A zipper-structured lipopeptide is expected to play a role of “intelligent valve” in the lipid bilayer. In this paper, a series of zipper-structured lipopeptides have been designed for preparing thermocontrollable hybrid liposomes. Their conformational transition as a function of temperature in lipid bilayer has been investigated for understanding the influences of molecular structure and bilayer property on biofunction. The melting temperatures Tm of the lipopeptides have been found to depend on their molecular structures. When the lipopeptides have been doped in bilayer, an increase of size of alkyl chain increases the stability of the α-helix resulting in a decrease in fluidity of lipid bilayer. However, an increase of amino groups at N-terminal is found to decrease the stability of the spatial structure. The thermocontrollability of the “valve” in lipid bilayer is confirmed by drug release experiments under different temperatures. Meanwhile, effects of bilayer properties on the thermosensitivity of lipopeptides have also been investigated. Results show the Tm of lipopeptide doped in bilayer decreases with the increase of membrane fluidity. Furthermore, the reversibility of the thermocontrolled “valve” is also proven by release drug under intermittent temperatures. It could be concluded that the molecular structure of the lipopeptide, as well as the property of bilayer, give great influence on the biofunction of the hybrid liposomes.

Azobenzene-contained glycolipids GlyAzoCns, newly structured azobenzene derivatives, which have an azobenzene moiety between the galactosyl and carbon chains of various sizes, have been synthesized. The GlyAzoCns undergo reversible photoinduced isomerization in both ethanol solution (free state) and liposomal bilayer (restricted state) upon irradiation with UV and vis light alternately. The drug release of Liposome@Gly induced by isomerization was found to be an instantaneous behavior. The photoinduced control of DOX release from liposome was investigated in various modes. The Liposome@Glys have been found to keep the entrapped DOX stably in the dark with less than 10% leakage in 10 h but release nearly 100% of cargos instantaneously with UV irradiation. The molecular structure of GlyAzoCns and the property of the liposomal bilayer were considered as important factors influencing drug release. Among the synthesized GlyAzoCns, GlyAzoC7 was shown to be the most efficient photosensitive actuator for controlling drug release. A lower proportion of cholesterol in Liposome@Glys was conducive to promote the release amount. Results indicated that the synthesized GlyAzoCns could act as a role of smart actuators in the liposome bilayer and control the drug to release temporarily and quantitatively.

The principal problem in the area of drug delivery is achieving better selectivity and controllability. A new core–shell nanoparticle composite (denoted MSN@Tf@Polymer) with dual-pH-sensitivity has been prepared as a drug carrier for intracellular drug delivery and release. MSN@Tf@Polymer consists of mesoporous silica nanoparticles (MSN), green-transferrin (Tf) and diblock copolymer (poly-2-diisopropylamino ethylmethacrylate-b-methoxy-poly ethyleneglycol: mPEG45-PDPAn). The core–shell structure is self-assembled layer by layer. Results show that nearly 80% doxorubicin hydrochloride (DOX) loaded in MSN@Tf@Polymer could be released in 5 h at pH 5.0, which is an improvement from the results obtained at pH 6.5 and pH 7.4. MTT assay and fluorescence inversion microscope experiments indicate that MSN@Tf is successfully taken up by liver cancer cells (Huh7) without apparent cytotoxicity, and Tf has strong intensity of fluorescence for subcellular localization. Confocal laser scanning microscopy (CLSM) experiments indicate that MSN@Tf@Polymer is able to enter the lysosome of the tumor cells. Furthermore, cell apoptosis experiments prove that DOX loaded in MSN@Tf@Polymer has the best anti-tumor effect compared with free DOX and DOX in bare MSN. MSN@Tf@Polymer has high biocompatibility, enhanced drug loading, site-specific delivery and in situ stimulus release and will also hopefully be applied as an intracellular drug delivery system.

The authors describe biocompatible nanomicelle based drug carriers that can be used for simultaneous (a) fluorescence tracking, (b) pH-controlled release of the cancer drug doxorubicin (DOX), and (c) targeting the folate receptor. The pH-sensitive triblock copolymer is composed of poly-2-(diisopropylamino) ethyl methacrylate and methoxypoly (ethylene glycol) which were prepared by radical polymerization and ‘click’ chemistry. The copolymers undergo self-assembly to form spherical micelles with diameters between 100 and 200 nm and a pH-trigger capability at pH values from 5.8 to 6.2. The micelles enabled DOX to be released at pH 5.0 at a much higher rate than at pH 7.4. Studies on cellular uptake revealed selective internalization of the DOX-loaded nanomicelles into HeLa cells where they can be imaged fluorometrically. Quantitative analysis of the green fluorescence indicated that the FITC-labeled micelles possess a transfection efficiency of about 79% while that of the nanomicellles with folate is only ∼40% under the same conditions. Confocal laser scanning microscopy indicates that the micelles invade the lysosome of HeLa cells and that the DOX released by micelles causes strong cell lethality. In our preception, this work provides useful insights in terms of designing multifunctional drug carriers and of improving the applicability of copolymer micelles for drug delivery systems.

Thermo-sensitive drug carriers are receiving increasing attention for use with localized hyperthermia at abnormal tissue sites or to easily implement hyperthermia. In this study, a thermo-sensitive lipopeptide was designed, consisting of a carbon chain and a leucine zipper with an amino acid sequence CH3-(CH2)4-CO-NH-VAQLEVK-VAQLESK-VSKLESK-VSSLESK-COOH. They could form dimers by the hydrophobic force at body temperature and separate into single random coils above the melting temperature (Tm). The lipopeptide was mixed with phospholipids to form a hybrid liposome (Lipo-LPe). The Tm of the free lipopeptide and lipopeptide in Lipo-LPe was found to be 48.0 °C and 42.5 °C from circular dichroism data, respectively. Compared with the pure liposome, the phase-transition temperature (Ttr) of Lipo-LPe, which was obtained by differential scanning calorimetry, was increased by about 5 °C, showing an improvement of thermal stability. The drug release rate of Lipo-LPe was slightly decreased at body temperature but greatly increased at mild hyperthermia in vitro. Drug release under intermittent heating was performed, and the reversibility of thermo-sensitive on/off switch was confirmed. Furthermore, Lipo-LPe achieved the maximum amount of cell death under mild hyperthermia. We concluded that Lipo-LPe, as a novel thermo-sensitive drug carrier, provides a promising opportunity for controlling drug release.

One important thing in tumor chemotherapy is to develop the targeting, precise timing, and quantitative drug delivery/release system. According to the weak acid of tumor extracellular environment, a pH-sensitive bola-type triblock copolymer (PEGm-PDPAn-PEGm) was synthesized and mixed with phospholipid to form functional hybrid liposomes (liposome@Bola). When compared to pure liposome, the stability of the liposome@Bola was enhanced greatly and the drug leakage was inhibited at pH 7.4. However, under pH 6.0, the drug released quickly through the nanopores on the lipid bilayer created by the escape of copolymers. Under a strongly acidic environment, the drug release of liposome@Bola could be blocked again due to the coverage of free copolymers. The kinetic curves of drug release had been modeled by using some frequently used models. It was found that the release of liposome@Bola under pH 6.0 was biphasic with a slow release by means of membrane permeation and a rapid second phase which was released through nanopores on liposome membrane. The results indicated that the pH-responsive liposome@Bola could be expected to be a good potential in controllable drug delivery system.

Microparticles with a core–shell structure were synthesized from SiO2 particles as core and thermally sensitive hyaluronate–poly(N-isopropylacrylamide) (HA–PNIPAM) hydrogel as shell. The SiO2–HA–PNIPAM microparticles were injectable at room temperature and assembled to settle on to biosurfaces. Dynamic light-scattering measurements at different temperatures showed that the temperature-dependence of the diameters (d) of SiO2–HA–PNIPAM microparticles was reversible. d decreased abruptly when the temperature was increased to their lower critical solution temperature of 307 K. The Mw of HA and the extent of modification by glycidyl methacrylate, Dm, had clear effects on the sizes of the microparticles and their thermal sensitivity. Fluorescein, selected as model drug, was encapsulated in the gel shell to study the dynamics of drug release by this microparticle at body temperature.

1- or 6-Triazologluco- and galactolipid derivatives bearing a lipid chain length of 16 carbons were efficiently constructed via click chemistry. The differentiation in their surface pressure-molecular area (π–A) isotherms first implies that these structurally and configurationally diverse amphiphiles adopt different distribution manner at air–water interfaces. The Langmuir–Blodgett (LB) films of the synthesized glycoconjugates on mica surface were subsequently prepared and visualized via atomic force microscopy (AFM), which exhibited diverse topographies and possess different contact angles with water. These data further suggest that the structural variation as well as epimeric identity of triazologlycolipids may result in their distinct interfacial behaviors at the air–solid interface. Furthermore, the addition of increasing amounts of 1-triazologalactolipid 2 to poly-diacetylene (PDA) was determined to impact the π–A isotherm of the latter, prompting us to further fabricate new colorimetrically detectable mixed-type vesicles containing triazologlycolipids for biochemical studies.

A molecular thermodynamic model was developed for describing the restricted swelling behavior of a thermo-sensitive hydrogel confined in a limited space. The Gibbs free energy includes two contributions, the contribution of mixing of polymer and solvent calculated by using the lattice model of random polymer solution, and the contribution due to the elasticity of polymer network. This model can accurately describe the swelling behavior of restricted hydrogels under uniaxial and biaxial constraints by using two model parameters. One is the interaction energy parameter between polymer network and solvent, and the other is the size parameter depending on the degree of cross-linking. The calculated results show that the swelling ratio reduces significantly and the phase transition temperature decreases slightly as the restricted degree increases, which agree well with the experimental data.A molecular thermodynamic model was developed for describing the restricted swelling behavior of a thermo-sensitive hydrogel confined in a limited space. The calculated results show that the swelling ratio reduces significantly and the phase transition temperature decreases slightly as the restricted degree increases, which agree well with the experimental data.Download full-size image

Thermo-sensitive drug carriers are receiving increasing attention for use with localized hyperthermia at abnormal tissue sites or to easily implement hyperthermia. In this study, a thermo-sensitive lipopeptide was designed, consisting of a carbon chain and a leucine zipper with an amino acid sequence CH3-(CH2)4-CO-NH-VAQLEVK-VAQLESK-VSKLESK-VSSLESK-COOH. They could form dimers by the hydrophobic force at body temperature and separate into single random coils above the melting temperature (Tm). The lipopeptide was mixed with phospholipids to form a hybrid liposome (Lipo-LPe). The Tm of the free lipopeptide and lipopeptide in Lipo-LPe was found to be 48.0 °C and 42.5 °C from circular dichroism data, respectively. Compared with the pure liposome, the phase-transition temperature (Ttr) of Lipo-LPe, which was obtained by differential scanning calorimetry, was increased by about 5 °C, showing an improvement of thermal stability. The drug release rate of Lipo-LPe was slightly decreased at body temperature but greatly increased at mild hyperthermia in vitro. Drug release under intermittent heating was performed, and the reversibility of thermo-sensitive on/off switch was confirmed. Furthermore, Lipo-LPe achieved the maximum amount of cell death under mild hyperthermia. We concluded that Lipo-LPe, as a novel thermo-sensitive drug carrier, provides a promising opportunity for controlling drug release.