internalized these particles, and particle uptake correlated with the glycolytic profile of the cells. Nanoparticle treatment of breast cancer transplants on chick embryo chorioallantoic membranes efficiently reduced the cancer stem cell population of the tumor. Our data reveal that specific CSC characteristics can be utilized in nanoparticle design to improve CSC-targeted drug delivery and therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/mt.2016.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881775PMC
May 2016

Targeted modulation of cell differentiation in distinct regions of the gastrointestinal tract via oral administration of differently PEG-PEI functionalized mesoporous silica nanoparticles.

Int J Nanomedicine 2016 18;11:299-313. Epub 2016 Jan 18.

Cell Biology, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.

Targeted delivery of drugs is required to efficiently treat intestinal diseases such as colon cancer and inflammation. Nanoparticles could overcome challenges in oral administration caused by drug degradation at low pH and poor permeability through mucus layers, and offer targeted delivery to diseased cells in order to avoid adverse effects. Here, we demonstrate that functionalization of mesoporous silica nanoparticles (MSNs) by polymeric surface grafts facilitates transport through the mucosal barrier and enhances cellular internalization. MSNs functionalized with poly(ethylene glycol) (PEG), poly(ethylene imine) (PEI), and the targeting ligand folic acid in different combinations are internalized by epithelial cells in vitro and in vivo after oral gavage. Functionalized MSNs loaded with γ-secretase inhibitors of the Notch pathway, a key regulator of intestinal progenitor cells, colon cancer, and inflammation, demonstrated enhanced intestinal goblet cell differentiation as compared to free drug. Drug-loaded MSNs thus remained intact in vivo, further confirmed by exposure to simulated gastric and intestinal fluids in vitro. Drug targeting and efficacy in different parts of the intestine could be tuned by MSN surface modifications, with PEI coating exhibiting higher affinity for the small intestine and PEI-PEG coating for the colon. The data highlight the potential of nanomedicines for targeted delivery to distinct regions of the tissue for strict therapeutic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S94013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725644PMC
August 2016

Prolonged Dye Release from Mesoporous Silica-Based Imaging Probes Facilitates Long-Term Optical Tracking of Cell Populations In Vivo.

Small 2016 Mar 25;12(12):1578-92. Epub 2016 Jan 25.

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, P.O. Box 123, FI-20521, Turku, Finland.

Nanomedicine is gaining ground worldwide in therapy and diagnostics. Novel nanoscopic imaging probes serve as imaging tools for studying dynamic biological processes in vitro and in vivo. To allow detectability in the physiological environment, the nanostructure-based probes need to be either inherently detectable by biomedical imaging techniques, or serve as carriers for existing imaging agents. In this study, the potential of mesoporous silica nanoparticles carrying commercially available fluorochromes as self-regenerating cell labels for long-term cellular tracking is investigated. The particle surface is organically modified for enhanced cellular uptake, the fluorescence intensity of labeled cells is followed over time both in vitro and in vivo. The particles are not exocytosed and particles which escaped cells due to cell injury or death are degraded and no labeling of nontargeted cell populations are observed. The labeling efficiency is significantly improved as compared to that of quantum dots of similar emission wavelength. Labeled human breast cancer cells are xenotransplanted in nude mice, and the fluorescent cells can be detected in vivo for a period of 1 month. Moreover, ex vivo analysis reveals fluorescently labeled metastatic colonies in lymph node and rib, highlighting the capability of the developed probes for tracking of metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201503392DOI Listing
March 2016

Sugar-decorated mesoporous silica nanoparticles as delivery vehicles for the poorly soluble drug celastrol enables targeted induction of apoptosis in cancer cells.

Eur J Pharm Biopharm 2015 Oct 14;96:11-21. Epub 2015 Jul 14.

Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland. Electronic address:

Cancerous cells have a rapid metabolism by which they take up sugars, such as glucose, at significantly higher rates than normal cells. Celastrol is a traditional herbal medicine known for its anti-inflammatory and anti-cancer activities. The poor aqueous solubility and lack of target selectivity of celastrol result in low therapeutic concentration of the drug reaching subcellular compartments of the target tissue, making it an interesting candidate for nanoparticulate delivery. The goal of this study was to utilize glucose as an affinity ligand decorated on mesoporous silica nanoparticles (MSNs), with the aim of delivering these celastrol-loaded MSNs with high specificity to cancer cells and inducing minimal off-target effects in healthy cells. MSNs were thus functionalized with sugar moieties by two different routes, either by conjugation directly to the MSN surface or mediated by a hyperbranched poly(ethylene imine), PEI layer; the latter to increase the cellular uptake by providing an overall positive surface charge as well as to increase the reaction sites for sugar conjugation. The effect of surface functionalization on the target-specific efficacy of the particles was assessed by analyzing the uptake in HeLa and A549 cells as cancer cell models, as compared to mouse embryonic fibroblasts (MEF) as a representative for normal cells. To this end a comprehensive analysis strategy was employed, including flow cytometry, confocal microscopy, and spectrophotometry. When the apoptotic effect of celastrol was evaluated, the anti-cancer activity of celastrol was shown to be significantly enhanced when it was loaded into the specifically designed MSNs. The particles themselves did not induce any toxicity, and normal cells displayed minimal off-target effects. In summary, we show that glucose-functionalized MSNs can be used as efficient carriers for targeted celastrol delivery to achieve specific induction of apoptosis in cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2015.07.009DOI Listing
October 2015

Combination of magnetic field and surface functionalization for reaching synergistic effects in cellular labeling by magnetic core-shell nanospheres.

Biomater Sci 2014 Dec 6;2(12):1750-1760. Epub 2014 Aug 6.

Laboratory for Physical Chemistry, Åbo Akademi University, Porthansgatan 3, 20500 Turku, Finland.

Aimed at utilizing high-magnetization nanospheres for magnetic field-enhanced cellular labeling, core-shell structured sandwich-like magnetic mesoporous silica nanospheres were developed. While the magnetite cluster core can provide a high magnetic response for overcoming Brownian motion in cell culture media, the layered silica shell facilitates an efficient fluorescent dye labeling. However, the problem of particle aggregation in cell media, which is strongly enhanced under a magnetic field, significantly impeded the uptake by cells, resulting in difficulties in the precise analysis of the degree of particle internalization by fluorescence-based techniques (flow cytometry and confocal microscopy). To overcome this, reflection-based assessment was employed. Further, emphasis was put on utilizing the unique role of surface-hyperbranched polyethylenimine (PEI) in efficient prevention of particle aggregation prior to cell internalization in the presence of an external magnetic field. The interparticle attraction forces originating from magnetic dipole-dipole interactions are hereby balanced by the steric and electrostatic repulsion forces provided by the PEI functionalization, which leads to dispersed nanospheres in cell culture media during the magnetic-field induced cell labeling. As a consequence, PEI functionalization and the presence of the magnetic field synergistically enhanced the efficiency of MRI-fluorescence dual-mode labeling for cellular tracking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c4bm00221kDOI Listing
December 2014

Shape engineering vs organic modification of inorganic nanoparticles as a tool for enhancing cellular internalization.

Nanoscale Res Lett 2012 Jul 1;7(1):358. Epub 2012 Jul 1.

Centre for Functional Materials, Laboratory of Physical Chemistry, Department of Natural Sciences, Åbo Akademi University, Porthansgatan 3-5, Turku, FI-20500, Finland.

In nanomedicine, physicochemical properties of the nanocarrier affect the nanoparticle's pharmacokinetics and biodistribution, which are also decisive for the passive targeting and nonspecific cellular uptake of nanoparticles. Size and surface charge are, consequently, two main determining factors in nanomedicine applications. Another important parameter which has received much less attention is the morphology (shape) of the nanocarrier. In order to investigate the morphology effect on the extent of cellular internalization, two similarly sized but differently shaped rod-like and spherical mesoporous silica nanoparticles were synthesized, characterized and functionalized to yield different surface charges. The uptake in two different cancer cell lines was investigated as a function of particle shape, coating (organic modification), surface charge and dose. According to the presented results, particle morphology is a decisive property regardless of both the different surface charges and doses tested, whereby rod-like particles internalized more efficiently in both cell lines. At lower doses whereby the shape-induced advantage is less dominant, charge-induced effects can, however, be used to fine-tune the cellular uptake as a prospective 'secondary' uptake regulator for tight dose control in nanoparticle-based drug formulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1556-276X-7-358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519764PMC
July 2012