Micelle-like Nanoparticles Research Articles

Self-assembling micelle-like nanoparticles based on phospholipid–polyethyleneimine conjugates for systemic gene delivery

With few exceptions, where local administration is feasible, progress towards broad clinical application of gene therapies requires the development of effective delivery systems. Here we report a novel non-viral gene delivery vector, ‘micelle-like nanoparticle’ (MNP) suitable for systemic application. MNP were engineered by condensing plasmid DNA with a chemical conjugate of phospholipid with polyethylenimine (PLPEI) and then coating the complexes with an envelope of lipid monolayer additionally containing polyethylene glycol–phosphatidyl ethanolamine (PEG–PE), resulting in spherical ‘hard-core’ nanoparticles loaded with DNA. MNP allowed for complete protection of the loaded DNA from enzymatic degradation, resistance to salt-induced aggregation, and reduced cytotoxicity. MNP also demonstrated prolonged blood circulation and low RES accumulation. Intravenous injection of MNP loaded with plasmid DNA encoding for the Green Fluorescence Protein (GFP) resulted in an effective transfection of a distal tumor. Thus, MNP provide a promising tool for systemic gene therapy.

Methoxy poly(ethylene glycol)- b-poly(valerolactone) diblock polymeric micelles for enhanced encapsulation and protection of camptothecin

Amphiphilic block copolymers, methoxy poly(ethylene glycol)- b-poly(valerolactone) (mPEG- b-PVL), were synthesized via ring opening polymerization of δ-valerolactone in the presence of methoxy poly(ethylene glycol) (mPEG). The copolymers form micelle-like nanoparticles by their amphiphilic characteristics and their structures were examined by Nuclear Magnetic Resonance (NMR). The sizes of nanoparticles ranged from 60 to 120 nm as measured by dynamic light scattering detection, and were larger with higher molecular weight of the copolymers. The Critical Micelle Concentration (CMC) of these nanoparticles in water decreased with increasing molecular weight of hydrophobic segment. Stability analysis showed that the micellar solutions maintain their sizes at 37 °C for six weeks without aggregation or dissociation. The lyophilization method was better than the evaporation method when camptothecin (CPT) was incorporated to the micelles. The former method yielded higher CPT loading efficiency and lower aggregation. The loading efficiency of CPT could be more than 96% and a steady release rate of CPT was kept for twenty six days. Moreover, the mPEG- b-PVL polymeric micelles offered good protection of CPT lactone form at 37 °C for sixteen days. The copolymers showed no cytotoxicity towards L929 mouse muscular cells when incubated for one day. Taken together, the mPEG- b-PVL copolymer has potential to be used for the delivery of CPT or other similar drugs.

PREPARATION AND MORPHOLOGIES OF MICELLE-LIKE AGGREGATES BASED ON DENDRITIC POLY(ETHER-AMIDE)

采用e-己内酯（CL）开环聚合的方法首先合成树枝状聚（醚-酰胺）基（DPEA）星形聚合物star-PCL,再与异氰酸基封端的PEG（PEG-NCO）偶合制备了两亲性树枝状聚（醚-酰胺）基星形嵌段聚合物star-PCL-b-PEG.利用FT-IR、^1H-NMR和GPC分析测试手段对star-PCL-b-PEG的结构进行了表征.通过滴加选择性溶剂的方法,制备了star-PCL-b-PEG以水为介质的类似“平头”聚集体胶束溶液.采用荧光光谱法测得star-PCL-b-PEG水溶液的临界胶束浓度（CMC）为1.623mg/L;采用激光光散射仪测得其在浓度0.15mg/mL和0.5mg/mL的流体力学半径分别为86.2nm和224.6nm,其多分散指数分别为0.115和0.197.透射电镜（TEM）观察发现胶束的形貌受共溶剂的特性,初始聚合物浓度,水含量等因素的影响.

Camptothecin-incorporating N-phthaloylchitosan-g-mPEG self-assembly micellar system: Effect of degree of deacetylation

Amphiphilic grafted copolymers, N-phthaloylchitosan-grafted poly (ethylene glycol) methyl ether (PLC-g-mPEG), were synthesized from chitosan with different degree of deacetylation (DD = 80%, 85%, 90% and 95%). Due to their amphiphilic characteristic, these copolymers could form micelle-like nanoparticles. The critical micelle concentration (CMC) of these nanoparticles with different DD in water was similar (28 μg/ml). Under transmission electron microscope (TEM), the nanoparticles exhibited a regular spherical shape with core–shell structure. The particle sizes determined by dynamic light scattering were in the range of 100–250 nm, and increased as the %DD of chitosan increased. The cytotoxicity of phthaloylchitosans (PLC) and PLC-g-mPEG in Hela cells line were evaluated. The results showed that cytotoxicity of PLC and PLC-g-mPEG increased with increasing %DD of chitosan. The cytotoxicity of PLC-g-mPEG was significantly lower than that of PLC. Camptothecin as a model drug was loaded into the inner core of the micelles by dialysis method. It was found that %DD of chitosan, corresponding to the N-phthaloyl groups in the inner core of the nanoparticle obtained, was a key factor in controlling %yield, stability of the drug-loaded micelles, and drug release behavior. As the %DD increased, the CPT-loaded micelles stability increased. Release of CPT from the micelles was dependent on the %DD and a sustained release was obtained in high %DD.

Micelle-like nanoparticles of star-branched PEO–PLA copolymers as chemotherapeutic carrier

Four-armed (star-branched) block copolymers of l-PLA and PEO were synthesized using ring opening polymerization with different LA / EO ratio. Micellar aggregates were prepared from these block copolymers and characterized. Some surface segregation of PEG was found : the extent depends on the state of the material (whether it is in film or particle form), as well as on molecular geometry. The degradation behavior of star-shaped copolymer was studied over a three week period and compared to its linear counterpart. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanoparticles. The drug release profile showed that the release of paclitaxel from these polymers could be controlled over 2 weeks. The kinetics of drug release for star-branched, tri- and di-block copolymers were compared. The micelles from star-shaped branch showed more complete release of drug than the diblock copolymers; also, the lower hydrodynamic radius of star-shaped polymers may result in better clearance of the carrier polymer from the body.

Micelle-like nanoparticles of PLA–PEG–PLA triblock copolymer as chemotherapeutic carrier

Triblock copolymer PLA–PEG–PLA were synthesized using ring opening polymerization with different LA/EG ratio. Micellar aggregates were prepared from these block copolymers and characterized. The degradation characteristics of selected copolymers were assessed in both micellar and film forms. Surface segregation of PEG was also quantified as a function of copolymer composition. Anti-cancer drugs 5-FU and paclitaxel were loaded into the micellar nanospheres with good efficiency. The drug release profile showed good control over the release of paclitaxel from these polymers.

Preparation and drug release behaviors of nimodipine-loaded poly(caprolactone)–poly(ethylene oxide)–polylactide amphiphilic copolymer nanoparticles

Amphiphilic block copolymers, poly(caprolactone)–poly(ethylene glycol)–poly(lactide) (PCELA), were synthesized by ring opening polymerization of caprolactone and lactide initiated with the hydroxyl groups of poly(ethylene glycol) (PEG). These copolymers could form micelle-like nanoparticles due to their amphiphilic characteristic. From the observation of transmission electron microscopy (TEM), the nanoparticles exhibited a regular spherical shape with core-shell structure. The critical micelle concentrations (CMC) of these nanoparticles in water were decreased as molecular weight of PEG decreased. The particle sizes obtained by dynamic light scattering of these nanoparticles were in the range of 100–200 nm, and increased as the hydrophobic property of the nanoparticles increased. Nimodipine as a model drug was loaded in these nanoparticles to investigate the drug release behavior. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticle size, nanoparticle yields, drug-entrapment efficiency, and drug release behavior. When the PEG content is about 2% (wt), the release profile of PCELA nanoparticles appeared to follow zero-order kinetics.

Macrocyclic glycoclusters. Self-aggregation and phosphate-induced agglutination behaviors of calix[4]resorcarene-based quadruple-chain amphiphiles with a huge oligosaccharide pool.

Macrocyclic glycocluster compounds 2n (n = 2-7) with four alkyl (undecyl) chains and eight oligosaccharide moieties on the opposite sides of the calix[4]resorcarene macrocycle are prepared from the reactions of the corresponding octaamine derivative with maltooligosaccharide lactones. Combined evidence from dynamic light scattering (DLS), gel permeation chromatography (GPC), and transmission electron microscopy (TEM) indicates that they form small micelle-like nanoparticles (d congruent with 3 nm) in water. In the presence of Na2HPO4/NaH2PO4, nanoparticles are agglutinated with phosphate ions as a glue to grow in size up to 60-100 nm, as revealed by DLS as well as microscopy (TEM and AFM). The phosphate-induced agglutination processes can be followed by surface plasmon resonance (SPR). Amphiphile 2n is readily immobilized on the hydrophobized sensor chip of SPR to give a closely packed monolayer with oligosaccharide moieties exposed to bulk water. While there is no further adsorption of 2n on the resulting monolayer, this does occur when the latter is pretreated with the phosphate salts, ultimately giving rise to a multilayer upon repeated treatment of the chip with 2n and Na2HPO4/NaH2PO4 in an alternate manner. Kinetic analyses show that the phosphate-mediated inter(saccharide) interactions in terms of rate and affinity are markedly dependent on the oligosaccharide chain lengths (n), becoming more favorable with increasing n's. The novel aggregation and agglutination behaviors observed are discussed in terms of immobilizable and irreversible micelles on the basis of the cone-shaped structure of quadruple-chain amphiphile 2n having a huge saccharide pool and the efficiency of multiple hydrogen bonding therein. The unique intermolecular binding properties of compound 22 and analogues so far reported are reviewed in light of the present finding.

A Novel Polyelectrolyte with Branched Azo Side Chains: Synthesis, Characterization and Self-Assembled Nanostructures

A novel polyelectrolyte (PEAPB 6 P-AA) functionalized with branched azo side chains has been synthesized. Aggregation of the azo chromophores of PEAPB 6 P-AA in H 2 O/tetrahydrofuran (THF) mixed solvent was detected from its influences on UV-vis spectra and photoresponsive behavior. Micelle-like nanoparticles were found when the concentration of PEAPB 6 P-AA increased to above 0.2 mmol . L -1 in the mixed solvent (THF/H 2 O = 1:20 vol.-%). Multilayers of the micelle-like nanoparticles and poly(diallyldimethylammonium chloride) (PDAC) were fabricated by an electrostatic layer-by-layer self-assembly process. Particularly high wettability of the multilayer surfaces was observed, which affirmed the self-assembled micelle-like structure of the particles.