Person:

Kohane, Daniel

We report a novel nanoparticulate drug delivery system that undergoes reversible volume change from 150 to 40 nm upon phototriggering with UV light. The volume change of these monodisperse nanoparticles comprising spiropyran, which undergoes reversible photoisomerization, and PEGylated lipid enables repetitive dosing from a single administration and enhances tissue penetration. The photoswitching allows particles to fluoresce and release drugs inside cells when illuminated with UV light. The mechanism of the light-induced size switching and triggered-release is studied. These particles provide spatiotemporal control of drug release and enhanced tissue penetration, useful properties in many disease states including cancer.

Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds. These biomaterials, which are usually made of either biological polymers such as alginate or synthetic polymers such as poly(lactic acid) (PLA), help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit. Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches.

The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local electrical activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs.

The coupling of diagnostic capability and effective therapy in a single multifunctional nanomedicine is desirable but remains challenging. Here, we developed multifunctional nanoparticles consisting of a gold nanostar (AuNS) core with a shell of metal-drug coordination polymer (CP). The AuNS core enabled plasmonic photothermal effect and two-photon photoluminescence (TPL), while the CP shell of gadolinium and gemcitabine monophosphate allowed chemotherapy and MRI imaging. The AuNS@CP nanoparticles exhibited a strong T1 contrast signal and could monitor the localization of nanoparticles in vivo through noninvasive MR imaging, while intravital TPL imaging could be used to study nanoparticle behavior in tumors at the microscopic level. The combination of photothermal therapy and chemotherapy inhibited tumor growth in vivo.

Incorporation of proteins into dextran sulfate (DS)-chitosan (CS) nanoparticles (DSCS NPs) is commonly performed using entrapment procedures, in which protein molecules are mixed with DS and CS until particle formation occurs. As DS is an analog of heparin, the authors examined whether proteins could be directly incorporated into preformed DSCS NPs through a heparin binding domain-mediated interaction. The authors formulated negatively-charged DSCS NPs, and quantified the amount of charged DS in the outer shell of the particles. The authors then mixed the DSCS NPs with heparin-binding proteins (SDF-1α, VEGF, FGF-2, BMP-2, or lysozyme) to achieve incorporation. Data show that for DSCS NPs containing 100 nmol charged glucose sulfate units in DS, up to ~1.5 nmol of monomeric or ~0.75 nmol of dimeric heparin-binding proteins were incorporated without significantly altering the size or zeta potential of the particles. Incorporation efficiencies of these proteins were 95%–100%. In contrast, serum albumin or serum globulin showed minimal incorporation (8% and 4%, respectively) in 50% physiological saline, despite their large adsorption in water (80% and 92%, respectively). The NP-incorporated SDF-1α and VEGF exhibited full activity and sustained thermal stability. An in vivo aerosolization study showed that NP-incorporated SDF-1α persisted in rat lungs for 72 h (~34% remaining), while free SDF-1α was no longer detectable after 16 h. As many growth factors and cytokines contain heparin-binding sites/domains, incorporation into preformed DSCS NPs could facilitate in vivo applications of these proteins.

Daniel Kohane speaks to Francesca Lake, Managing Editor: Obtaining his MD and PhD in Physiology from Boston University (MA, USA), Dan Kohane went on to complete residencies in Pediatrics at Boston Children’s Hospital (MA, USA) and Anesthesiology at Massachusetts General Hospital (USA), followed by a fellowship in Pediatric Critical Care at Boston Children’s Hospital. He is currently a Professor of Anesthesia at Harvard Medical School (MA, USA) and a Senior Associate in Pediatric Critical Care at Boston Children’s Hospital, where he directs the Laboratory for Biomaterials and Drug Delivery. His research focuses on drug delivery and biomaterials, and in particular, nanomedicine.

Purpose We tested the feasibility of using titanium to enhance adhesion of the Boston Keratoprosthesis (B-KPro), ultimately to decrease the risk of implant-associated complications. Methods: Cylindrical rods were made of poly(methyl methacrylate) (PMMA), PMMA coated with titanium dioxide (TiO2) over a layer of polydopamine (PMMATiO2), smooth (Ti) and sandblasted (TiSB) titanium, and titanium treated with oxygen plasma (Tiox and TiSBox). Topography and surface chemistry were analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Adhesion force between rods and porcine corneas was measured ex vivo. Titanium sleeves, smooth and sandblasted, were inserted around the stem of the B-KPro and implanted in rabbits. Tissue adhesion to the stem was assessed and compared to an unmodified B-Kpro after 1 month. Results: X-ray photoelectron spectroscopy demonstrated successful deposition of TiO2 on polydopamine-coated PMMA. Oxygen plasma treatment did not change the XPS spectra of titanium rods (Ti and TiSB), although it increased their hydrophilicity. The materials did not show cell toxicity. After 14 days of incubation, PMMATiO2, smooth titanium treated with oxygen plasma (Tiox), and sandblasted titanium rods (TiSB, TiSBox) showed significantly higher adhesion forces than PMMA ex vivo. In vivo, the use of a TiSB sleeve around the stem of the B-KPro induced a significant increase in tissue adhesion compared to a Ti sleeve or bare PMMA. Conclusions: Sandblasted titanium sleeves greatly enhanced adherence of the B-KPro to the rabbit cornea. This approach may improve adhesion with the donor cornea in humans as well. Translational Relevance This approach may improve adhesion with donor corneas in humans.

On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve block in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve block to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produces reactive oxygen species that react with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin. We also show repeatable ultrasound-triggered nerve blocks in vivo, with nerve-block duration depending on the extent and intensity of insonation. We did not detect any systemic toxicity, and tissue reaction was benign in all groups. On-demand, personalized local anaesthesia could be beneficial for the managing of relatively localized pain states, and potentially minimize opioid use.