Hypothesis: The combination of polymeric surfactants into mixed micelles is expected to improve properties relevant to their use in drug delivery, such as micellar size, gelation, and toxicity. We investigated synergistic effects in mixtures of D-¿-Tocopheryl polyethylene glycol succinate (TPGS), an FDA-approved PEGylated derivative of vitamin E, and Tetronic surfactants, pH-responsive and thermogelling polyethylene oxide (PEO)-polypropylene oxide (PPO) 4-arm block copolymers. We hypothesized that mixed micelles would form under specific conditions and provide a handle to tune formulation characteristics. Experiments: We examined the morphology of the self-assembled structures in mixtures of TPGS with two Tetronic: T1107 and T908, using a combination of dynamic light scattering (DLS), small-angle neutron scattering (SANS), NMR spectroscopy (NOESY and diffusion NMR) and oscillatory rheology, over a range of compositions, temperatures and pH. Cell viability was assessed in NIH/3T3 fibroblasts. Findings: The combination of TPGS with either of the two Tetronic produces spherical core-shell micelles that comprise both surfactants in their structure (mixed micelles). T1107 unimers incorporate into TPGS aggregates below the critical micelle temperature of the poloxamine, while mixed micelles only form under limited conditions with T908. At high concentration/temperature, small proportions of TPGS extend the gel phase, more markedly with T1107, with similar elastic moduli (30-50 kPa) and a BCC crystalline structure. Cell viability of NIH/3T3 fibroblasts grown in the hydrogels increases significantly when the poloxamine gels are doped with TPGS, making the combination of poloxamines and TPGS a promising platform for drug delivery.

The combination of polymeric surfactants with different features into mixed micelles give access to properties that may be superior to the single-component micelles. In this work, we investigated synergistic effects in mixtures of D-alpha-Tocopheryl polyethylene glycol succinate (TPGS) with poloxamines (also known as Tetronic), pH-responsive and thermogelling polyethylene oxide (PEO)-polypropylene oxide (PPO) 4-arm block copolymers. We examined the morphology of the self-assembled micelles of TPGS with Tetronic 1107 (T1107) and 908 (T908) in the presence of naproxen (NA), used as a model drug, and assessed the capacity of the single and mixed micelles to trap the guest, using a combination of small-angle neutron scattering (SANS) and NMR spectroscopy (1D, 2D-NOESY and diffusion NMR), over a range of compositions and temperatures, in the dilute regime and gel state. NA did not interact with T1107 or T908 in their unimer form, but it was incorporated into the hydrophobic core of the micelles above the critical micellar temperature (CMT). In contrast, TPGS dissolved NA at any temperature, mainly in the tocopherol core, with some partitioning in the PEG-shell. The micellar structure was not altered by the presence of NA, except for an expansion of the core size, a result of the preferential accumulation of NA in that compartment. The solubility of the drug in single component micelles increased markedly with temperature, while mixed micelles produced an intermediate enhancement o

Miltefosine (MF), an alkylphospholipid originally developed for breast cancer treatment, is a highly active drug for the treatment against leishmaniasis, a neglected tropical disease considered the world's second leading cause of death by a parasitic agent after malaria. MF exhibits dose-limiting gastrointestinal side effects in patients and its penetration through lipophilic barriers is reduced. In this work we propose a reformulation of MF by incorporating the drug to poly(ethylene)oxide (PEO)-based polymeric micelles, specifically, D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and Tetronic block copolymers (T904 and T1107). A full structural characterization of the aggregates has been carried out by SANS (small-angle neutron scattering) and dynamic light scattering (DLS), in combination with proton 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, to determine the precise location of the drug. The structure of MF micelles has been characterized as a function of the temperature and concentration. In the presence of the block-copolymers, MF forms mixed micelles in a wide range of temperatures, TPGS being the co-surfactant that incorporates more MF unimers. The hydrophobic tail of MF and those of the block copolymers are in close contact within the micelles, which present a core-shell structure with a hydrophilic corona formed by the PEG blocks of the TPGS and the zwitterion head group of the MF. In order to identify the best carrier, the antileishmanicidal activity of MF in the different formulations has been tested on macrophages, promastigotes and intracellular amastigotes. The combination of the three vehicles with MF makes the formulated drug more active than MF alone against L. major promastigotes, however, only the combination with T904 increases the MF activity against intracellular amastigotes. With the aim of exploring gel-based formulations of the drug, the combination of MF and T1107 under gelation conditions has also been investigated.

Pseudopolyrotaxanes (PPRs) are supramolecular host-guest complexes constituted by the reversible threading of macrocycles along a polymer chain. We report the formation of hybrid PPRs (hPPRs), where two types of cyclodextrins (CDs) thread either simultaneously or sequentially on four-arm poly-(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymers (Tetronic): native alpha-CD (CD) (with higher affinity for PEO) and dimethylated beta-CD (DIMEB, with higher affinity for PPO). The competitive complexation along the chains is examined with three Tetronics, differing mainly in the length of their PEO blocks: T904, T1107, and T1307. While PPRs formed with alpha-CD are insoluble, due to the hydrogen-bond network formed between adjacent alpha-CDs, the presence of DIMEB leads to soluble hybrid PPRs, slows down the kinetics of complexation, and increases the number of alpha-CDs threaded per arm. The morphology of the constructs in solution over time is followed by time-resolved small-angle neutron scattering (TR-SANS), while their crystalline structure is studied by X-ray diffraction. Whereas the complexation of the polymeric surfactant with DIMEB shifts the unimer-micelle equilibrium toward unimers, the presence of alpha-CD slows down demicellization and reduces its extent. Overall, the co-threading of two cyclodextrins on the same polymer provides a handle to tune the complexation process and the final properties of the PPR, including solubility, kinetics of complexation, and composition of the complexes.

The solubilisation of methylparaben (MP), an antimicrobial agent used as a food preservative and in cosmetics and personal-care products, in two poloxamines of different Hydrophilic-Lipophilic Balance (HLB), namely Tetronic 904 (T904) and 1107 (T1107), has been studied. The influence of the preservative on the aggregation behaviour of both Tetronics has been analysed by dynamic light scattering (DLS) and small-angle neutron scattering (SANS), while the precise location of the molecule in the aggregates as well as the effects of the micellar solubilisation on the reactivity of the preservative have been elucidated by NMR and UV spectroscopies. The presence of MP reduces the critical micelle temperature (CMT) of any of the poloxamines and induces the formation of larger micelles at room temperature compared to the plain poloxamines; in addition, a remarkable temperature dependent effect on the structure of the micelles has been detected, which progressively evolve from core-shell spheres to rods as the temperature increases. The incorporation of the preservative into the micelles modifies its reactivity against alkaline hydrolysis, resulting in a decrease of its reaction rate constant in which the dominant factor for the reduction in the hydrolysis rate is the incorporation into the micelle core, with a little effect of the length of the hydrophilic polyethylene oxide (PEO) blocks.

Pseudo-polyrotaxanes (PPRs) are supramolecular host-guest complexes constituted by the reversible threading of a macrocycle along a polymer chain. The resuting dynamic "molecular necklaces" offer potential applications in nanotechnology, drug delivery, and biomaterials. We report the formation of PPRs by threading of cyclodextrins (CDs), cyclic oligosaccharides, onto X-shaped PEO-PPO block copolymers with two opposite presentation of their hydrophobic and hydrophilic blocks: Tetronic 904 (T904) and its reverse counterpart Tetronic 90R4 (T90R4). We assess the effects that relative block position on the polymeric surfactants and cavity size of CD have on the composition, morphology, thermodynamics, and kinetics of PPRs by using a combination of X-ray diffraction, scanning electron microscopy, NMR, UV-vis spectroscopy, and time-resolved small-angle neutron scattering (TR-SANS). Solid PPRs with lamellar microstructure and crystalline channel-like structures are obtained with native CDs and both Tetronics above a threshold concentration of the macrocycle, which varies with the type of CD and surfactant. While gamma-CD can form PPRs with both Tetronics, alpha-CD only forms a PPR with T90R4 at high concentrations. The results can be explained in terms of the preferential complexation of alpha-CD with EO and gamma-CD with PO monomers, which also has a direct impact on the kinetics of PPR formation.

Tetronics are X-shaped block-copolymers of polyethylene oxide and polypropylene oxide, which self-assemble into micelles and can undergo a sol-gel transition; these transitions are dependent on temperature, concentration but also pH, due to the central diamine group of the tetrablock. We report the nanoscale morphologies underlying these different phases and the rheology of the systems for a very large, highly hydrophilic block copolymer, Tetronic 908, through the combined use of oscillatory rheology, steadyblock-state and time-resolved fluorescence, small-angle neutron scattering (SANS), dynamic light scattering (DLS) and Fourier transform infrared attenuated total reflectance (FTIR-ATR). At low concentrations, SANS reveal core-shell micelles of ca. 10 nm radius, presenting a dehydrated core and a highly hydrated shell, with relatively small aggregation numbers (N-agg approximate to 13). The micelles are notably affected by the pH, due to the protonation of the central amine spacer at low pH (pH approximate to 2), which shifts micellization to higher temperature, with smaller micelles than at natural pH. In the intermediate concentration regime (10-15%), micelles become smaller (N-agg approximate to 5), and present a higher hydration of the core. In the high concentration regime, Tetronic 908 undergoes a sol-gel transition above a threshold temperature, which is fully inhibited at acidic pH. SANS data from the gel phase reveal a BCC order of tightly packed spheres. Temperature sweeps in oscillatory rheology show a shift of the onset of gelation towards lower temperatures as concentration increases, an increase in the elastic modulus G' and an expansion of gel region over a larger range of temperatures. SANS and rheology reveal that at pH below the natural pH (ca. 8), gelation is shifted to higher temperatures, but the morphology of the gels is similar, while under highly acidic conditions the gelation is fully suppresed. (C) 2018 Elsevier Inc. All rights reserved.

Leishmaniasis is a neglected tropical disease caused by intracellular parasites from the genus Leishmania. This neglected tropical disease is responsible for significant morbidity and mortality worldwide. One of the most important challenges for the treatment of leishmaniasis is the oral administration of drugs. Such need combined to the predicted high bioavailability of miltefosine prompted its validation. Its antileishmanial activity was better than that of the intravenous sodium stibogluconate. In 2002, it was approved as the first oral drug against leishmaniasis. Miltefosine is being an attractive drug for leishmaniasis due to its cost-effective and oral administration. On the other hand, nanocarriers drug delivery systems used to enhance activity and reduce side effects of antileishmanial drugs. This chapter reviews the most common nanocarriers used for miltefosine, focusing on polymeric micelles, characterized for their core-shell structure. Micelles formed with PEO-PPO block copolymers (Pluronics and Tetronics) and TPGS (PEGylated derivative of vitamin E) are described, as well as their composition, biological activity, and interaction with miltefosine. Promising systems, based on this drug, are reported by the combination of several copolymers, forming polymeric mixed micelles, and the further organization of some PEO-PPO block copolymers micelles into hydrogels.