Didem Şen Karaman

FRET-reporter nanoparticles to monitor redox-induced intracellular delivery of active compounds

Nanoparticle-mediated drug delivery holds great promise for more specific and efficient therapies, mostly due to their high payload and the integration of targeted delivery functions. However, it is typically not possible to monitor the intracellular release of active compounds directly, which hampers the assessment of novel delivery platforms and non-cytotoxic compounds. Herein, we implemented a FRET (fluorescence resonance energy transfer)-reporter system to semi-quantitatively follow the time-course of the intracellular release of a redox-cleavable compound from a nanoparticle delivery platform. We used silica core–shell particles that could be readily modified with a high density of reactive amino groups, and attached fluorescent reporter molecules as model drug cargo. We coupled a FRET-donor fluorophore via a stable covalent bond, while the FRET-acceptor fluorophore was linked via a disulfide-bridge. Therefore, a loss of FRET reported on redox-induced acceptor compound release. These FRET-reporter nanoparticles allowed us to determine both the time course of cellular internalization as well as the intracellular compound release. Our data show that particle internalization is the rate-limiting step, while compound cleavage occurs quickly after internalization. The presented FRET-reporter approach has the advantage to directly monitor the compound cleavage, as compared to indirect read-outs that are based on their cytotoxic action. We therefore propose that our FRET-reporter particles are suitable to monitor intracellularly redox-releasable compounds that are typically not cytotoxic, such as siRNAs.

Modulation of the structural properties of mesoporous silica nanoparticles to enhance the T1-weighted MR imaging capability

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 T1 weighted relaxation time. After preliminary evaluation of the prepared MSNs as nanoparticulate T1/positive contrast agents based on relaxivity, the structure of the MSN matrix was affirmed as the most decisive property to enhance the r1 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 T1-weighted MR imaging.

Multimodality Imaging of Silica and Silicon Materials In Vivo

Recent progress in the development of silica- and silicon-based multimodality imaging nanoprobes has advanced their use in image-guided drug delivery, and the development of novel systems for nanotheranostic and diagnostic applications. As biocompatible and flexibly tunable materials, silica and silicon provide excellent platforms with high clinical potential in nanotheranostic and diagnostic probes with well-defined morphology and surface chemistry, yielding multifunctional properties. In vivo imaging is of great value in the exploration of methods for improving site-specific nanotherapeutic delivery by silica- and silicon-based drug-delivery systems. Multimodality approaches are essential for understanding the biological interactions of nanotherapeutics in the physiological environment in vivo. The aim here is to describe recent advances in the development of in vivo imaging tools based on nanostructured silica and silicon, and their applications in single and multimodality imaging.

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

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.

Current Approaches for Exploration of Nanoparticles as Antibacterial Agents

The ascending anxiety regarding antimicrobial resistance as well as the recalcitrant nature of biofilm-associated infections call for the development of alternative strategies to treat bacterial diseases. Nanoparticles have been considered as one of the emerging and promising platforms in this respect. Their unique physical and chemical properties may lead to fine-tuned interactions between them and bacteria. In this chapter, we aim to provide an overview on the use of nanoparticles as antimicrobial agents. Both antibacterial and anti-biofilm activities of nanoparticles and their current approaches will be reviewed. The in vitro methods that are used to evaluate the potency of nanoparticles as antimicrobial agents will be discussed in detail.

NIR light-activated dual-modality cancer therapy mediated by photochemical internalization of porous nanocarriers with tethered lipid bilayers

To overcome endo/lysosomal restriction as well as to increase the clinical availability of nanomedicine, we report on a NIR stimuli-responsive nanoplatform based on mesoporous silica nanoparticles tethered with lipid bilayers (MSN@tLB) for chemotherapy and photodynamic dual-modality therapy. In this nanosystem, a hydrophilic drug molecule zoledronic acid (ZOL) was first incorporated into the MSN core with modifications of hyperbranched polyethylenimine (PEI). To prevent the leakage of the payload, the LB shell was covalently tethered onto the MSN core via the PEI cushion which can greatly enhance the stability of the LB. Meanwhile, a hydrophobic photosensitizer IR-780 iodide was introduced into the hydrophobic compartment to endow the system with photo-activation properties. The as-prepared MSN-ZOL@tLB-IR780 possesses high dispersion stability stemming from the LB, as well as negligible cytotoxicity. After cellular internalization and endo/lysosomal capture of the nanoparticles, photochemical internalization (PCI) mediated simultaneous cargo release and endo/lysosomal escape were achieved by local ROS production upon 808 nm irradiation, thus leading to highly efficient chemo-photodynamic therapy on cancer cells in vitro. Such a system presents a sophisticated platform that integrates biocompatibility, spatiotemporal control, NIR-responsiveness, and synergistic therapies to promote cancer therapy.

Modeling of a hybrid Langmuir adsorption isotherm for describing interactions between drug molecules and silica surfaces

The interaction between disulfiram (Antabus®) and silica was studied experimentally by adsorption from apolar solvent onto highly porous silica material (Santa Barbara amorphous material-3) with large surface area. The adsorption isotherm was fitted to the Langmuir model by accounting 2 different affinities contributing to the overall behavior, which were attributed to 2 different types of silanol groups (i.e., geminal and vicinal) present on amorphous silica surfaces. This assumption was supported by theoretical calculations. In addition, the model could describe the adsorption of ibuprofen to the carrier material, indicating that the model bears big potential for describing the interactions between silica surfaces and drug molecules.

Silica-based nanoparticles as drug delivery systems: Chances and challenges

Abstract Silica-based nanoparticles are used as excipients in pharmaceutical technology. Recently, mesoporous silica nanoparticles have emerged as drug delivery systems. Their porous structure enables the high drug-loading of drugs with poor water solubility. The silica matrix protects entrapped drugs against enzymatic degradation. Furthermore, the premature release of drugs is hindered by pore-gating strategies. Adding a targeting ligand to the silica-based nanoparticles directs them to diseased cells and can diminish side-effects in healthy cells. Silica-based nanoparticles are preferably injected intravenously, since this administration route lacks the disadvantages of oral, dermal, and pulmonary delivery. Once injected, silica-based nanoparticles encounter blood cells and complement proteins. Complement protein binding, hemolysis, and coagulation are challenges for drug delivery systems, because this reduces their efficacy and also challenges their safety. Consequently, hemocompatibility testing is a must for nano drug carriers. This chapter provides an overview of the chances and challenges for silica-based nanoparticles in intravenous drug delivery.

A method for optical imaging and monitoring of the excretion of fluorescent nanocomposites from the body using artificial neural networks

In this study, a new approach to the implementation of optical imaging of fluorescent nanoparticles in a biological medium using artificial neural networks is proposed. The studies were carried out using new synthesized nanocomposites - nanometer graphene oxides, covered by the poly(ethylene imine)-poly(ethylene glycol) copolymer and by the folic acid. We present an example of a successful solution of the problem of monitoring the removal of nanocomposites based on nGO and their components with urine using fluorescent spectroscopy and artificial neural networks. However, the proposed method is applicable for optical imaging of any fluorescent nanoparticles used as theranostic agents in biological tissue.