Physiological and Pathological Factors Affecting Drug Delivery to the Brain by Nanoparticles.

The prevalence of neurological/neurodegenerative diseases, such as Alzheimer's disease is known to be increasing due to an aging population and is anticipated to further grow in the decades ahead. The treatment of brain diseases is challenging partly due to the inaccessibility of therapeutic agents to the brain. An increasingly important observation is that the physiology of the brain alters during many brain diseases, and aging adds even more to the complexity of the disease. There is a notion that the permeability of the blood-brain barrier (BBB) increases with aging or disease, however, the body has a defense mechanism that still retains the separation of the brain from harmful chemicals in the blood. This makes drug delivery to the diseased brain, even more challenging and complex task. Here, the physiological changes to the diseased brain and aged brain are covered in the context of drug delivery to the brain using nanoparticles. Also, recent and novel approaches are discussed for the delivery of therapeutic agents to the diseased brain using nanoparticle based or magnetic resonance imaging guided systems. Furthermore, the complement activation, toxicity, and immunogenicity of brain targeting nanoparticles as well as novel in vitro BBB models are discussed

Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Intravenously injected nanopharmaceuticals induce adverse cardiopulmonary reactions in sensitive human subjects and these reactions are reproducible in pigs. The underlying mechanisms are poorly understood, but a role for both the complement system and reactive macrophages has been implicated. Here we show the dominance and importance of early pulmonary intravascular macrophage clearance kinetics in adverse particle-mediated cardiopulmonary distress in pigs and irrespective of complement activation. Delaying particle recognition by macrophages within the first few minutes of injection overcome adverse reactions in pigs. This was achieved by two independent approaches: (i) changing particle geometry from a spherical shape (which trigger cardiopulmonary distress) to either rod- or disk-shape morphology and (ii) by physically adhering spheres to the surface of erythrocytes. These approaches bypasses particle surface engineering approaches to prevent robust macrophage recognition as well as the use of immunological or pharmacological modulators to reduce/overcome nanomedicine related adverse cardiopulmonary distress