ABSTRACT
Gastrointestinal function is very difficult to assess with any current technology [9]. Global measures of bowel transit are commonly achieved by monitoring the progression of ingested radiolabeled markers through the GI tract using g-scintigraphy [10, 11]. Standard methodologies to assess gastric and intestinal motor and secretory function require the unpleasant insertion of pressure and/or pH sensing catheters via mouth or anus. The limited length and sensor number only permit locally restricted measurements of intraluminal pressure and/or pH. Catheter placement in the esophagus, stomach or rectum can mostly be controlled without additional medical imaging; however, placement in the small intestine and colon is still performed under fluoroscopic control [12].1H MRI has the ability to simultaneously assess multiple aspects of GI motor and secretory function, such as gastric emptying, secretion and peristaltic activity, gallbladder and duodenal contractions, intestinal fluid content, transit and activity, on both a local and global scale [13-19]. This represents a step improvement compared to current gold standard technology. However, some key challenges remain that make it difficult to relate these imaging-derived data to the transport, processing, and absorption of nutrients, i.e., the primary function of the GI tract. First, imaging of the morphology of the GI tract is difficult because it is continuously moving, and the complex three-dimensional anatomy is highly variable among individuals; even for a single individual, the position of the bowel loops varies over time due to feeding
and physical activity [20]. Second, the GI tract exists in distinct “fasted” and “fed” functional states, characterized by fundamentally different physiologic motor and secretory activity. Third, MRI is not capable of visualizing changes in intraluminal pressure, which demands the concurrent use of MR compatible catheters for method validation and clinical acceptance. Fourth, even with the use of modern MR contrast agents, MRI has difficulties in detecting and differentiating macronutrients within the GI tract. This is partly due to the fact that structural properties of macroscopic luminal contents change during their passage from the stomach to the rectum, and partly due to the enormous flux within the bowel.Current intestinal MRI methods apply bowel preparation using paramagnetic MR contrast agents together with osmotic laxatives to artificially extend the bowel lumen and improve luminal contrast [21, 22]. However, paramagnetic contrast agents provide only a relatively small contrast enhancement in comparison to the range of signal intensities of the adjacent tissues [23]. The use of super-paramagnetic contrast agents is limited by inherent susceptibility artifacts [24]. Higher intraluminal contrast, without the need of special bowel preparations, can be achieved if MR active compounds with no similar in vivo counterparts are exogenously administered, effectively making these compounds the only signal sources. 19F, as the MR detectable element with the highest MR sensitivity of the stable isotopes after 1H, is very well suited for this purpose, since nearly no 19F is found in the human body. Therefore, combined 19F and 1H MRI has the potential to help overcome some of the above-mentioned limitations and to provide improved non-invasive and simultaneous imaging of GI morphology and function. Moreover, 19F labeling and tracking of GI catheters would allow for catheter-guided 1H/19F imaging of local and global GI motor function and morphology and vice versa allow for MR image-guided GI catheter placement. 13.1.3 Monitoring of GI Drug DeliveryBesides the processing and absorption of nutrients, the GI tract is also the most important route for the delivery of drugs to the systemic circulation. Alike nutrient digestion, drug bioavailability depends on gastric emptying, intestinal transport, and the
intraluminal (mechanical) processing of the ingested dosage form [25, 26]. Depending on the absorption window of the drug in the intestine, various oral dosage forms have been developed exhibiting dedicated controlled release characteristics and/ or defined GI transit times. g-scintigraphy is the current gold standard for monitoring the GI transit of radiolabeled drug delivery systems [10, 27]. Magnetic marker monitoring (MMM) [28] and magnetic pill tracking [29] have been proposed as alternative radiation-free imaging modalities for biopharmaceutical studies. 19F MRI shows potential as another radiation free alternative for monitoring the GI transit of small fluorine-containing markers in the GI tract [30]. Combined 19F and 1H MRI would then complement the monitoring of labeled oral dosage forms by integrating information on organ morphology and function. 13.1.4 Requirements for Combined 19F/1H MRI of
the GI TractIn standard MRI, only a few part per million (ppm) of excited nuclear spins contribute to the net magnetization forming the detected MR signal. In addition to this inherent low sensitivity of MRI in general, several unresolved technological issues must be addressed before combined 19F and 1H MRI can be fully exploited in the human GI research setting. Multi-channel, multinuclear MRI systems with efficient abdominal coils must become readily available. A field of view minimum of 35 cm (feet-headdirection), by 35 cm (left-right-direction), by 20 cm (anterior-posterior-direction) must be covered by a preferably homogenous radio frequency (RF) excitation (B1) field. Ideally, these must be actively decoupled to allow for unperturbed simultaneous 1H and 19F imaging. Moreover, a range of sequential and/or simultaneous abdominal scanning sequences providing different tissue and luminal contrasts is required for GI anatomy to visualize transport and motor activity, along with the 19F data.The low inherent sensitivity of 19F MRI also demands the use of very signal-efficient exogenous 19F markers. Perfluorocarbons (PFCs) exhibit high 19F atom density and consists mostly of carbon and fluorine atoms. For imaging, also the degree of symmetry of the carbon-fluorine bonds determines the MR spectrum and
useful signal intensity. Perfluoro-[15]-crown-5 ether (PFCE) and hexafluorobenzene (HFB) with their symmetric structure exhibit only a single peak in their MR spectra and provide high signal intensity for imaging. Like most perfluorocarbons, these two compounds are biologically inert and lack acute toxicity and are therefore promising for human applications [31]. Due to its high volatility, HFB is rapidly lost through the lungs by respiration [32, 33]. In contrast, the low vapor pressure of PFCE results in very slow clearance (up to several months) from the reticuloendothelial system [34, 35]. None of the two compounds has been approved for human use, and accordingly they cannot be applied through direct oral intake. Nevertheless, oral application of 19F compounds in humans can be realized by safe encapsulation. 13.2 19F Labeling of Capsules and CathetersTo monitor GI function non-invasively, including local and global transit times, as well as intestinal motor activity, our laboratory aimed at developing a background-free 19F MRI approach making use of encapsulated 19F compounds. A proof-of-principle demonstration of human 19F/1H GI MRI has been achieved by Schwarz et al. [37], who successfully visualized the intestinal movements and transit of a large-sized capsule (length 22 mm, diameter 7 mm) of polychlorotrifluoroethylene (PCTFE) shell material filled with 350 µl perfluorononane (C9F20) in a healthy subject. However, to better emulate nutrient-like luminal passage and improve patient comfort, the capsule containing the 19F compound should be smaller in size within the limits of known sensitivities and without compromising safety. Various methods for encapsulation of liquid 19F-based core materials into nano-and micro-capsules have been proposed [38-40]. However, capsules with diameters ranging from micrometers to nanometers in size have been reported to be absorbed into the bloodstream [41]. Considering this, and taking into account that possible shell material degradation or liquid leakage is possible [40], micro-and nanometer-sized capsules should currently not be considered for human 19F MRI GI applications, unless full toxicological tests are performed.This section is based on work presented in Chapter 4 of [36].
