Philipp Schmidt

Bio: Philipp Schmidt is an academic researcher from Novartis. The author has contributed to research in topics: MRI contrast agent & In vivo. The author has an hindex of 6, co-authored 8 publications receiving 230 citations. Previous affiliations of Philipp Schmidt include University of Würzburg.

Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers

Abstract: Generation 4 polyamidoamine (PAMAM) and, for the first time, hyperbranched poly(ethylene imine) or polyglycerol dendrimers have been loaded with Gd3+ chelates, and the macromolecular adducts have been studied in vitro and in vivo with regard to MRI contrast agent applications. The Gd3+ chelator was either a tetraazatetracarboxylate DOTA-pBn4- or a tetraazatricarboxylate monoamide DO3A-MA3- unit. The water exchange rate was determined from a 17O NMR and 1H Nuclear Magnetic Relaxation Dispersion study for the corresponding monomer analogues [Gd(DO3A-AEM)(H2O)] and [Gd(DOTA-pBn-NH2)(H2O)]- (kex298=3.4 and 6.6x10(6) s-1, respectively), where H3DO3A-AEM is {4-[(2-acetylaminoethylcarbamoyl)methyl]-7,10-bis(carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)}-acetic acid and H4DOTA-pBn-NH2 is 2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. For the macromolecular complexes, variable-field proton relaxivities have been measured and analyzed in terms of local and global motional dynamics by using the Lipari-Szabo approach. At frequencies below 100 MHz, the proton relaxivities are twice as high for the dendrimers loaded with the negatively charged Gd(DOTA-pBn)- in comparison with the analogous molecule bearing the neutral Gd(DO3A-MA). We explained this difference by the different rotational dynamics: the much slower motion of Gd(DOTA-pBn)--loaded dendrimers is likely related to the negative charge of the chelate which creates more rigidity and increases the overall size of the macromolecule compared with dendrimers loaded with the neutral Gd(DO3A-MA). Attachment of poly(ethylene glycol) chains to the dendrimers does not influence relaxivity. Both hyperbranched structures were found to be as good scaffolds as regular PAMAM dendrimers in terms of the proton relaxivity of the Gd3+ complexes. The in vivo MRI studies on tumor-bearing mice at 4.7 T proved that all dendrimeric complexes are suitable for angiography and for the study of vasculature parameters like blood volume and permeability of tumor vessels.

First in vivo MRI assessment of a self‐assembled metallostar compound endowed with a remarkable high field relaxivity

Abstract: {Fe[Gd2bpy(DTTA)2(H2O)4]3}4- is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd3+ centers confined into a small mol. space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r1 = 15.8 mM-1 s-1 at 200 MHz, 37°C, in H2O). Here we report the first in vivo MRI feasibility study, complemented with dynamic g scintigraphic imaging and biodistribution expts. using the 153Sm-enriched compd. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small mol. wt. contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H2O)]- = GdDOTA). The metallostar was well tolerated by the animals at the concns. of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg-1 body wt.; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg-1 BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T1), as calcd. from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approx. four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate mol. wt., the metallostar does not function as a blood pool agent. The dynamic g scintigraphic studies performed in Wistar rats with the metallostar compd. having 153Sm enrichment also proved the renal elimination pathway. The biodistribution expts. are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.

Feasibility and limits of magnetically labeling primary cultured rat T cells with ferumoxides coupled with commonly used transfection agents.

Abstract: Visualization and quantification of inflammatory processes is of high importance for early diagnosis of a multitude of diseases. Magnetic resonance imaging (MRI) using iron oxide (FeO) nanoparticles as contrast agents allows the study of macrophage infiltration during inflammation in a variety of tissues. Macrophages are effectors of the immune response, their appearance being orchestrated by activated T lymphocytes. Therefore, tracking of labeled T lymphocytes, which initiate the immune process, should enable earlier detection of tissue inflammation. In this study, we investigate the feasibility of specifically labeling harvested T cells by using dextran-coated FeO nanoparticles and commonly available transfection agents (TAs). Physicochemical properties of the newly formed FeO/TA vesicles were determined as well as their cell toxicity and their T cell activation potential. The labeling efficiency of each FeO/TA combination was evaluated by measuring the transverse MRI relaxation rate R(2) by X-ray spectroscopy and magnetic selection. Toxicity and labeling efficacy differed significantly among TAs. The best results were achieved by using polyamine TAs and in particular by using poly-l-lysine at a concentration of 1.5 microg/mL administered in combination with 22.5 microg iron/mL. By using this protocol, up to 60% of harvested T cells could be labeled. Microscopic investigation revealed FeO/TA nanoparticles not only localized within the cytoplasma of the cells but also sticking to the outer membrane surface.

Lanthanide probes for bioresponsive imaging.

Abstract: The chemistry of the less familiar elements is a fascinating topic especially for the inorganic minded. The lanthanides, or rare earths, comprise the 5d block of the periodic table and represent a huge array of applications from catalysis to lasers, and of course, imaging agents.1 Recent advances in luminescence and magnetic resonance microscopy have, in part, been stimulated by extraordinary success in the development of new lanthanide probes. The unique properties of the lanthanides provide for a deep tool chest for the chemist, biologist and the imaging scientist to exploit, and that exploitation is in full swing. In this review we focus on two classes of lanthanide probes that are subsets of the larger area of metalloimaging: luminescent and magnetic lanthanides. In Section 2 we discuss the general design and photophysical properties of lanthanides and how these parameters are tuned to develop bioresponsive probes for optical imaging. In Section 3 we provide a brief description of how MR images are acquired and the how MRI contrast agents are engineered to respond to biological events of interest. These guiding principles have driven research that has produced a truly diverse number of new agents that are target specific and bioresponsive (or bioactivatable). While other imaging modalities utilize lanthanide-based probes, these topics are beyond the scope of this review. We direct the reader to explore some excellent reviews in the important areas of radiometals and multimodal imaging.2–5

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers

Abstract: Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

Challenges for Molecular Magnetic Resonance Imaging

Abstract: 3.3. Magnetic Particle Imaging 3029 4. Challenges for CEST Agents 3029 4.1. Technical Issues 3029 4.2. Chemical Issues 3031 4.3. Biological Issues 3032 5. Challenges for Heteronuclear MR Imaging 3033 5.1. F-Based Probes 3033 6. Challenges for Hyperpolarized Probes 3034 6.1. Brute Force 3034 6.2. Optical Pumping and Spin Exchange 3035 6.3. Dynamic Nuclear Polarization (DNP) 3035 6.4. para-Hydrogen Induced Polarization (PHIP) 3037 6.5. Use of Gd Contrast Agents with Hyperpolarized Substances 3038

Dendritic polyglycerols for biomedical applications.

Abstract: The application of nanotechnology in medicine and pharmaceuticals is a rapidly advancing field that is quickly gaining acceptance and recognition as an independent area of research called "nanomedicine". Urgent needs in this field, however, are biocompatible and bioactive materials for antifouling surfaces and nanoparticles for drug delivery. Therefore, extensive attention has been given to the design and development of new macromolecular structures. Among the various polymeric architectures, dendritic ("treelike") polymers have experienced an exponential development due to their highly branched, multifunctional, and well-defined structures. This Review describes the diverse syntheses and biomedical applications of dendritic polyglycerols (PGs). These polymers exhibit good chemical stability and inertness under biological conditions and are highly biocompatible. Oligoglycerols and their fatty acid esters are FDA-approved and are already being used in a variety of consumer applications, e.g., cosmetics and toiletries, food industries, cleaning and softening agents, pharmaceuticals, polymers and polymer additives, printing photographing materials, and electronics. Herein, we present the current status of dendritic PGs as functional dendritic architectures with particular focus on their application in nanomedicine, in drug, dye, and gene delivery, as well as in regenerative medicine in the form of non-fouling surfaces and matrix materials.

Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases

Abstract: High-resolution imaging of molecules intrinsically involved in malignancy and metastasis would be of great value for clinical detection and staging of tumors. We now report in vivo visualization of matrix metalloproteinase activities by MRI and fluorescence of dendrimeric nanoparticles coated with activatable cell penetrating peptides (ACPPs), labeled with Cy5, gadolinium, or both. Uptake of such nanoparticles in tumors is 4- to 15-fold higher than for unconjugated ACPPs. With fluorescent molecules, we are able to detect residual tumor and metastases as small as 200 μm, which can be resected under fluorescence guidance and analyzed histopathologically with fluorescence microscopy. We show that uptake via this mechanism is comparable to that of other near infrared protease sensors, with the added advantage that the approach is translatable to MRI. Once activated, the Gd-labeled nanoparticles deposit high levels (30–50 μM) of Gd in tumor parenchyma with even higher amounts deposited in regions of infiltrative tumor, resulting in useful T1 contrast lasting several days after injection. These results should improve MRI-guided clinical staging, presurgical planning, and intraoperative fluorescence-guided surgery. The approach may be generalizable to deliver radiation-sensitizing and chemotherapeutic agents.