Effect of the alkyl group in the piperazine N-substitution on the therapeutic action of rifamycins: A drug-membrane interaction study.

In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seem to be due to the N-alkyl substituent and can contribute to provide a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis.

A multitechnique approach on adsorption, self-assembly and quercetin solubilization by Tetronics® micelles in aqueous solutions modulated by glycine.

Ethylene oxide-propylene oxide (EO-PO) block copolymer micelles are useful potential nanoreservoirs for the delivery of hydrophobic drugs. Considering that glycine is an excipient and can favorably affect the surface/micellar behavior and thus improve solubilization power/dispersion stability/wetting characteristics we have reported here studies on aqueous solution behavior of two commercially available branched block copolymers (Tetronics®) with differing hydrophobicities namely Tetronics® 1307 and 1304, hereafter referred as T1307 and T1304, in the presence of glycine. Steady state fluorescence studies using pyrene as a probe, equilibrium and dynamic surface tension measurements, wetting and dispersion stability studies of Teflon (polytetrafluoroethylene; PTFE) and solubilization studies of a hydrophobic antioxidant/anticancer drug quercetin (QN) have been examined. The cloud point (CP) and critical micelle temperature (CMT) decrease while micelle hydrodynamic size (Dh) increases with the addition of glycine as well as on loading of the drug in the micelles. Water penetration through packed PTFE powder and dynamic surface tension confirm the enhanced micellization process for aqueous Tetronic® solutions in presence of glycine and accordingly restricted diffusion for the surfactant molecules towards air-water and PTFE-water interface. The contact angles for Tetronic® solutions in presence of glycine indicate moderate decrease. The pressure-area curves of the copolymers in water and glycine solutions were also constructed. Surface and micellar properties of copolymers are markedly altered in the presence of glycine and can be tuned for use of these nanocarriers in delivery systems.

Surface and Aggregation Behavior of Pentablock Copolymer PNIPAM7-F127-PNIPAM7 in Aqueous Solutions.

The triblock Pluronic F127 was modified by introducing poly(N-isopropylacrylamide) (PNIPAM) at both the poly(ethylene oxide) ends, and the pentablock copolymer so-prepared was characterized by gel permeation chromatography and (1)H NMR. The degree of polymerization of NIPAM blocks at the two ends was 7. The solution behavior and microstructure of copolymer aggregates in water and aqueous salt solution were examined and compared with F127 by UV-visible absorption spectroscopy, microdifferential scanning calorimetry, dynamic light scattering (DLS), and small-angle neutron scattering (SANS). The behavior of the pentablock copolymer at the air/water interface was determined by Langmuir film balance. Two lower critical solution temperatures were observed for pentablock copolymer, corresponding to poly(propylene oxide) and PNIPAM blocks, respectively. DLS studies show that micelle size increased with increase in temperature and in the presence of salt. SANS measurements provided temperature-dependent structural evolution of copolymer micelles in water and salt solution. The copolymer displays an isotherm with four classical regions (pancake, mushroom, brush, and condensed state). The study has potential applications in controlled drug delivery due to the tunable phase behavior and biocompatibility of the copolymer.

Interaction of poloxamine block copolymers with lipid membranes: Role of copolymer structure and membrane cholesterol content.

Interactions of X-shaped poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymers with cell membranes were investigated recording the π-A isotherms of monolayer systems of dipalmitoylphosphatidylcholine (DPPC):cholesterol 100:0; 80:20 and 60:40 mol ratio and evaluating the capability of the copolymers to trigger haemolysis or to protect from haemolytic agents. Four varieties of poloxamine (Tetronic 904, 908, 1107 and 1307) were chosen in order to cover a wide range of EO and PO units contents and molecular weights, and compared to a variety of poloxamer (Pluronic P85). The π-A isotherms revealed that the greater the content in cholesterol, the stronger the interaction of the block copolymers with the lipids monolayer. The interactions were particularly relevant at low pressures and low lipid proportions, mimicking the conditions of damaged membranes. Relatively hydrophobic copolymers bearing short PEO blocks (e.g., T904 and P85) intercalated among the lipids expanding the surface area (ΔGexc) but not effectively sealing the pores. These varieties showed haemolytic behavior. Oppositely, highly hydrophilic copolymers bearing long PEO blocks (e.g., T908, T1107 and T1307) caused membrane contraction and outer leaflet sealing due to strong interactions of PEO with cholesterol and diamine core with phospholipids. These later varieties were not haemolytic and exerted a certain protective effect against spontaneous haemolysis for both intact erythrocytes and cholesterol-depleted erythrocytes.

NaCl-triggered self-assembly of hydrophilic poloxamine block copolymers.

Tetronic 1307 (T1307) is a hydrophilic poloxamine (HLB>24) with a high molecular mass owing to its long PEO and PPO blocks. In spite of good biocompatibility, its use as a component of drug delivery systems is limited by its high critical micelle concentration (CMC) and temperature (CMT). The aim of this work was to elucidate whether the addition of NaCl or the combination of salts and temperature may bring T1307 micellization and gelling features into more practically useful values. Increasing NaCl concentration in the 0.154 M (isotonic) to 2M (hypertonic) range made the copolymer more hydrophobic and more prone to self-assemble into unimodal micelles, as observed by means of π-A isotherms, (1)H NMR, dynamic light scattering (DLS), small-angle neutron scattering (SANS), and pyrene fluorescence. The decrease in CMC and CMT observed for T1307 in 0.5 M NaCl medium (tolerable hypertonic solution), compared to water, notably favored the solubility of hydrophobic drugs such as curcumin and quercetin. Moreover, phase diagram, intrinsic viscosity and sol-to-gel transition were markedly affected by NaCl concentration. Overall, the strong dependence of T1307 self-assembly features on NaCl opens interesting possibilities for tuning the performance of T1307 as a component of nanocarriers and in situ gelling systems.