Therapeutic surfactant-stripped frozen micelles.

Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like 'top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and 'bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2-3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated.

Dual-Responsive Lipid Nanotubes: Two-Way Morphology Control by pH and Redox Effects.

Lipid nanotubes are the preferred structures for many applications, especially biological ones, and thus have attracted much interest recently. However, there is still a significant need for developing more lipid nanotubes that are reversibly controllable to improve their functionality and usability. Here, we presented a two-way reversible morphology control of the nanotubes formed by the recently designed molecule AQUA (C25H29NO4). Because of its special design, the AQUA has both pH-sensitive and redox-active characters provided by the carboxylic acid and anthraquinone groups. Upon chemical reduction, the nanotubes turned into thinner ribbons, and this structural transformation was significantly reversible. The reduction of the AQUA nanotubes also switched the nanotubes from electrically conductive to insulative. Nanotube morphology can additionally be altered by decreasing the pH below the pKa value of the AQUA, at ∼4.9. Decreasing the pH caused the gradual unfolding of the nanotubes, and the interlayer distance in the nanotube's walls increased. This morphological change was fast and reversible at a wide pH range, including the physiological pH. Thus, the molecular design of the AQUA allowed for an unprecedented two-way and reversible morphology control with both redox and pH effects. These unique features make AQUA a very promising candidate for many applications, ranging from electronics to controlled drug delivery.

Stimuli-responsive lipid nanotubes in gel formulations for the delivery of doxorubicin.

Lipid nanotubes (LNTs) are one of the most advantageous structures for drug delivery and targeting. LNTs formed by a specially designed molecule called AQUA (AQ-NH-(CH2)10COOH (AQ: anthraquinone group) is used for drug delivery, and doxorubicin (DOX) is the drug selected. DOX and AQUA have some similarities in their molecular structures, so a significant amount of DOX can be loaded to LNTs. The AQUA LNTs are pH responsive, and drug loading increased almost linearly by increasing the pH, reaching a maximum value (96%) at pH 9.0. In terms of drug release, lower pHs are preferred. Drug-loaded LNTs are also mixed with four different gels (chitosan, alginate, hydroxypropyl methylcellulose and polycarbophil) to use the advantages of these gels. The drug release efficiency is studied using a Franz diffusion cell in which sheep colon membranes and dialysis membranes are utilized. The amount of released DOX from the chitosan gel formulations was quite high. Sodium alginate gels had lower release and slower diffusion of DOX. The cytotoxic effect of DOX-loaded AQUA LNTs has also been determined on cell cultures. Our new lipid nanotubes are a non-toxic, effective, biodegradable, biocompatible, stable and promising system for drug delivery and can be used for colonic administration of DOX for the treatment of colorectal cancer (CRC).

Restoration of the interfacial properties of lung surfactant with a newly designed hydrocarbon/fluorocarbon lipid.

Serum proteins, especially fibrinogen, inactivate the lung surfactant mixture by adsorbing quickly and irreversibly to the alveolar air/aqueous interface. As a consequence of the inactivation, the surfactant becomes dysfunctional, and respiration cannot be maintained properly. Preventing the adsorption of surface active serum proteins to the air/water interface is important because this phenomenon causes fatal diseases such as acute respiratory distress syndrome (ARDS). Although some treatments exist, improvements in synthetic surfactants that can resist this inactivation are still expected. In this context, a novel ion pair lipid (IPL, CF3(CF2)7SO3(-)(CH2CH3)3N(+)(CH2OCH2)10(CH2)15CH3) has been designed and synthesized. This surfactant reduces the inhibitory effect of fibrinogen by selectively interacting with DPPC (dipalmitoylphosphatidylcholine) and mimicking some of the interfacial properties of the pulmonary surfactant protein B (SP-B). Surface pressure-area isotherms and fluorescence microscopy images demonstrate that IPL can mix and interact synergistically with DPPC due to its unique molecular structure. Hysteresis behaviors of the monolayers, which are composed of mixtures of DPPC and IPL at different molar ratios, indicate that with increasing amounts of IPL, the lipid losses from the interface induced by the presence of fibrinogen significantly decrease. It is also found that IPL is able to adsorb to monolayers formed in the presence of fibrinogen, whereas fibrinogen cannot penetrate the monolayers formed in the presence of IPL. These results indicate that by mimicking some of the interfacial properties of SP-B, this novel hybrid molecule is promising in terms of preventing fibrinogen adsorption and therefore resisting surfactant inactivation.

Formation of chiral nanotubes by the novel anthraquinone containing-achiral molecule.

Self-assembled lipid nanotubes arouse lots of interest due to their exceptional properties such as very simple production procedures, large variety of applications and high biocompatibility. In this study, the new eccentric but simple molecule, AQua (AQ-NH-(CH(2))(10)COOH; where AQ is anthraquinone), which integrates redox-active and pH sensitive character with nanotube forming capability has been designed. AQua forms self-assembled nanotubes by the chiral symmetry-breaking mechanism, in a high yield in the presence of ethanolamine. The nanotubes obtained in AQua-ethanolamine mixture are stable with time and resistant against drying and dilution at constant pH. However, pH change with dilution (without pH control) causes the unfolding of the nanotubes indicating the pH sensitive character. Existence of redox active anthraquinone group along with the carboxylic acid moiety gives the probability of reversibly controllable character to our nanotubes. The effect of the base type which is used to adjust the pH of the dispersion has also been investigated, and helix-tube-ribbon mixture is obtained when NaOH is used instead of ethanolamine. Although there are limited number of studies particularly in the field of reversibly controllable and/or redox active lipid nanotubes, controlled self-assembly and disassembly of these appreciable aggregates are very important for their usage in special applications. Thus, this study is hoped to be one of the remarkable studies for the development of reversibly controllable, redox active self assembled nanotubes.

A highly sensitive detection platform based on surface-enhanced Raman scattering for Escherichia coli enumeration.

A very sensitive and highly specific heterogeneous immunoassay system, based on surface-enhanced Raman scattering (SERS) and gold nanoparticles, was developed for the detection of bacteria and other pathogens. Two different types of gold nanoparticles (citrate-stabilized gold nanosphere and hexadecyltrimethylammonium bromide (CTAB)-stabilized gold nanorod particles) were examined and this immunoassay was applied for the detection of Escherichia coli. Raman labels were constructed by using these spherical and rod-shaped gold nanoparticles which were first coated with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) and subsequently with a molecular recognizer. The working curve was obtained by plotting the intensity of the SERS signal of the symmetric NO(2) stretching of DTNB at 1,333 cm(-1) versus the concentration of the E. coli. The analytical performance of gold particles was evaluated via a sandwich immunoassay, and linear calibration graphs were obtained in the E. coli concentration range of 10(1)-10(5) cfu/mL with a 60-s accumulation time. The sensitivity of the Raman label fabricated with gold nanorods was more than three times higher than spherical gold nanoparticles. The selectivity of the developed sensor was examined with Enterobacter aerogenes and Enterobacter dissolvens, which did not produce any significant response. The usefulness of the developed immunoassay to detect E. coli in real water samples was also demonstrated.

A new strategy to form multicompartment micelles: fluorocarbon-hydrocarbon ion-pair surfactant.

The hydrophobic core of the multicompartment micelles consists of incompatible and clearly separated distinct subdomains which make them different from the classical micelles. Owing to these properties multicompartment micelles have a great potential to be used as solubilization agents and carriers for a wide variety of applications where it is important to prevent the uncontrolled interaction of the solubilizates before reaching the target and to convey them to the specified point simultaneously. Here we show that effective compartmentalization inside the micelle and high solubilization capacity for the two immiscible water-insoluble materials in cases of both simultaneous and separate solubilization can be achieved by newly designed ion-pair hybrid surfactant CH(3)(CH(2))(11)(OCH(2)CH(2))(23)N(+)(C(2)H(5))(3)SO(3)(-)(CF(2))(7)CF(3) (C(12)E(23)N(+)SO(3)(-)F(8)) through the agency of favorable molecular design. Molecular structure is tailored by the approach of using a balance of forces to obtain compartmentalization, which is without precedent. This new molecule also has the properties of quite low critical micelle concentration and an extensive surfactant concentration range for solubilization which are additional important advantageous features.