A Role for Nanoparticles in Treating Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the main causes of disability in children and young adults, as well as a significant concern for elderly individuals. Depending on the severity, TBI can have a long-term impact on the quality of life for survivors of all ages. The primary brain injury can result in severe disability or fatality, and secondary brain damage can increase the complexities in cellular, inflammatory, neurochemical, and metabolic changes in the brain, which can last decades post-injury. Thus, survival from a TBI is often accompanied by lifelong disabilities. Despite the significant morbidity, mortality, and economic loss, there are still no eective treatment options demonstrating an improved outcome in a large multi-center Phase III trial, which can be partially attributed to poor target engagement of delivered therapeutics. Thus, there is a significant unmet need to develop more eective delivery strategies to overcome the biological barriers that would otherwise inhibit transport of materials into the brain to prevent the secondary long-term damage associated with TBI. The complex pathology of TBI involving the blood-brain barrier (BBB) has limited the development of eective therapeutics and diagnostics. Therefore, it is of great importance to develop novel strategies to target the BBB. The leaky BBB caused by a TBI may provide opportunities for therapeutic delivery via nanoparticles (NP). The focus of this review is to provide a survey of NP-based strategies employed in preclinical models of TBI and to provide insights for improved NP based diagnostic or treatment approaches. Both passive and active delivery of various NPs for TBI are discussed. Finally, potential therapeutic targets where improved NP-mediated delivery could increase target engagement are identified with the overall goal of providing insight into open opportunities for NP researchers to begin research in TBI

Thrombin-Inhibiting Perfluorocarbon Nanoparticles: A New Class of Therapeutic for Acute Thrombosis Treatment and Diagnosis

Optimization of the mediation of acute thrombi remains a significant research challenge in the treatment of emergency conditions including heart attack and ischemic stroke. We have demonstrated that a nanoparticle carrying potent direct thrombin inhibitors can advance the treatment of acute thrombosis arising from various cardiovascular pathologies. The thrombin-inhibiting nanoparticles presented herein are designed to focus the antithrombotic impact of direct thrombin inhibitors at the site of thrombus formation and to provide imaging contrast to highlight the formation or the abatement and eventual disintegration of the thrombus. Perfluorocarbon nanoparticles were functionalized by covalent addition of PPACK or bivalirudin to carboxy-PEG capped lipid components to the stabilizing lipids. Over 10000 inhibitors were added per particle. In vitro experiments evaluated inhibition of thrombin cleavage of the chromogenic substrate Chromozym TH and defined the kinetics of the particle-thrombin interaction. Thrombin-inhibiting activity of the component inhibitors was undiminished on the nanoparticles and, as explored in appended work, the nanoparticles had a significant kinetic advantage over the lone inhibitors. To demonstrate efficacy of the particles as inhibitors of clot-bound thrombin, fibrinopeptide A ELISAs assayed the production of fibrin in plasma exposed to the surface of forming clots treated with PPACK, bivalirudin, PPACK nanoparticles, or bivalirudin nanoparticles. Similarly treated clots were monitored for growth in plasma via magnetic resonance imaging. Nanoparticles exceeded the activity of the component inhibitors in blocking FPA production by bound thrombin and formed an inhibitory layer that stopped further growth of clots in plasma. In vivo testing of thrombosis inhibition was performed in C57BL/6 mice and NZW rabbits using the Rose Bengal laser-induced thrombosis model (with ultrasonic flow probes tracking progress to occlusive thrombus). Thrombin-inhibiting particles were compared to Heparin, PPACK, bivalirudin, saline, and analogous non-functionalized particles as inhibitors of acute thrombosis in mice. Thrombin-inhibiting nanoparticles significantly delayed occlusion time in mice, outperforming heparin and the component inhibitors. Ultrasound and magnetic resonance imaging were employed to evaluate deposition of nanoparticles in mouse or rabbit thrombi. Thrombi were analyzed following in vivo experiments, using imaging and histochemical methods. Magnetic resonance imaging and spectroscopy revealed the specific deposition of thrombin-inhibiting nanoparticles in thrombi. For evaluation of fine clot morphology, mouse thrombi were examined with transmission electron microscopy. For evaluation of fibrin and platelet content in the thrombus Carstair\u27s staining was employed. Clots formed following nanoparticle administration exhibited lesser platelet content. In additional experiments, bleeding times and APTT measurements determined the systemic effects of the nanoparticles. Though the thrombin-inhibiting nanoparticles delayed thrombotic occlusion at a site of arterial injury to 1.5-2 hours, significant effects on blood pool coagulation parameters were observed for less than 20 minutes. We have demonstrated that the thrombin-inhibiting nanoparticle is kinetically superior to conventional direct inhibitors. In vivo, the potent inhibition kinetics, combined with the pharmacokinetic and pharmacodynamic properties of perfluorocarbon nanoparticles enabled superior inhibition of thrombosis while maintaining an excellent safety profile with short-lived systemic effects. Imaging data indicated the formation of layers of nanoparticles at sites of arterial injury. Thrombin-inhibiting nanoparticles are thus derived here as a new tool for treatment of acute thrombosis. The particles open a new avenue in this field of medical research as the first therapeutic to form a detectable, site-specific, and quantifiable anticoagulant layer that seals against the progress of acute thrombosis

Absolute Quantitation for MR Molecular Imaging of Angiogenesis

Medical imaging is undergoing a transition from an art that is used to make static images of human physiology into a scientific tool that employs advanced techniques to measure clinically relevant data. Recently, the role of magnetic resonance imaging in cardiovascular and oncological research has grown, largely due to the implementation of new quantitative techniques in the clinic. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are particularly rich in their capability to quantify both physiology and disease via biomarker detection. While this is true for many applications of MRI in cardiovascular and oncological research, 19F MR molecular imaging is particularly useful when coupled to the use of emerging site-targeted molecular imaging agents for diagnosis and therapy, such as αvβ3 integrin-targeted perfluorocarbon (PFC) nanoparticle (NP) emulsions. Unfortunately, the radiological world is realizing that although image quality may be consistently high, the absolute quantitative values being calculated vary widely across time, techniques, laboratories, and imaging platforms. The overall objective of this work is to advance the state of the art for 19F MR molecular imaging of perfluorocarbon nanoparticle emulsion contrast agents. To reach this objective, three specific aims have been identified: (1) to create new tools and techniques for 19F MR molecular imaging of PFC nanoparticles, (2) to develop translatable procedures for absolute quantification of 19F nuclei with MR molecular imaging, and (3) to evaluate the potential for clinical translation with ex vivo and in vivo preclinical experiments. Robust, standardized techniques are developed in this work to improve the accuracy of in vivo quantitative 19F MR molecular imaging, validate system performance, calibrate measurements to ensure repeatability of these quantitative metrics, and evaluate the potential for clinical translation. As these quantitative metrics become routine in medical imaging procedures, these standardized calibrations and techniques are expected to be critical for accurate interpretation of underlying pathophysiology. This will also impact the development of new therapies and diagnostic techniques/agents by reducing the variability of image-based measurements, thereby increasing the impact of the studies and reducing the overall time and cost to translate new technologies into the clinic

Photoacoustic Drug Delivery

Photoacoustic (PA) technology holds great potential in clinical translation as a new non-invasive bioimaging modality. In contrast to conventional optical imaging, PA imaging (PAI) enables higher resolution imaging with deeper imaging depth. Besides applications for diagnosis, PA has also been extended to theranostic applications. The guidance of PAI facilitates remotely controlled drug delivery. This review focuses on the recent development of PAI-mediated drug delivery systems. We provide an overview of the design of different PAI agents for drug delivery. The challenges and further opportunities regarding PA therapy are also discussed

Bionanomedicine: A “Panacea” In Medicine?

Recent advances in nanotechnology, biotechnology, bioinformatics, and materials science have prompted novel developments in the field of nanomedicine. Enhancements in the theranostics, computational information, and management of diseases/disorders are desperately required. It may now be conceivable to accomplish checked improvements in both of these areas utilising nanomedicine. This scientific and concise review concentrates on the fundamentals and potential of nanomedicine, particularly nanoparticles and their advantages, nanoparticles for siRNA conveyance, nanopores, nanodots, nanotheragnostics, nanodrugs and targeting mechanisms, and aptamer nanomedicine. The combination of various scientific fields is quickening these improvements, and these interdisciplinary endeavours to have significant progressively outstretching influences on different fields of research. The capacities of nanomedicine are immense, and nanotechnology could give medicine a completely new standpoint

New MRI Techniques for Nanoparticle Based Functional and Molecular Imaging

Although in clinical use for several decades, magnetic resonance imaging: MRI) is undergoing a transition from a qualitative anatomical imaging tool to a quantitative technique for evaluating myriad diseases. Furthermore, MRI has made great strides as a potential tool for molecular imaging of cellular and tissue biomarkers. Of the candidate contrast agents for molecular MRI, the excellent bio-compatibility and adaptability of perfluorocarbon nanoparticles: PFC NP) has established these agents as a potent targeted imaging agent and as a functional platform for non-invasive oxygen tension sensing. Direct readout and quantification of PFC NP can be achieved with fluorine: 19F) MRI because of the unique 19F signal emanating from the core PFC molecules. However, the signal is usually limited by the modest accumulated concentrations as well as several special NMR considerations for PFC NP, which renders 19F MRI technically challenging in terms of detection sensitivity, scan time, and image reconstruction. In the present dissertation, some of the pertinent NMR properties of PFC NP are investigated and new 19F MRI techniques developed to enhance their performance and expand the biomedical applications of 19F MRI with PFC NP. With the use of both theoretical and experimental methods, we evaluated J-coupling modulation, chemical shift and paramagnetic relaxation enhancement of PFC molecules in PFC NP. Our unique contribution to the technical improvement of 19F MRI of small animal involves:: 1) development of general strategies for RF 1H/19F coil design;: 2) design of novel MR pulse sequences for 19F T1 quantification; and: 3) optimization of imaging protocols for distinguishing and visualizing multiple PFC components: multi-chromatic 19F MRI). The first pre-clinical application of our novel 19F MRI techniques is blood vessel imaging and rapid blood oxygen tension measurement in vivo. Blood vessel anatomy and blood oxygen tension provide pivotal physiological information for routine diagnosis of cardiovascular disease. Using our novel Blood: flow)-Enhanced-Saturation-Recovery: BESR) sequence, we successfully visualized reduced flow caused by thrombosis in carotid arteries and jugular veins, and we quantified the oxygen tension in the cardiac ventricles of the mouse. The BESR sequence depicted the expected oxygenation difference between arterial and venous blood and accurately registered the response of blood oxygen tension to high oxygen concentration in 100% oxygen gas. This study demonstrated the potential application of PFC NP as a blood oxygen tension sensor and blood pool MR contrast agent for angiography. Another pre-clinical application investigated was functional kidney imaging with 19F MRI of circulating PFC NP. Conventional functional kidney imaging typically calls for the injection of small molecule contrast agents that may be nephrotoxic, which raises concerns for their clinical applications in patients with renal insufficiency. We demonstrated that our 19F MRI technique offers a promising alternative functional renal imaging approach that generates quantitative measurement of renal blood volume and intrarenal oxygenation. We successfully mapped the expected heterogeneous distribution of renal blood volume and confirmed the presence of an oxygenation gradient in healthy kidneys. We validated the diagnostic capability of 19F MRI in a mouse model of acute ischemia/reperfusion kidney injury. We also employed 19F MRI as a tool to test the therapeutic efficacy of a new nanoparticle-based drug, i. e. PPACK: D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) PFC NP, which was postulated to inhibit microvascular coagulation during acute kidney injury. Based on our preliminary 19F MRI findings, we observed that PPACK PFC NP effectively reduced coagulation in our animal model, as evidenced by lesser accumulation of particles trapped by the clotting process. This finding suggests the potential for 19F MRI to be used as a drug monitoring tool as well in common medical emergencies such as acute kidney failure