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2.
Bioconjug Chem ; 26(10): 2021-4, 2015 Oct 21.
Article in English | MEDLINE | ID: mdl-26340430

ABSTRACT

A strategy is introduced for enhancing the cellular selectivity of Amphotericin B (AmB) and other classes of membrane-disrupting agents. This strategy involves attaching the agent to a molecular umbrella to minimize the disruptive power of aggregated forms. Based on this approach, AmB has been coupled to a molecular umbrella derived from one spermidine and two cholic acid molecules and found to have antifungal activities approaching that of the native drug. However, in sharp contrast to AmB, the hemolytic activity and the cytotoxcity of this conjugate toward HEK293 T cells have been dramatically reduced.


Subject(s)
Amphotericin B/chemistry , Amphotericin B/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Amphotericin B/adverse effects , Animals , Cholic Acid/chemistry , Drug Evaluation, Preclinical/methods , Erythrocytes/drug effects , HEK293 Cells/drug effects , Hemolytic Agents/chemistry , Hemolytic Agents/pharmacology , Humans , Spermidine/chemistry , Structure-Activity Relationship
3.
Bioconjug Chem ; 25(8): 1408-11, 2014 Aug 20.
Article in English | MEDLINE | ID: mdl-25068916

ABSTRACT

A tetrawalled and an octawalled molecular umbrella conjugate of amphotericin B (AmB) have been synthesized. Both conjugates exhibit high water solubility, a low tendency to aggregate, negligible hemolytic activity at 100 µM, and an ability to release a derivative of AmB under reducing conditions that exhibits high antifungal activity. Whereas the larger, octawalled conjugate shows slight adsorption to liposomal membranes and an ability to cross them by passive transport, the tetrawalled analogue shows significant adsorption and much lower bilayer transport activity. The potential of molecular umbrella-AmB conjugates as therapeutic agents is briefly discussed.


Subject(s)
Amphotericin B/chemistry , Antifungal Agents/chemistry , Hydrophobic and Hydrophilic Interactions , Micelles , Solubility , Structure-Activity Relationship , Water/chemistry
4.
Bioconjug Chem ; 25(2): 197-201, 2014 Feb 19.
Article in English | MEDLINE | ID: mdl-24433067

ABSTRACT

The synthesis, computer modeling, and biological activity of an octawalled molecular umbrella short interfacing RNA (siRNA) conjugate is described. This molecular umbrella-siRNA conjugate exhibited mRNA knockdown activity in vitro in the absence of a transfection reagent. Evaluation of this molecular umbrella conjugate in vivo, using the rat eye via intravitreal injection, resulted in sequence specific mRNA knockdown in the retina with no obvious signs of toxicity, as judged by ophthalmic examination.


Subject(s)
Drug Carriers , Eye , RNA, Small Interfering/administration & dosage , Drug Administration Routes , HEK293 Cells , Humans , Molecular Dynamics Simulation
5.
Chem Commun (Camb) ; 49(34): 3576-8, 2013 May 04.
Article in English | MEDLINE | ID: mdl-23525335

ABSTRACT

Structurally unmatched hyperthin (14 nm) polyelectrolyte multi-layers (PEMs) formed on poly[1-(trimethylsilyl)-1-propyne] supports exhibit exceptionally high CO(2)/N(2) permeation selectivities, ranging from 100 to 150. Structurally matched PEMs show similar selectivities with significantly higher permeances.

6.
Acc Chem Res ; 46(12): 2743-54, 2013 Dec 17.
Article in English | MEDLINE | ID: mdl-23360121

ABSTRACT

The use of organic polymeric membranes to separate gaseous mixtures provides an attractive alternative to other methods such as selective adsorption and cryogenic distillation. The primary advantages of membrane-based separations are their relative energy efficiency and lower costs. Because the flux of a gas across a membrane is inversely proportional to the membrane's thickness, this method relies on fabricating membranes that are as thin as possible. However, as researchers have tried to produce "hyperthin" membranes (less than 100 nm), these membranes often form defects and lose their permeation selectivity. In this Account, we review some of the progress in our laboratories at Lehigh University to create hyperthin membranes with high permeation selectivities. We focus special attention on gaseous permeants that are relevant for the production of clean energy (H2 and CO2 formed from CH4) and the reduction of global warming (CO2 and N2, the major components of flue gas). Our studies make extensive use of Langmuir-Blodgett (LB) methods and porous surfactants derived from calix[6]arenes. We specially designed each surfactant to form cohesive monolayers and multilayers, and we introduced a "gluing" technique, where we cross-link porous surfactants containing quaternary ammonium groups ionically with polymeric counterions. Using ellipsometry, atomic force microscopy, X-ray photoelectron spectroscopy, monolayer isotherm, surface viscosity, and permeation measurements, we have characterized these hyperthin films. While molecular sieving appears to make a significant contribution to the permeation selectivity of some of these membranes, solution-diffusion pathways predominate. We also describe initial studies in which we formed hyperthin films from poly(ethylene glycol)-based polyelectrolytes using layer-by-layer deposition (LbL) methods. We have found remarkably high H2/CO2 and CO2/N2 permeation selectivities with these LB- and LbL-based hyperthin membranes. These results suggest that such materials may lead the way to materials that researchers can exploit to purify hydrogen produced from CH4 and to capture CO2 from flue gas.

7.
Bioconjug Chem ; 23(3): 336-9, 2012 Mar 21.
Article in English | MEDLINE | ID: mdl-22372891

ABSTRACT

PEGylated phospholipids are commonly used to increase the blood-circulation time of liposomes by providing a steric barrier around them. This paper documents a fundamentally new property of these lipids-an ability to stimulate the release of cholesterol from phospholipid membranes. Evidence for such stimulation has been obtained by measuring the transport of dehydroergosterol (DHE), a fluorescent simulant of cholesterol, from donor liposomes made from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG(2000)), and DHE to acceptor liposomes made from POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), and cholesterol. The potential of PEGylated lipids to serve as novel cholesterol-lowering agents is briefly discussed.


Subject(s)
Cholesterol/chemistry , Liposomes , Membranes, Artificial , Phospholipids/chemistry , Polyethylene Glycols/chemistry
8.
Langmuir ; 28(10): 4614-7, 2012 Mar 13.
Article in English | MEDLINE | ID: mdl-22364564

ABSTRACT

Polymeric surfactants were prepared by quaternization of poly(4-chloromethylstyrene) with N,N-dimethyl-N-n-dodecylamine and N,N-dimethyl-N-n-octylamine to give 1 and 2, respectively. Each of these polymers formed stable monolayers at the air/water interface. Injection of poly(acrylic acid) (PAA) beneath the surface of these films led to a substantial increase in their cohesiveness (i.e., "gluing"), as evidenced by a dramatic increase in their surface viscosity. Examination of monolayers of 1 by atomic force microscopy, after being transferred to silicon wafers that were surface-modified with n-octadecyltrichlorosilane, showed that the presence of PAA leads to intact film. In contrast, transfer of unglued monolayers resulted in poor coverage. Comparison of the barrier properties of single glued and unglued LB bilayers formed in the presence and in the absence of PAA have shown that PAA minimizes defect formation within these ultrathin assemblies.

9.
Bioconjug Chem ; 22(11): 2210-6, 2011 Nov 16.
Article in English | MEDLINE | ID: mdl-21985221

ABSTRACT

A series of diwalled and tetrawalled molecular umbrellas have been synthesized using cholic acid, spermidine, and lysine as starting materials. Coupling of these molecular umbrellas to an octaarginine peptide afforded agents that were capable of promoting the transport of small interfering RNA to HeLa cells, as judged by the knockdown of enhanced green fluorescent protein expression. The efficiency of this knockdown was found to increase with an increasing number of facially amphiphilic walls present, and also when a cleavable disulfide linker was replaced with a noncleavable, maleimido moiety; i.e., a group that is not susceptible to thiolate-disulfide interchange. The knockdown efficiency that was observed for one tetrawalled molecular umbrella-octaargine conjugate was comparable to that observed with a commercially available transfection agent, Lipofectamine 2000, but the conjugate showed less cytotoxicity.


Subject(s)
Drug Carriers/chemistry , Drug Carriers/metabolism , Peptides/chemistry , Peptides/metabolism , RNA, Small Interfering/metabolism , Drug Carriers/chemical synthesis , HeLa Cells , Humans , Molecular Structure , Peptides/chemical synthesis , RNA, Small Interfering/chemistry
10.
Chem Commun (Camb) ; 47(8): 2387-9, 2011 Feb 28.
Article in English | MEDLINE | ID: mdl-21170450

ABSTRACT

Single Langmuir-Blodgett (LB) bilayers derived from calix[n]arene-based surfactants (n = 4, 5 and 6) and poly(acrylic acid) (PAA) exhibit exceptional H(2)/CO(2) permeation selectivities. Evidence for the importance of ionic crosslinking and self-healing processes is presented.

11.
Langmuir ; 26(15): 12988-93, 2010 Aug 03.
Article in English | MEDLINE | ID: mdl-20666425

ABSTRACT

A homologous series of calix[4]arene-, calix[5]arene-, and calix[6]arene-based surfactants, containing pendant trimethylammonium and n-hexadecyl groups, have been compared with respect to their ability (i) to undergo ionic cross-linking at the air/water interface, (ii) to incorporate poly(4-styrenesulfonate) (PSS) in Langmuir-Blodgett (LB) bilayers, and (iii) to act as barriers toward He, N(2), and CO(2) when assembled into cross-linked LB bilayers. As these calix[n]arenes increase in size, their ability to undergo ionic cross-linking has been found to increase, the thickness of corresponding glued LB bilayers has been found to decrease, and their barrier properties and permeation selectivities have been found to increase. The likely origin for these effects and the probable mechanism by which He, N(2), and CO(2) cross these ultrathin films are discussed.

12.
Langmuir ; 26(8): 5316-8, 2010 Apr 20.
Article in English | MEDLINE | ID: mdl-20329715

ABSTRACT

The condensing action of cholesterol has been compared with that of a structural isomer having its hydroxyl group located at the C-25 position (i.e., 25-OH'), that is, an isomer favoring an "upside down" orientation in lipid membranes. Surface pressure-area isotherms of mixed monolayers made from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/cholesterol and DMPC/25-OH' have established that 25-OH' has a weaker condensing effect than cholesterol. Nearest-neighbor recognition measurements in liposomes made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) have also shown that 25-OH' has a weaker condensing effect in the physiologically relevant fluid bilayer state. These findings provide support for surface occupancy playing a role in the condensing action of cholesterol.


Subject(s)
Cholesterol/chemistry , Dimyristoylphosphatidylcholine/chemistry , Liposomes/chemistry , Molecular Structure , Surface Properties
13.
Bioconjug Chem ; 20(9): 1711-5, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19689127

ABSTRACT

A persulfated molecular umbrella derived from one spermine, four lysine, and eight deoxycholic acid molecules was found to exhibit ionophoric activity, as shown by pH discharge and Na(+) and Cl(-) transport experiments. In sharp contrast, a moderately more hydrophilic analogue derived from cholic acid showed no such ionophoric activity. Both molecular umbrellas crossed liposomal membranes by passive transport with experimental rates that were similar. These findings show how the interactions between such amphomorphic molecules and phospholipid bilayers are a sensitive function of the umbrella's hydrophilic/lipophilic balance (HLB). They also raise the possibility of exploiting molecular umbrellas in fundamentally new ways.


Subject(s)
Deoxycholic Acid/chemistry , Ionophores/chemical synthesis , Lysine/chemistry , Spermine/chemistry , Biological Transport , Chlorides/metabolism , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Kinetics , Liposomes , Sodium/metabolism
14.
J Am Chem Soc ; 131(4): 1338-9, 2009 Feb 04.
Article in English | MEDLINE | ID: mdl-19140686

ABSTRACT

The ability of a series of molecular umbrellas, derived from cholic acid, L-lysine, spermidine, and Cascade Blue, to cross fluid liposomal membranes made from 1-palmitoyl-2-oleyol-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG) (95/5, mol/mol) has been determined. In sharp contrast to the classic "size/lipophilicity" rule of membrane transport, those molecular umbrellas that were larger in size and less lipophilic crossed these liposomal membranes more readily. The likely origin for this unusual behavior is briefly discussed.


Subject(s)
Hydrophobic and Hydrophilic Interactions , Lipid Bilayers/chemistry , Liposomes/chemistry , Molecular Structure
15.
Bioconjug Chem ; 20(2): 183-92, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19053303

ABSTRACT

Molecular umbrellas are "amphomorphic" compounds that can produce a hydrophobic or hydrophilic exterior when exposed to a hydrophobic or hydrophilic microenvironment, respectively. Such molecules are composed of two or more facial amphiphiles that are connected to a central scaffold. Molecular umbrellas that have been synthesized to date, using bile acids as umbrella "walls", polyamines such as spermidine and spermine as scaffold material, and l-lysine as "branches", have been found capable of transporting certain hydrophilic peptides, nucleotides, and oligonucleotides across liposomal membranes by passive diffusion. They have also have been shown to increase water solubility and hydrolytic stability of a hydrophobic drug, and to exhibit significant antiviral activity. The ability of a fluorescently labeled molecular umbrella to readily enter live HeLa cells suggests that such conjugates could find use as drug carriers.


Subject(s)
Drug Carriers , Animals , Drug Carriers/chemical synthesis , Drug Carriers/chemistry , Drug Carriers/metabolism , Humans , Liposomes/metabolism , Nucleotides/chemistry , Nucleotides/metabolism , Peptides/chemistry , Peptides/metabolism , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism
16.
Bioconjug Chem ; 19(8): 1510-3, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18681467

ABSTRACT

A fluorescently labeled, persulfated molecular umbrella ( 1) has been synthesized from cholic acid, lysine, spermine, and Coumarin 343 and found capable of entering live HeLa cells. The distributions of 1 throughout the cytoplasm and the nucleus were diffuse and punctate, respectively. This finding, together with its ability to cross liposomal membranes by passive diffusion, suggests that passive diffusion plays a significant role in the ability of 1 to enter cells. The fact that 1 is concentrated at the nucleus raises the possibility that molecular umbrellas of this type could be used for the nuclear targeting of drugs.


Subject(s)
Cell Nucleus/metabolism , Drug Carriers/chemistry , Drug Carriers/metabolism , Anions/chemistry , Cell Membrane/metabolism , Fluorescent Dyes/chemistry , HeLa Cells , Humans , Lipid Bilayers/metabolism , Liposomes/metabolism , Microscopy, Confocal , Peptides/metabolism , Water/chemistry
17.
Langmuir ; 23(17): 8709-12, 2007 Aug 14.
Article in English | MEDLINE | ID: mdl-17629317

ABSTRACT

One of the most challenging questions that relates to the structure and function of biological membranes is whether the two halves of the bilayer "talk" to each other. In this letter, we show how the perturbation of the lateral organization of one leaflet of a fluid phospholipid bilayer by an external agent also alters the lateral organization of the adjoining leaflet. In addition, we show that the energy involved in such "cross talk" corresponds to ca. 100 cal/mol of phospholipid. These findings provide a basis for expecting similar cross talk to exist in cell membranes.


Subject(s)
Lipid Bilayers/chemistry , Phospholipids/chemistry , Dimerization , Molecular Structure , Research Design
18.
J Am Chem Soc ; 129(17): 5756-9, 2007 May 02.
Article in English | MEDLINE | ID: mdl-17411041

ABSTRACT

This paper introduces a fundamentally new concept in adsorbents, whereby the sorption of an aqueous solute by a cross-linked polymer is controlled by a gel to liquid-crystalline phase transition. To demonstrate proof of principle, a bilayer forming surfactant, N,N-dioctadecyl,N,N-dimethylammonium bromide (DODAB) has been immobilized onto a cation exchange resin, Dowex 50WX2, and its thermotropic phase behavior and solute-adsorption properties have been investigated. Examination by a combination of differential scanning calorimetry and X-ray scattering has confirmed the retention of a gel to liquid-crystalline phase transition of the surfactant, occurring between 296 and 318 K. Adsorption measurements that were made for 4-chlorotetrahydropyran, 1,2-dichloroethane, and benzyl alcohol have also confirmed uptake by the resin in the liquid-crystalline phase and release in the gel phase.

19.
Langmuir ; 22(26): 11224-9, 2006 Dec 19.
Article in English | MEDLINE | ID: mdl-17154607

ABSTRACT

Langmuir-Blodgett (LB) monolayers of 5,11,17,23,29,35-hexaformyl-37,38,39,40,41,42-hexakis(1-n-octyloxy)calix[6]arene (2), deposited onto silylated silicon wafers, were cross-linked (i.e., "covalently glued") via Schiff base formation with poly(allylamine). Direct evidence for imine formation was obtained from X-ray photoelectron spectroscopy and from attenuated total reflection IR spectroscopy. These modified surfaces could be removed from the aqueous subphase into air with retention of the assembly and its orientation relative to the surface, as evidenced by atomic force microscopy, water contact angle measurements, and film thickness determinations by ellipsometry. Similar assemblies were also synthesized via a postgluing procedure, in which the substrate containing the LB monolayer was removed from the subphase and rapidly immersed into an aqueous solution containing poly(allylamine). The potential of combining postgluing methods with continuous LB film deposition as a surface modification technique is briefly discussed.

20.
J Am Chem Soc ; 128(3): 682-3, 2006 Jan 25.
Article in English | MEDLINE | ID: mdl-16417333

ABSTRACT

This paper describes a new approach for modifying hydrophobic surfaces that is based on the use of ionically cross-linked (i.e., "glued") Langmuir-Blodgett monolayers. Specifically, this work shows how monolayers of 5,11,17,23,29,35-hexa(trimethylammonium methyl)-37,38,39,40,41,42-hexakis-n-hexadecyloxy-calix[6]arene (1a), which have been ionically cross-linked with poly(4-styrene-sulfonate) (PSS, MW 30,000-50,000), can be deposited onto silylated silicon wafers with their polar headgroups extending outward into air. This work also demonstrates the feasibility of using glued monolayers of 1a as "anchors" for attaching alternating layers of poly(diallyldimethylammonium) [PDADMA] and PSS ions onto these same hydrocarbon surfaces.

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