Emerging technologies of polymeric nanoparticles in cancer drug delivery

Polymeric nanomaterials have the potential to improve upon present chemotherapy delivery methods. They successfully reduce side effects while increasing dosage, increase residence time in the body, offer a sustained and tunable release, and have the ability to deliver multiple drugs in one carrier. However, traditional nanomaterial formulations have not produced highly therapeutic formulations to date due to their passive delivery methods and lack of rapid drug release at their intended site. In this paper, we have focused on a few “smart” technologies that further enhance the benefits of typical nanomaterials. Temperature and pHresponsive drug delivery devices were reviewed as methods for triggering release of encapsulating drugs, while aptamer and ligand conjugation were discussed as methods for targeted and intracellular delivery, with emphases on in vitro and in vivo works for each method

Self-healing properties of augmented injectable hydrogels over time

Injectable polymers offer great benefits compared to other types of implants; however, they tend to suffer from increased mechanical wear and may need a replacement implant to restore these mechanical properties. The purpose of this experiment is to investigate an injectable hydrogel\u27s self-healing ability to augment itself to a previously molded implant. This was accomplished by performing a tensile strength test to examine potential diminishing mechanical properties with increasing time, as well as dye penetration tests to examine the formation of interfacial bonds between healed areas of hydrogels. There were several time points in between injections that were explored, from 0 min between injections all the way up to 48 h in between injections. The tests showed no statistical differences of the increased injection times compared to the single injection for the tensile test. However, our results showed an increase of mechanical breaks at self-healed joints, as well as a linear regression test showed a decrease in dye diffusion rate as time between injections increase. These results show that the hydrogel has strong self-healing abilities, and as time between injections increase, they mechanical properties will slowly decrease. Based on this, the tests can be applied to other injectable implants and a noninvasive solution to a worn-down implant, as well as show scientific backing to a possibly unique and beneficial self-healing property

Complexation Hydrogels as Oral Delivery Vehicles of Therapeutic Antibodies: An in Vitro and ex Vivo Evaluation of Antibody Stability and Bioactivity

Oral administration of monoclonal antibodies (mAbs) may enable the localized treatment of infections or other conditions in the gastrointestinal tract (GI) as well as systemic diseases. As with the development of oral protein biotherapeutics, one of the most challenging tasks in antibody therapies is the loss of biological activity due to physical and chemical instabilities. New families of complexation hydrogels with pH-responsive properties have demonstrated to be excellent transmucosal delivery vehicles. This contribution focuses on the design and evaluation of hydrogel carriers that will minimize the degradation and maximize the in vivo activity of anti-TNF-α, a mAb used for the treatment of inflammatory bowel disease (IBD) in the GI tract and systemically for the treatment of rheumatoid arthritis. P(MAA-g-EG) and P(MAA-co-NVP) hydrogels systems were optimized to achieve adequate swelling behavior, which translated into improved protein loading and release at neutral pH simulating the small intestine conditions. Additionally, these hydrogel systems preserve antibody bioactivity upon release resulting in the systemic circulation of an antibody capable of effectively performing its biological function. The compatibility if these hydrogels for mAb bioactivity preservation and release makes them candidates for use as oral delivery systems for therapeutic antibodies

Assessing the Transport of Receptor-Mediated Drug Delivery Devices Across Biological Barriers

Administering therapeutics through the oral route or to the central nervous system presents significant challenges for large-molecule drugs, primarily due to the diffusive barriers and efflux mechanisms present in the cellular lining of the gastrointestinal (GI) tract and blood brain barrier (BBB). Receptor-mediated endocytosis (RME) has been extensively studied as a method for augmenting the transport of therapeutic devices across these barriers. These devices range from simple ligand-therapeutic conjugates to complex ligand-nanoparticle systems. Customarily, characterizing the uptake of these carriers relies on their comparisons to the native therapeutic, which provides no understanding of ligand or cellular performance. Therefore, the focus of this research is to investigate the transport potential of the RME pathway itself, so that ligands can act as suitable benchmarks for success.To better understand the pharmacokinetics of the RME pathway, a model for barrier transport was designed based on the endocytosis cycle of transferrin, a ligand often used in RME drug-delivery research. This model established the correlation between apical receptor concentration and maximum transport capability. Experimental studies confirmed this relationship, demonstrating an upper transport limit independent of the applied dose. This contrasts with the dose-proportional pathways native therapeutics rely on for transport. Thus, the direct comparison of these two transport mechanisms can produce misleading results that change with arbitrarily chosen doses. Furthermore, transport potential was hindered by repeated use of the RME-cycle.Commonly, nanoparticles are incorporated to amplify the payload capacity of RME-devices despite the burden they pose to the cell. The response of size and the size distribution of nanoparticle-ligand formulations on the cell were tested and contrasted to their increasing payloads. These results demonstrate that size has a major influence on nanoparticle transport, and future studies should base the success of this technology not on the performance of the therapeutic itself, but on the capabilities of the cell. Using receptor-binding studies, we were able to demonstrate how these capabilities can be predicted and potentially adopted for high-throughput screening methods.Ph.D., Chemical Engineering -- Drexel University, 201

Mississippi Canyon 252 Incident NRDA Tier 1 for Deepwater Communities

The northern Gulf of Mexico (GOM) is geologically diverse basin, described as the most complex continental slope region in the world. Regional topography of the slope consists of basins, knolls, ridges, and mounds derived from the dynamic adjustments of salt and the introduction of large volumes of sediment over long time scales. More than 99% of the sea floor in the GOM consists of soft sediment made up of various mixtures of primarily silt and clay. These wide-spread soft bottom communities are described in reports from major MMS studies by Gallaway et al. (1998) and Rowe and Kennicutt (2009). Relative to soft bottoms, hard bottoms and their associated communities are relatively uncommon by are notable for their high biodiversity and complexity

The Mass of the White Dwarf Companion in the Self-Lensing Binary KOI-3278: Einstein vs. Newton

KOI-3278 is a self-lensing stellar binary consisting of a white-dwarf secondary orbiting a Sun-like primary star. Kruse and Agol (2014) noticed small periodic brightenings every 88.18 days in the Kepler photometry and interpreted these as the result of microlensing by a white dwarf with about 63$\%$ of the mass of the Sun. We obtained two sets of spectra for the primary that allowed us to derive three sets of spectroscopic estimates for its effective temperature, surface gravity, and metallicity for the first time. We used these values to update the Kruse and Agol (2014) Einsteinian microlensing model, resulting in a revised mass for the white dwarf of $0.539^{+0.022}_{-0.020} \, M_{\odot}$. The spectra also allowed us to determine radial velocities and derive orbital solutions, with good agreement between the two independent data sets. An independent Newtonian dynamical MCMC model of the combined velocities yielded a mass for the white dwarf of $0.5122^{+0.0057}_{-0.0058} \, M_{\odot}$. The nominal uncertainty for the Newtonian mass is about four times better than for the Einsteinian, $\pm 1.1\%$ vs. $\pm 4.1\%$ and the difference between the two mass determinations is $5.2 \%$. We then present a joint Einsteinian microlensing and Newtonian radial velocity model for KOI-3278, which yielded a mass for the white dwarf of $0.5250^{+0.0082}_{-0.0089} \, M_{\odot}$. This joint model does not rely on any white dwarf evolutionary models or assumptions on the white dwarf mass-radius relation. We discuss the benefits of a joint model of self-lensing binaries, and how future studies of these systems can provide insight into the mass-radius relation of white dwarfs.Comment: ApJ Accepted; 22 Pages, 8 Figures, 6 Tables and 4 Supplementary Table

Novel Guidewire Design and Coating for Continuous Delivery of Adenosine During Interventional Procedures.

Background: The no-reflow phenomenon compromises percutaneous coronary intervention outcomes. There is an unmet need for a device that prevents no-reflow phenomenon. Our goal was to develop a guidewire platform comprising a nondisruptive hydrophilic coating that allows continuous delivery of adenosine throughout a percutaneous coronary intervention. Methods and Results: We developed a guidewire with spaced coils to increase surface area for drug loading. Guidewires were plasma treated to attach hydroxyl groups to metal surfaces, and a methoxy-polyethylene glycol-silanol primer layer was covalently linked to hydroxyl groups. Using polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetate, a drug layer containing jet-milled adenosine was hydrogen-bonded to the polyethylene glycol-silanol layer and coated with an outer diffusive barrier layer. Coatings were processed with a freeze/thaw curing method. In vitro release studies were conducted followed by in vivo evaluation in pigs. Coating quality, performance, and stability with sterilization were also evaluated. Antiplatelet properties of the guidewire were also determined. Elution studies with adenosine-containing guidewires showed curvilinear and complete release of adenosine over 60 minutes. Porcine studies demonstrated that upon insertion into a coronary artery, adenosine-releasing guidewires induced immediate and robust increases (2.6-fold) in coronary blood flow velocity, which were sustained for ≈30 minutes without systemic hemodynamic effects or arrhythmias. Adenosine-loaded wires prevented and reversed coronary vasoconstriction induced by acetylcholine. The wires significantly inhibited platelet aggregation by \u3e80% in vitro. Guidewires passed bench testing for lubricity, adherence, integrity, and tracking. Conclusions: Our novel drug-releasing guidewire platform represents a unique approach to prevent/treat no-reflow phenomenon during percutaneous coronary intervention

The Lick AGN Monitoring Project 2011: Dynamical Modeling of the Broad-Line Region

We present models of the H$\beta$-emitting broad-line region (BLR) in seven Seyfert 1 galaxies from the Lick AGN (Active Galactic Nucleus) Monitoring Project 2011 sample, drawing inferences on the BLR structure and dynamics as well as the mass of the central supermassive black hole. We find that the BLR is generally a thick disk, viewed close to face-on, with preferential emission back toward the ionizing source. The dynamics in our sample range from near-circular elliptical orbits to inflowing or outflowing trajectories. We measure black hole masses of $\log_{10}(M_{\rm BH}/M_\odot) = 6.48^{+0.21}_{-0.18}$ for PG 1310$-$108, $7.50^{+0.25}_{-0.18}$ for Mrk 50, $7.46^{+0.15}_{-0.21}$ for Mrk 141, $7.58^{+0.08}_{-0.08}$ for Mrk 279, $7.11^{+0.20}_{-0.17}$ for Mrk 1511, $6.65^{+0.27}_{-0.15}$ for NGC 4593, and $6.94^{+0.14}_{-0.14}$ for Zw 229$-$015. We use these black hole mass measurements along with cross-correlation time lags and line widths to recover the scale factor $f$ used in traditional reverberation mapping measurements. Combining our results with other studies that use this modeling technique, bringing our sample size to 16, we calculate a scale factor that can be used for measuring black hole masses in other reverberation mapping campaigns. When using the root-mean-square (rms) spectrum and using the line dispersion to measure the line width, we find $\log_{10}(f_{{\rm rms},\sigma})_{\rm pred} = 0.57 \pm 0.19$. Finally, we search for correlations between $f$ and other AGN and BLR parameters and find marginal evidence that $f$ is correlated with $M_{\rm BH}$ and the BLR inclination angle, but no significant evidence of a correlation with the AGN luminosity or Eddington ratio.Comment: 26 pages, 14 figures. Accepted for publication in Ap

The Lick AGN Monitoring Project 2011: Dynamical Modeling of the Broad Line Region in Mrk 50

We present dynamical modeling of the broad line region (BLR) in the Seyfert 1 galaxy Mrk 50 using reverberation mapping data taken as part of the Lick AGN Monitoring Project (LAMP) 2011. We model the reverberation mapping data directly, constraining the geometry and kinematics of the BLR, as well as deriving a black hole mass estimate that does not depend on a normalizing factor or virial coefficient. We find that the geometry of the BLR in Mrk 50 is a nearly face-on thick disk, with a mean radius of 9.6(+1.2,-0.9) light days, a width of the BLR of 6.9(+1.2,-1.1) light days, and a disk opening angle of 25\pm10 degrees above the plane. We also constrain the inclination angle to be 9(+7,-5) degrees, close to face-on. Finally, the black hole mass of Mrk 50 is inferred to be log10(M(BH)/Msun) = 7.57(+0.44,-0.27). By comparison to the virial black hole mass estimate from traditional reverberation mapping analysis, we find the normalizing constant (virial coefficient) to be log10(f) = 0.78(+0.44,-0.27), consistent with the commonly adopted mean value of 0.74 based on aligning the M(BH)-{\sigma}* relation for AGN and quiescent galaxies. While our dynamical model includes the possibility of a net inflow or outflow in the BLR, we cannot distinguish between these two scenarios.Comment: Accepted for publication in ApJ. 8 pages, 6 figure

Four sub-Saturns with dissimilar densities: windows into planetary cores and envelopes

We present results from a Keck/HIRES radial velocity campaign to study four sub-Saturn-sized planets, K2-27b, K2-32b, K2-39b, and K2-108b, with the goal of understanding their masses, orbits, and heavy-element enrichment. The planets have similar sizes (RP=4.5-5.5 ), but have dissimilar masses (MP=16-60 ), implying a diversity in their core and envelope masses. K2-32b is the least massive (MP = 16.5 ± 2.7 M) and orbits in close proximity to two sub-Neptunes near a 3:2:1 period commensurability. K2-27b and K2-39b are significantly more massive at MP = 30.9 ± 4.6 M and MP = 39.8 ± 4.4 M, respectively, and show no signs of additional planets. K2-108b is the most massive at MP = 59.4 ± 4.4 M, implying a large reservoir of heavy elements of about ≈50 . Sub-Saturns as a population have a large diversity in planet mass at a given size. They exhibit remarkably little correlation between mass and size; sub-Saturns range from ≈6-60 M, regardless of size. We find a strong correlation between planet mass and host star metallicity, suggesting that metal-rich disks form more massive planet cores. The most massive sub-Saturns tend to lack detected companions and have moderately eccentric orbits, perhaps as a result of a previous epoch of dynamical instability. Finally, we observe only a weak correlation between the planet envelope fraction and present-day equilibrium temperature, suggesting that photo-evaporation does not play a dominant role in determining the amount of gas sub-Saturns accrete from their protoplanetary disks