Tumor delivery of liposomal doxorubicin prepared with poly-L-glutamic acid as a drug-trapping agent

<p><i>Context</i>: Poly-l-glutamic acid (PGA) is an anionic polymer with a large number of carboxyl groups that can interact electrostatically with cationic drugs such as doxorubicin (DOX).</p> <p><i>Objective</i>: For stable encapsulation of DOX into liposomes, we prepared triethylamine (TEA)-PGA-liposomes using PGA as an internal trapping agent.</p> <p><i>Methods</i>: We prepared TEA-PGA-liposomes by remote loading of DOX with a TEA gradient into preformed liposomes prepared with 1, 2, or 4 mg/mL PGA (molecular weights 4800, 9800, and 20 500), and evaluated their biodistribution and antitumor effects on Lewis lung carcinoma (LLC) tumor-bearing mice.</p> <p><i>Results</i>: TEA-PGA-liposomes using the higher the molecular weight or concentration of PGA showed a slower release of DOX from the liposomes. TEA-PGA-liposomes prepared with a high concentration of PGA could enhance DOX accumulation in tumors and prolonged DOX circulation in the serum, indicating that DOX may be retained stably in the liposomal interior by interaction with PGA. Furthermore, injection of TEA-PGA-liposomes prepared with 4 mg/mL of PGA₉₈₀₀ or 2 mg/mL PGA₂₀₅₀₀ strongly inhibited tumor growth in LLC tumor-bearing mice.</p> <p><i>Conclusions</i>: PGA may be a potential trapping agent for liposomal DOX for tumor drug delivery.</p

Catalytic Oxidation of Thiols within Cavities of Phthalocyanine Network Polymers

Two three-dimensional (3D) network polymers (<b>1</b> and <b>2</b>), in which zinc­(II) or cobalt­(II) phthalocyanines were interconnected with twisted 9,9′-spirobifluorene linkers, were synthesized in order to investigate their performance as heterogeneous catalysts for thiol oxidations. From the spectroscopic analyses of two dimers (<b>3</b> and <b>4</b>) as component units of the network polymers, <b>3</b> connected with a short linker revealed electronic interaction between the two phthalocyanine units. Micrometer-sized polymer particles were formed due to the condensation of the twisted 9,9′-spirobifluorene linkers in the presence of zinc or cobalt ions. The dispersed solutions of <b>1</b> and <b>2</b> had sharp Q-bands, indicating the prevention of stacking among phthalocyanine moieties within the polymers. Powdered X-ray diffraction pattern and N₂ adsorption–desorption analyses suggested that <b>1</b> created small and rigid cavities as compared with <b>2</b> through the regular spatially arrangement of the phthalocyanine moieties in the 3D networks. The photocatalytic and catalytic activities of <b>1</b> and <b>2</b> for thiol oxidations using molecular oxygen were examined. We found that the catalytic activity of <b>1</b> was higher than that of <b>2</b> having larger cavities

siRNA delivery to lung-metastasized tumor by systemic injection with cationic liposomes

<div><p></p><p><i>Context</i>: Cationic liposomes can efficiently deliver siRNA to the lung by intravenous injection of cationic liposome/siRNA complexes (lipoplexes).</p><p><i>Objective:</i> The aim of this study was to examine a formulation of cationic liposomes for siRNA delivery to lung metastasis of breast tumor.</p><p><i>Materials and methods</i>: For the preparation of cationic liposomes, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or dimethyldioctadecylammonium bromide (DDAB) as a cationic lipid and cholesterol (Chol) or 1,2-dioleoyl-l-α-glycero-3-phosphatidylethanolamine (DOPE) as a neutral lipid were used. <i>In vitro</i> and <i>in vivo</i> gene silencing effects by cationic lipoplexes were evaluated after transfection into stably luciferase-expressing human breast tumor MCF-7-Luc cells and after intravenous injection into mice with lung MCF-7-Luc metastasis, respectively. Intracellular localization of siRNA after transfection into MCF-7 cells by cationic lipoplexes and biodistribution of siRNA after intravenous injection of cationic lipoplexes into the mice with lung metastasis were examined by confocal and fluorescent microscopy analyses, respectively.</p><p><i>Results</i>: In <i>in vitro</i> transfection, DOTAP/DOPE and DDAB/DOPE lipoplexes of luciferase siRNA strongly suppressed luciferase activity in MCF-7-Luc cells, but DOTAP/Chol and DDAB/Chol lipoplexes did not, although DOTAP/Chol and DDAB/Chol lipoplexes exhibited higher cellular uptake than DOTAP/DOPE and DDAB/DOPE lipoplexes. When their cationic lipoplexes were intravenously injected into mice with lung MCF-7-Luc metastasis, siRNAs were mainly accumulated in the lungs; however, the reduced luciferase activities in the lung-metastasized tumors were observed only by injections of DOTAP/Chol and DOTAP/DOPE lipoplexes, but not by DDAB/Chol and DDAB/DOPE lipoplexes.</p><p><i>Conclusions</i>: DOTAP-based liposomes might be useful as an <i>in vivo</i> siRNA delivery carrier that can induce gene silencing in lung-metastasized tumors.</p></div

Therapeutic effect for liver-metastasized tumor by sequential intravenous injection of anionic polymer and cationic lipoplex of siRNA

<p>Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of anionic polymer and cationic liposome/siRNA complex (cationic lipoplex). In this study, we investigated whether siRNA delivered by this sequential injection could significantly suppress mRNA expression of the targeted gene in liver metastasis and inhibit tumor growth. When cationic lipoplex was intravenously injected into mice bearing liver metastasis of human breast tumor MCF-7 at 1 min after intravenous injection of chondroitin sulfate C (CS) or poly-l-glutamic acid (PGA), siRNA was accumulated in tumor-metastasized liver. In terms of a gene silencing effect, sequential injections of CS or PGA plus cationic lipoplex of luciferase siRNA could reduce luciferase activity in liver MCF-7-Luc metastasis. Regarding the side effects, sequential injections of CS plus cationic lipoplex did not exhibit hepatic damage or induction of inflammatory cytokines in serum after repeated injections, but sequential injections of PGA plus cationic lipoplex did. Finally, sequential injections of CS plus cationic lipoplex of protein kinase N3 siRNA could suppress tumor growth in the mice bearing liver metastasis. From these findings, sequential injection of CS and cationic lipoplex of siRNA might be a novel systemic method of delivering siRNA to liver metastasis.</p

Small interfering RNA delivery into the liver by cationic cholesterol derivative-based liposomes

<p><i>Purpose</i>: Previously, we reported that the cationic liposomes composed of a cationic cholesterol derivative, cholesteryl (2-((2-hydroxyethyl)amino)ethyl)carbamate (OH-C-Chol) and 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphoethanolamine (DOPE) (termed LP-C), could deliver small interfering RNAs (siRNAs) with high transfection efficiency into tumor cells. In this study, to develop a liposomal vector for siRNA delivery <i>in vivo</i>, we prepared the poly(ethyleneglycol) (PEG)-modified cationic liposomes (LP-C-PEG) and evaluated their transfection efficiency <i>in vitro</i> and <i>in vivo</i>.</p> <p><i>Materials and methods</i>: We prepared LP-C-PEG/siRNA complexes (LP-C-PEG lipoplexes) formed in water or 50 mM NaCl solution, and evaluated their siRNA biodistribution and gene silencing effect in mice after intravenous injection.</p> <p><i>Results</i>: LP-C-PEG lipoplexes strongly exhibited <i>in vitro</i> gene silencing effects in human breast tumor MCF-7 cells as well as LP-C lipoplexes. In particular, formation of LP-C and LP-C-PEG lipoplexes in the NaCl solution increased the cellular association. When LP-C-PEG lipoplexes with Cy5.5-labeled siRNA formed in water or NaCl solution were injected into mice, accumulation of the siRNA was observed in the liver. Furthermore, injection of LP-C-PEG lipoplexes with ApoB siRNA could suppress ApoB mRNA levels in the liver and reduce very-low-density lipoprotein/low-density lipoprotein levels in serum compared with that after Cont siRNA transfection, although the presence of NaCl solution in forming the lipoplexes did not affect gene silencing effects <i>in vivo</i>.</p> <p><i>Conclusions</i>: LP-C-PEG may have potential as a gene vector for siRNA delivery to the liver.</p

Double-Step Gate Phenomenon in CO₂ Sorption of an Elastic Layer-Structured MOF

A double-step CO₂ sorption by [Cu­(4,4′-bpy)₂(BF₄)₂] (ELM-11) was observed during isothermal measurements at 195, 253, 273, and 298 K and was accompanied by interlayer expansion in the layered structure of ELM-11. The first step occurred in the range of the relative pressure (<i>P</i>/<i>P</i>₀) from 10^–3 to 10^–2. The second step was observed at <i>P</i>/<i>P</i>₀ ≈ 0.3 at the four temperatures. Structural changes in ELM-11 during the CO₂ sorption process were examined by X-ray diffraction (XRD) measurements. The structural change for the first step was well understood from a detailed structural analysis, as reported previously. The XRD results showed further expansion of the layers during the second step as compared to the already expanded structure in the first step, and both steps were found to be caused by the gate phenomenon. The energy for the expansion of the layer structure was estimated from experimental and simulated data

Dynamic Quantum Molecular Sieving Separation of D₂ from H₂–D₂ Mixture with Nanoporous Materials

Quantum molecular sieving separability of D₂ from an H₂–D₂ mixture was measured at 77 K for activated carbon fiber, carbon molecular sieve, zeolite and single wall carbon nanotube using a flow method. The amount of adsorbed D₂ was evidently larger than H₂ for all samples. The maximum adsorption ratio difference between D₂ and H₂ was 40% for zeolite (MS13X), yielding a selectivity for D₂ with respect to H₂ of 3.05

Gas Adsorption Mechanism and Kinetics of an Elastic Layer-Structured Metal–Organic Framework

The gate adsorption mechanism and kinetics of an elastic layer-structured metal–organic framework (ELM), [Cu­(bpy)₂(BF₄)₂]_<i>n</i> (ELM-11), that shows typical single-step CO₂ gate adsorption/desorption isotherms accompanied with dynamic structural transformation in a wide temperature range were investigated. Adsorption of quite a small amount of CO₂ on the external surface of ELM-11 crystals was observed at the pressure just below a gate adsorption pressure and induced a slight structural change in ELM-11. The structural change should start occurring at the outer parts of ELM-11 and transmit to more inner parts with rising pressure. The adsorption provides the stabilization of the framework through the interaction between fluid–solid and fluid–fluid and enables the framework to expand largely along the stacking direction. The CO₂ adsorption rate of ELM-11 is almost comparable to that of Zeolite 5A at around ambient temperatures and shows temperature dependence with an anti-Arrhenius trend: higher adsorption rate with lower temperature

Aqueous Nanosilica Dispersants for Carbon Nanotube

Nanosilicas can disperse single-wall carbon nanotube (SWCNT) in aqueous solution efficiently; SWCNTs are stably dispersed in aqueous media for more than 6 months. The SWCNT dispersing solution with nanosilica can produce highly conductive transparent films which satisfy the requirements for application to touch panels. Even multiwall carbon nanotube can be dispersed easily in aqueous solution. The highly stable dispersion of SWCNTs in the presence of nanosilica is associated with charge transfer interaction which generates effective charges on the SWCNT particles, giving rise to electrostatic repulsion between the SWCNTs in the aqueous solution. Adhesion of charged nanosilicas on SWCNTs in the aqueous solution and a marked depression of the S₁₁ peak of optical absorption spectrum of the SWCNT with nanosilicas suggest charge transfer interaction of nanosilicas with SWCNT. Thus-formed isolated SWCNTs are fixed on the flexible three-dimensional silica jelly structure in the aqueous solution, leading to the uniform and stable dispersion of SWCNTs

Quantum Molecular Sieving Effects of H₂ and D₂ on Bundled and Nonbundled Single-Walled Carbon Nanotubes

The quantum molecular sieving effects of pore-structure-controlled single-walled carbon nanotubes (SWCNTs) for H₂ and D₂ were evaluated at 20, 40, and 77 K. The adsorption amounts of D₂ were larger than those of H₂. The lower the adsorption temperature, the greater the difference between the D₂ and H₂ adsorption amounts. Bundled SWCNTs with interstitial pores of diameter 0.6 nm gave the greatest adsorption difference between D₂ and H₂ per unit pore volume. Diffusion-dominated behavior was observed in the low-pressure region at 20 and 40 K as a result of lower mobility. Bundled SWCNTs with only interstitial pores provided a significant quantum molecular sieving as a result of strongly interacting potential wells