Reprogramming virus nanoparticles to bind metal ions upon activation with heat.

We have reprogrammed the stimulus-responsive conformational change property of a virus nanoparticle (VNP) to enable the surface exposure of metal binding motifs upon activation with heat. The VNP is based on the widely investigated adeno-associated virus (AAV). An intrinsic bioactive functionality of AAV was genetically replaced with a hexahistidine (His) tag. The peptide domain with the inserted His tag is normally inaccessible. Upon external stimulation with heat, the VNP undergoes a conformational change, resulting in externalization of His tag-containing domains and the conferred ability to bind metal. We show that beyond this newfound functionality of the capsid, the VNPs maintain many of the wild-type capsid properties. Our work lays the groundwork for developing stimulus-responsive VNPs that can be used as "smart" building blocks for the creation of higher order structures.

Privileged delivery of polymer nanoparticles to the perinuclear region of live cells via a non-clathrin, non-degradative pathway.

The efficacy of many therapeutic molecules could be greatly enhanced by polymer-based nanoparticle systems capable of delivering them to the direct vicinity of the cell nucleus. However, degradation of the particles and encapsulated drugs within the enzyme-rich and low-pH environments of the endo/lysosomal pathway of cells has dramatically limited the efficacy of such systems. In this paper, we discovered that small polymeric particles (<25 nm) but not larger particles (>42 nm) enter live cells via a novel mechanism that leads to trafficking outside the endo/lysosomal pathway. Sub-25 nm particles rapidly transport to the perinuclear region of cells in vesicles that never acidify. The pathway is non-degradative, cholesterol independent, and non-clathrin and non-caveolae mediated. This privileged non-acidic pathway may be general since our results are surprisingly obtained with standard latex polymer beads without addition of ligands and may, therefore, provide a promising route for drug and gene delivery using biomaterial-based nanodevices.

Cavernous aneurysm and pituitary adenoma: management of dual intrasellar lesions.

A 53-year-old female with a functioning pituitary adenoma was found to also have an unruptured asymptomatic aneurysm in the cavernous sinus portion of the internal carotid artery on MRI. The adenoma had a suprasellar extension with optic chiasm compression and extended into the right cavernous sinus. An aneurysm-like flow-void adjacent to the left internal carotid artery in the sella and embedded in the adenoma was also found. The aneurysm was confirmed by conventional angiography. We used a right fronto-pterional approach to clip the aneurysm and to remove the pituitary tumor in a one-stage procedure. The outcome was good on long-term follow-up. It is important to thoroughly evaluate the anatomic relations around the sella turcica prior to procedures with limited exposure, including transsphenoidal surgery, to avoid unrecognized complications and morbidity.

White matter connectivity of human hypothalamus.

The macroscopic extrinsic white matter connectivity and the internal structure of the hypothalamus are still incompletely defined in humans. We investigated whether in-vivo diffusion tensor imaging tractography provides evidence of systematization according to hypothalamic compartmentalization. Six defined hypothalamic macroscopic compartments, preoptic, supraoptic, anteroventral, anterodorsal, lateral and posterior, were probed, within the right and left hemispheres of 14 subjects. Important new insights into the macroscopic structure of hypothalamus and white matter connections were found; the preoptic, anteroventral, lateral and posterior compartments are strongly connected to the cortex. The anteroventral connects particularly to the prefrontal cortex while the preoptic compartment connects mainly to the deep anterior brain. The anterodorsal connects mainly to the medial thalamus and the midline gray matter. There is a rightward frontal trend of hemispheric connectivity for the preoptic, anteroventral and lateral compartments. These findings may aid new neuromodulation applications and understanding in brain connectomics.

Characterization of the intracellular dynamics of a non-degradative pathway accessed by polymer nanoparticles.

Recently, 24 nm polymer nanoparticles were found to access a privileged non-degradative intracellular pathway that leads to perinuclear accumulation. Here, we report the intracellular dynamics of vesicles containing polymer nanoparticles within this non-degradative pathway, characterized by clathrin- and caveolae-independent endocytosis, as compared to endosomes originating from classical clathrin-mediated endocytosis. Similar to transport of acidic endosomes and lysosomes, the dynamic movements of non-degradative vesicles exhibit substantial heterogeneity, including caged diffusion and pearls-on-a-string trajectories, a reflection of microtubule-dependent active transport that leads to rapid accumulation near the cell nucleus. However, the ensemble-averaged intracellular transport rate of vesicles in the non-degradative pathway is 4-fold slower than that of the acidic vesicles of late endosomes and lysosomes, highlighted by a 3-fold smaller fraction of actively transported vesicles. The distinct intracellular dynamics further confirms that small nanoparticles are capable of entering cells via a distinct privileged pathway that does not lead to lysosomal processing. This non-degradative pathway may prove beneficial for the delivery of therapeutics and nucleic acids to the nucleus or nearby organelles.