Contrasting Properties of Polymeric Nanocarriers for MRI-Guided Drug Delivery.

Poor pharmacokinetics and low aqueous solubility combined with rapid clearance from the circulation of drugs result in their limited effectiveness and generally high therapeutic doses. The use of nanocarriers for drug delivery can prevent the rapid degradation of the drug, leading to its increased half-life. It can also improve the solubility and stability of drugs, advance their distribution and targeting, ensure a sustained release, and reduce drug resistance by delivering multiple therapeutic agents simultaneously. Furthermore, nanotechnology enables the combination of therapeutics with biomedical imaging agents and other treatment modalities to overcome the challenges of disease diagnosis and therapy. Such an approach is referred to as "theranostics" and aims to offer a more patient-specific approach through the observation of the distribution of contrast agents that are linked to therapeutics. The purpose of this paper is to present the recent scientific reports on polymeric nanocarriers for MRI-guided drug delivery. Polymeric nanocarriers are a very broad and versatile group of materials for drug delivery, providing high loading capacities, improved pharmacokinetics, and biocompatibility. The main focus was on the contrasting properties of proposed polymeric nanocarriers, which can be categorized into three main groups: polymeric nanocarriers (1) with relaxation-type contrast agents, (2) with chemical exchange saturation transfer (CEST) properties, and (3) with direct detection contrast agents based on fluorinated compounds. The importance of this aspect tends to be downplayed, despite its being essential for the successful design of applicable theranostic nanocarriers for image-guided drug delivery. If available, cytotoxicity and therapeutic effects were also summarized.

Polyaminoacid Based Core@shell Nanocarriers of 5-Fluorouracil: Synthesis, Properties and Theranostics Application.

Cancer is one of the most important health problems of our population, and one of the common anticancer treatments is chemotherapy. The disadvantages of chemotherapy are related to the drug's toxic effects, which act on cancer cells and the healthy part of the body. The solution of the problem is drug encapsulation and drug targeting. The present study aimed to develop a novel method of preparing multifunctional 5-Fluorouracil (5-FU) nanocarriers and their in vitro characterization. 5-FU polyaminoacid-based core@shell nanocarriers were formed by encapsulation drug-loaded nanocores with polyaminoacids multilayer shell via layer-by-layer method. The size of prepared nanocarriers ranged between 80-200 nm. Biocompatibility of our nanocarriers as well as activity of the encapsulated drug were confirmed by MTT tests. Moreover, the ability to the real-time observation of developed nanocarriers and drug accumulation inside the target was confirmed by fluorine magnetic resonance imaging (19F-MRI).

Effective Detection of Nafion®-Based Theranostic Nanocapsules through 19F Ultra-Short Echo Time MRI.

The application of the Three-Dimensional Ultra-Short Echo Time (3D UTE) pulse sequence at a high magnetic field for visualization of the distribution of 19F loaded theranostic core-shell nanocapsules with Nafion® (1,1,2,2-tetrafluoroethene; 1,1,2,2-tetrafluoro-2- [1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluoroethenoxy)propan-2-yl] oxyethanesulfonic acid) incorporated into the shell is presented. The nanocarriers were formed via the layer-by-layer technique with biodegradable polyelectrolytes: PLL (Poly-L-lysine), and with Nafion®: polymer with high 19F content. Before imaging, an MR (magnetic resonance) spectroscopy and T1 and T2 measurements were performed, resulting in values of T2 between 1.3 ms and 3.0 ms, depending on the spectral line. To overcome limitations due to such short T2, the 3D UTE pulse sequence was applied for 19F MR imaging. First Nafion® solutions of various concentrations were measured to check the detection limit of our system for the investigated molecule. Next, the imaging of a phantom containing core-shell nanocapsules was performed to assess the possibility of visualizing their distribution in the samples. Images of Nafion® containing samples with SNR ≥ 5 with acquisition time below 30 minutes for 19F concentration as low as 1.53·10-2 mmol 19F/g of sample, were obtained. This is comparable with the results obtained for molecules, which exhibit more preferable MR characteristics.

Nafion-Based Nanocarriers for Fluorine Magnetic Resonance Imaging.

The aim of our study was to develop a novel method for nanocarriers' preparation as a fluorine magnetic resonance imaging (19F MRI)-detectable drug delivery system. The novelty of the proposed approach is based on the application of fluorinated polyelectrolyte Nafion as a contrast agent since typical MRI contrast agents are based on paramagnetic gadolinium or ferro/superparamagnetic iron oxide compounds. An advantage of using an 19F-based tracer comes from the fact that the 19F image is detected at a different resonance frequency than the 1H image. In addition, the close to zero natural concentration of 19F nuclei in the human body makes fluorine atoms a promising MRI marker without any natural background signal. That creates the opportunity to localize and identify only exogenous fluorinated compounds with 100% specificity. The nanocarriers were formed by the deposition of polyelectrolytes on nanoemulsion droplets via the layer-by-layer technique with the saturation approach. The polyelectrolyte multilayer shell was composed of Nafion, the fluorinated ionic polymer used for labeling by 19F nuclei, and poly-l-lysine (PLL). The surface of such prepared nanocarriers was further pegylated by adsorption of pegylated polyanion, poly-l-glutamic acid (PGA). The 19F MRI-detectable hydrophobic nanocarriers with an average size of 170 nm and a sufficient signal-to-noise ratio have been developed and optimized to be used for passive tumor targeting and drug delivery.

Magnetically responsive polycaprolactone nanocarriers for application in the biomedical field: magnetic hyperthermia, magnetic resonance imaging, and magnetic drug delivery.

There are huge demands on multifunctional nanocarriers to be used in nanomedicine. Herein, we present a simple and efficient method for the preparation of multifunctional magnetically responsive polymeric-based nanocarriers optimized for biomedical applications. The hybrid delivery system is composed of drug-loaded polymer nanoparticles (poly(caprolactone), PCL) coated with a multilayer shell of polyglutamic acid (PGA) and superparamagnetic iron oxide nanoparticles (SPIONs), which are known as bio-acceptable components. The PCL nanocarriers with a model anticancer drug (Paclitaxel, PTX) were formed by the spontaneous emulsification solvent evaporation (SESE) method, while the magnetically responsive multilayer shell was formed via the layer-by-layer (LbL) method. As a result, we obtained magnetically responsive polycaprolactone nanocarriers (MN-PCL NCs) with an average size of about 120 nm. Using the 9.4 T preclinical magnetic resonance imaging (MRI) scanner we confirmed, that obtained MN-PCL NCs can be successfully used as a MRI-detectable drug delivery system. The magnetic hyperthermia effect of the MN-PCL NCs was demonstrated by applying a 25 mT radio-frequency (f = 429 kHz) alternating magnetic field. We found a Specific Absorption Rate (SAR) of 55 W g-1. The conducted research fulfills the first step of investigation for biomedical application, which is mandatory for the planning of any in vitro and in vivo studies.

Fe3O4@SiO2@Au nanoparticles for MRI-guided chemo/NIR photothermal therapy of cancer cells.

Novel functionalized (biofunctionalization followed by cisplatin immobilization) Fe3O4@SiO2@Au nanoparticles (NPs) were designed. The encapsulation of Fe3O4 cores inside continuous SiO2 shells preserves their initial structure and strong magnetic properties, while the shell surface can be decorated by small Au NPs, and then cisplatin (cPt) can be successfully immobilized on their surface. The fabricated NPs exhibit very strong T 2 contrasting properties for magnetic resonance imaging (MRI). The functionalized Fe3O4@SiO2@Au NPs are tested for a potential application in photothermal cancer therapy, which is simulated by irradiation of two colon cancer cell lines (SW480 and SW620) with a laser (λ = 808 nm, W = 100 mW cm-2). It is found that the functionalized NPs possess low toxicity towards cancer cells (∼10-15%), which however could be drastically increased by laser irradiation, leading to a mortality of the cells of ∼43-50%. This increase of the cytotoxic properties of the Fe3O4@SiO2@Au NPs, due to the synergic effect between the presence of cPt plus Au NPs and laser irradiation, makes these NPs perspective agents for potential (MRI)-guided stimulated chemo-photothermal treatment of cancer.

Gadolinium labeled polyelectrolyte nanocarriers for theranostic application.

Here, we designed a novel Gadolinium (Gd) labeled drug-loaded polyelectrolyte nanocarriers for theranostics. The nanocarriers were formed via layer-by-layer technique with biodegradable polyelectrolytes: PLL (Poly-L-lysine), PLL-Gd (Gadolinium-labeled Poly-L-lysine) and PGA (Poly-L-glutamic acid). Anticancer drug (Paclitaxel) was encapsulated in the formed nanocarriers. The average size of synthesized nanocarriers was around 150 nm. The empty gadolinium labeled nanocarriers did not show any deleterious effects on tested cells (CT26-CEA, B16F10, 4T1 and PBMC), whereas encapsulated paclitaxel retained its cytotoxic/cytostatic activity. Using T2 and T1 NMR relaxation measurements with 9.4 T preclinical MRI scanner, we demonstrated that gadolinium labeled nanocarriers can be detected due to a locally altered contrast in the MR image. Thus, they may become a promising platform for future theranostic applications.