Radiopaque tantalum oxide (TaO_x) nanoparticles can be fabricated with a variety of surface chemistries enabling the use of computed tomography to image a vast array of important biolgical phenomena and nanoparticle delivery schemes.

Reports of molecular and cellular imaging using computed tomography (CT) are rapidly increasing. Many of these reports use gold nanoparticles. Bismuth has similar CT contrast properties to gold while being approximately 1000-fold less expensive. Herein we report the design, fabrication, characterization, and CT and fluorescence imaging properties of a novel, dual modality, fluorescent, polymer encapsulated bismuth nanoparticle construct for computed tomography and fluorescence imaging. We also report on cellular internalization and preliminary in vitro and in vivo toxicity effects of these constructs. 40 nm bismuth(0) nanocrystals were synthesized and encapsulated within 120 nm Poly(DL-lactic-co-glycolic acid) (PLGA) nanoparticles by oil-in-water emulsion methodologies. Coumarin-6 was co-encapsulated to impart fluorescence. High encapsulation efficiency was achieved ∼70% bismuth w/w. Particles were shown to internalize within cells following incubation in culture. Bismuth nanocrystals and PLGA encapsulated bismuth nanoparticles exhibited >90% and >70% degradation, respectively, within 24 hours in acidic, lysosomal environment mimicking media and both remained nearly 100% stable in cytosolic/extracellular fluid mimicking media. μCT and clinical CT imaging was performed at multiple X-ray tube voltages to measure concentration dependent attenuation rates as well as to establish the ability to detect the nanoparticles in an ex vivo biological sample. Dual fluorescence and CT imaging is demonstrated as well. In vivo toxicity studies in rats revealed neither clinically apparent side effects nor major alterations in serum chemistry and hematology parameters. Calculations on minimal detection requirements for in vivo targeted imaging using these nanoparticles are presented. Indeed, our results indicate that these nanoparticles may serve as a platform for sensitive and specific targeted molecular CT and fluorescence imaging.

Ovarian cancer (OvCa) is the most lethal gynecologic malignancy, with two-thirds of patients having late-stage disease (II-IV) at diagnosis. Improved diagnosis and therapies are needed, yet preclinical animal models for ovarian cancer research have primarily been restricted to rodents, for data on which can fail to translate to the clinic. Thus, there is currently a need for a large animal OvCa model. Therefore, we sought to determine if pigs, being more similar to humans in terms of anatomy and physiology, would be a viable preclinical animal model for OvCa. We injected human OSPC-ARK1 cells, a chemotherapy-resistant primary ovarian serous papillary carcinoma cell line, into the neck muscle and ear tissue of four severe combined immune deficient (SCID) and two non-SCID pigs housed in novel biocontainment facilities to study the ability of human OvCa cells to form tumors in a xenotransplantation model. Tumors developed in ear tissue of three SCID pigs, while two SCID pigs developed tumors in neck tissue; no tumors were detected in non-SCID control pigs. All tumor masses were confirmed microscopically as ovarian carcinomas. The carcinomas in SCID pigs were morphologically similar to the original ovarian carcinoma and had the same immunohistochemical phenotype based on expression of Claudin 3, Claudin 4, Cytokeratin 7, p16, and EMA. Confirmation that OSPC-ARK1 cells form carcinomas in SCID pigs substantiates further development of orthotopic models of OvCa in pigs.

Metallic particles have shaped the use of magnetic resonance imaging (MRI) for molecular and cellular imaging. Although these particles have generally been developed for extracellular residence, either as blood pool contrast agents or targeted contrast agents, the coopted use of these particles for intracellular labeling has grown over the last 20 years. Coincident with this growth has been the development of metal oxide particles specifically intended for intracellular residence, and innovations in the nature of the metallic core. One promising nanoparticle construct for MRI‐based cell tracking is polymer encapsulated metal oxide nanoparticles. Rather than a polymer coated metal oxide nanocrystal of the core: shell type, polymer encapsulated metal oxide nanoparticles cluster many nanocrystals within a polymer matrix. This nanoparticle composite more efficiently packages inorganic nanocrystals, affording the ability to label cells with more inorganic material. Further, for magnetic nanocrystals, the clustering of multiple magnetic nanocrystals within a single nanoparticle enhances r₂ and relaxivity. Methods for fabricating polymer encapsulated metal oxide nanoparticles are facile, yielding both varied compositions and synthetic approaches. This review presents a brief history into the use of metal oxide particles for MRI‐based cell tracking and details the development and use of biodegradable, polymer encapsulated, metal oxide nanoparticles and microparticles for MRI‐based cell tracking. Magn Reson Med 73:376–389, 2015.

Purpose To design, fabricate, characterize, and in vivo assay clinically viable magnetic particles for MRI‐based cell tracking. Methods Poly(lactide‐co‐glycolide) (PLGA) encapsulated magnetic nano and microparticles were fabricated. Multiple biologically relevant experiments were performed to assess cell viability, cellular performance, and stem cell differentiation. In vivo MRI experiments were performed to separately test cell transplantation and cell migration paradigms, as well as in vivo biodegradation. Results Highly magnetic nano (∼100 nm) and microparticles (∼1–2 µm) were fabricated. Magnetic cell labeling in culture occurred rapidly achieving 3–50 pg Fe/cell at 3 h for different particles types, and >100 pg Fe/cell after 10 h, without the requirement of a transfection agent, and with no effect on cell viability. The capability of magnetically labeled mesenchymal or neural stem cells to differentiate down multiple lineages, or for magnetically labeled immune cells to release cytokines following stimulation, was uncompromised. An in vivo biodegradation study revealed that NPs degraded ∼80% over the course of 12 weeks. MRI detected as few as 10 magnetically labeled cells, transplanted into the brains of rats. Also, these particles enabled the in vivo monitoring of endogenous neural progenitor cell migration in rat brains over 2 weeks. Conclusion The robust MRI properties and benign safety profile of these particles make them promising candidates for clinical translation for MRI‐based cell tracking. Magn Reson Med 71:1238–1250, 2014.