A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis — Insight into the observed synergism

The synergism between low-frequency sonophoresis (LFS) and chemical penetration enhancers (CPEs), especially surfactants, in transdermal enhancement has been investigated extensively since this phenomenon was first observed over a decade ago. In spite of the identifying that the origin of this synergism is the increased penetration and subsequent dispersion of CPEs in the skin in response to LFS treatment, to date, no mechanism has been directly proposed to explain how LFS induces the observed increased transport of CPEs. In this study, we propose a plausible physical mechanism by which the transport of all CPEs is expected to have significantly increased flux into the localized-transport regions (LTRs) of LFS-treated skin. Specifically, the collapse of acoustic cavitation microjets within LTRs induces a convective flux. In addition, because amphiphilic molecules preferentially adsorb onto the gas/water interface of cavitation bubbles, amphiphiles have an additional adsorptive flux. In this sense, the cavitation bubbles effectively act as carriers for amphiphilic molecules, delivering surfactants directly into the skin when they collapse at the skin surface as cavitation microjets. The flux equations derived for CPE delivery into the LTRs and non-LTRs during LFS treatment, compared to that for untreated skin, explain why the transport of all CPEs, and to an even greater extent amphiphilic CPEs, is increased during LFS treatment. The flux model is tested with a non-amphiphilic CPE (propylene glycol) and both nonionic and ionic amphiphilic CPEs (octyl glucoside and sodium lauryl sulfate, respectively), by measuring the flux of each CPE into untreated skin and the LTRs and non-LTRs of LFS-treated skin. The resulting data shows very good agreement with the proposed flux model.National Institutes of Health (U.S.) (Grant EB-00351)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Grant DAAD-19-02-D-002

Microfluidic Platform for Combinatorial Synthesis and Optimization of Targeted Nanoparticles for Cancer Therapy

Taking a nanoparticle (NP) from discovery to clinical translation has been slow compared to small molecules, in part by the lack of systems that enable their precise engineering and rapid optimization. In this work we have developed a microfluidic platform for the rapid, combinatorial synthesis and optimization of NPs. The system takes in a number of NP precursors from which a library of NPs with varying size, surface charge, target ligand density, and drug load is produced in a reproducible manner. We rapidly synthesized 45 different formulations of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs of different size and surface composition and screened and ranked the NPs for their ability to evade macrophage uptake in vitro. Comparison of the results to pharmacokinetic studies in vivo in mice revealed a correlation between in vitro screen and in vivo behavior. Next, we selected NP synthesis parameters that resulted in longer blood half-life and used the microfluidic platform to synthesize targeted NPs with varying targeting ligand density (using a model targeting ligand against cancer cells). We screened NPs in vitro against prostate cancer cells as well as macrophages, identifying one formulation that exhibited high uptake by cancer cells yet similar macrophage uptake compared to nontargeted NPs. In vivo, the selected targeted NPs showed a 3.5-fold increase in tumor accumulation in mice compared to nontargeted NPs. The developed microfluidic platform in this work represents a tool that could potentially accelerate the discovery and clinical translation of NPs.Prostate Cancer Foundation (Award in Nanotherapeutics)National Cancer Institute (U.S.) (Center of Cancer Nanotechnology Excellence at MIT-Harvard U54-CA151884National Heart, Lung, and Blood Institute (Programs of Excellence in Nanotechnology HHSN268201000045C)National Science Foundation (U.S.). Graduate Research FellowshipAmerican Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipNational Cancer Institute (U.S.) (Center of Cancer Nanotechnology Excellence. Graduate Research Fellowship

Progenitors of gravitational wave mergers: Binary evolution with the stellar grid-based code ComBinE

The first gravitational wave detections of mergers between black holes and neutron stars represent a remarkable new regime of high-energy transient astrophysics. The signals observed with LIGO-Virgo detectors come from mergers of extreme physical objects which are the end products of stellar evolution in close binary systems. To better understand their origin and merger rates, we have performed binary population syntheses at different metallicities using the new grid-based binary population synthesis code ComBinE. Starting from newborn pairs of stars, we follow their evolution including mass loss, mass transfer and accretion, common envelopes and supernova explosions. We apply the binding energies of common envelopes based on dense grids of detailed stellar structure models, make use of improved investigations of the subsequent Case BB Roche-lobe overflow and scale supernova kicks according to the stripping of the exploding stars. We demonstrate that all the double black hole mergers, GW150914, LVT151012, GW151226, GW170104, GW170608 and GW170814, as well as the double neutron star merger GW170817, are accounted for in our models in the appropriate metallicity regime. Our binary interaction parameters are calibrated to match the accurately determined properties of Galactic double neutron star systems, and we discuss their masses and types of supernova origin. Using our default values for the input physics parameters, we find a double neutron star merger rate of about 3.0 Myr-1 for Milky-Way equivalent galaxies. Our upper limit to the merger-rate density of double neutron stars is R≃400 yr-1 Gpc-3 in the local Universe (z=0)

Progenitors of gravitational wave mergers: Binary evolution with the stellar grid-based code ComBinE

The first gravitational wave detections of mergers between black holes and neutron stars represent a remarkable new regime of high-energy transient astrophysics. The signals observed with LIGO-Virgo detectors come from mergers of extreme physical objects which are the end products of stellar evolution in close binary systems. To better understand their origin and merger rates, we have performed binary population syntheses at different metallicities using the new grid-based binary population synthesis code ComBinE. Starting from newborn pairs of stars, we follow their evolution including mass loss, mass transfer and accretion, common envelopes and supernova explosions. We apply the binding energies of common envelopes based on dense grids of detailed stellar structure models, make use of improved investigations of the subsequent Case BB Roche-lobe overflow and scale supernova kicks according to the stripping of the exploding stars. We demonstrate that all the double black hole mergers, GW150914, LVT151012, GW151226, GW170104, GW170608 and GW170814, as well as the double neutron star merger GW170817, are accounted for in our models in the appropriate metallicity regime. Our binary interaction parameters are calibrated to match the accurately determined properties of Galactic double neutron star systems, and we discuss their masses and types of supernova origin. Using our default values for the input physics parameters, we find a double neutron star merger rate of about 3.0 Myr^-1 for Milky-Way equivalent galaxies. Our upper limit to the merger-rate density of double neutron stars is R=400 yr^-1 Gpc^-3 in the local Universe (z=0).Comment: 36 pages, 26 figures, 8 tables, plus 9 pages appendix. Accepted 2018 August 6 by MNRAS after revision according to referee report (in particular, including further discussions on the progenitor binary of GW170817

Therapeutic effect of orally administered microencapsulated oxaliplatin for colorectal cancer

Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Oral delivery of therapeutics remains the most patient accepted form of medication. The development of an oral delivery formulation for local delivery of chemotherapeutics in the gastrointestinal tract can potentially alleviate the adverse side effects including systemic cytotoxicity, as well as focus therapy to the lesions. Here we develop an oral formulation of the chemotherapeutic drug oxaliplatin for the treatment of colorectal cancer. Oxaliplatin was encapsulated in pH sensitive, mucoadhesive chitosan-coated alginate microspheres. The microparticles were formulated to release the chemotherapeutics after passing through the acidic gastric environment thus targeting the intestinal tract. In vivo, these particles substantially reduced the tumor burden in an orthotopic mouse model of colorectal cancer, and reduced mortality.Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)National Institutes of Health (U.S.)Alnylam Pharmaceuticals (Firm

An Extremely Lithium-Rich Bright Red Giant in the Globular Cluster M3

We have serendipitously discovered an extremely lithium-rich star on the red giant branch of the globular cluster M3 (NGC 5272). An echelle spectrum obtained with the Keck I HIRES reveals a Li I 6707 Angstrom resonance doublet of 520 milli-Angstrom equivalent width, and our analysis places the star among the most Li-rich giants known: log[epsilon(Li)] ~= +3.0. We determine the elemental abundances of this star, IV-101, and three other cluster members of similar luminosity and color, and conclude that IV-101 has abundance ratios typical of giants in M3 and M13 that have undergone significant mixing. We discuss mechanisms by which a low-mass star may be so enriched in Li, focusing on the mixing of material processed by the hydrogen-burning shell just below the convective envelope. While such enrichment could conceivably only happen rarely, it may in fact regularly occur during giant-branch evolution but be rarely detected because of rapid subsequent Li depletion.Comment: 7-page LaTeX file, including 2 encapsulated ps figures + 1 table; accepted for publication in the Astrophysical Journal Letter

Scattering theory for Klein-Gordon equations with non-positive energy

We study the scattering theory for charged Klein-Gordon equations: \{{array}{l} (\p_{t}- \i v(x))^{2}\phi(t,x) \epsilon^{2}(x, D_{x})\phi(t,x)=0,[2mm] \phi(0, x)= f_{0}, [2mm] \i^{-1} \p_{t}\phi(0, x)= f_{1}, {array}. where: \epsilon^{2}(x, D_{x})= \sum_{1\leq j, k\leq n}(\p_{x_{j}} \i b_{j}(x))A^{jk}(x)(\p_{x_{k}} \i b_{k}(x))+ m^{2}(x), describing a Klein-Gordon field minimally coupled to an external electromagnetic field described by the electric potential $v(x)$ and magnetic potential $\vec{b}(x)$. The flow of the Klein-Gordon equation preserves the energy: h[f, f]:= \int_{\rr^{n}}\bar{f}_{1}(x) f_{1}(x)+ \bar{f}_{0}(x)\epsilon^{2}(x, D_{x})f_{0}(x) - \bar{f}_{0}(x) v^{2}(x) f_{0}(x) \d x. We consider the situation when the energy is not positive. In this case the flow cannot be written as a unitary group on a Hilbert space, and the Klein-Gordon equation may have complex eigenfrequencies. Using the theory of definitizable operators on Krein spaces and time-dependent methods, we prove the existence and completeness of wave operators, both in the short- and long-range cases. The range of the wave operators are characterized in terms of the spectral theory of the generator, as in the usual Hilbert space case

Low-Frequency Sonophoresis: Application to the Transdermal Delivery of Macromolecules and Hydrophilic Drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation. Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications. What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods. Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.National Institutes of Health (U.S.) (Grant EB-00351)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Grant DAAD-19-02-D-002

Fabrication of a Hybrid Microfluidic System Incorporating both Lithographically Patterned Microchannels and a 3D Fiber-Formed Microfluidic Network

A device containing a 3D microchannel network (fabricated using sacrificial melt-spun microfibers) sandwiched between lithographically patterned microfluidic channels offers improved delivery of soluble compounds to a large volume compared to a simple stack of two microfluidic channel layers. With this improved delivery ability comes an increased fluidic resistance due to the tortuous network of small-diameter channels.United States. Army (Engineer Research and Development Center-Construction Engineering Research Laboratory (ERDC-CERL))National Institutes of Health (U.S.) (NIH grant 5F32EB011866)National Institutes of Health (U.S.) (NIH Grant 1K99EB013630)National Institutes of Health (U.S.) (NIH NHLBI grant 1 R21 HL106585-01)National Heart, Lung, and Blood Institute (NIH NHLBI grant 1 R21 HL106585-01