Inflammation is associated with a range of serious human conditions including autoimmune and cardiovascular diseases and cancer. The ability to image active inflammatory processes greatly enhances our ability to diagnose and treat these diseases at an early stage. We describe molecular compositions enabling sensitive and precise imaging of inflammatory hotspots in vivo. Methods: Functionalized fluorocarbon nanoemulsion, with fluorous-encapsulated radiometal chelate (FERM), serves as a platform for multimodal imaging probe development. The 19 Fcontaining FERM nanoemulsion encapsulates 89 Zr in the fluorous oil, via fluorinated hydroxamic acid chelate. Simple mixing of radiometal with pre-formed aqueous nanoemulsion prior to use yields FERM, a stable in vivo cell tracer, enabling whole-body 89 Zr positron emission tomography (PET) and 19 F magnetic resonance imaging ( 19 F MRI) following a single intravenous injection. Results: FERM nanoemulsion is intrinsically taken up by phagocytic immune cells, particularly macrophages, with high specificity. FERM stability is demonstrated by a high correlation between 19 F and 89 Zr content in blood (correlation coefficient > 0.99). Image sensitivity is observed in an acute infection rodent model at low dose (37 kBq). The versatility of FERM is further demonstrated in inflammatory bowel disease and 4T1 tumor models. Conclusion:Multimodal detection using FERM yields robust whole-body lesion detection and leverages the strengths of combined PET/ 19 F MRI. FERM nanoemulsion production is scalable and potentially useful for precise diagnosis, stratification and treatment monitoring of inflammatory diseases.
R ecent cancer therapy efforts have focused on efficient and targeted tumor cell killing and hypoxia reduction (1,2). Adoptive cell therapy has emerged as the fourth pillar of cancer therapy, offering specific eradication of hematologic cancers. Therapeutic cell engineering is now being used to target solid tumors, which are proving to be more challenging (3,4). Roadblocks include tumor-induced immunosuppression and inefficient cell trafficking as well as poor tumor penetration and persistence (4,5). Importantly, these characteristics may be predictive of therapeutic outcome. Tumor mechanisms of immunosuppression generate chronic inflammation and hypoxia in the vicinity of the tumor, which result in increased tumor angiogenesis, recurrence, and malignant progression (1,6). Effector cells in the tumor microenvironment can induce cell killing, and we hypothesize that tumor oximetry is altered as an indirect consequence of these apoptotic processes. Recent advances in noninvasive imaging and biosensor probe technologies enable the noninvasive, real-time observation of the intracellular partial pressure of oxygen (Po 2) during T cell-mediated immunotherapy. Moreover, perfluorocarbon (PFC) exhibits weak molecular cohesion, enabling gas dissolution (7). This intrinsic property was first exploited in the 1990s (8) using emulsified PFC to form biocompatible and injectable oxygen-laden blood substitutes and breathing liquids (9,10). Gas dissolved in fluorinated emulsions is not bound to the carrier but rather is exchanged with the local environment (11). Dissolution of oxygen in PFC lowers the fluorine 19 (19 F) spin-lattice relaxation time (T1) (10,12). The T1 varies linearly with the absolute Po 2 , which is calculated from a linear calibration curve (13-16). Thus, one can exploit the intracellular PFC label, with its intrinsic Po 2 sensing properties, to perform cell-specific oximetry in vivo (15,16).
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