Nano-engineering block copolymer aggregates for drug delivery

This review describes the properties of block copolymer micelles which influence their efficiency as drug delivery vehicles for hydrophobic drugs. The key performance related properties we discuss are loading capacity, release kinetics, circulation time, biodistribution, size, size distribution and stability. Each of the properties is discussed in detail with specific attention given to the way in which they may be changed or controlled, the aim being to allow the reader to tailor-make block copolymer micelles for a particular application. In addition, the last section of the review focuses on the morphology of the micelles as another performance related property which, to this point, remains unexplored in this connection.     

Fluorescent conjugated block copolymer nanoparticles by controlled mixing

Monitoring of the formation of stable fluorescent nanoparticles from controlled mixing of a THF solution of poly(fluorene ethynylene)-block-poly(ethylene glycol) in a microfluidic laminar flow crossjunction by spatially resolved fluorescence spectroscopy reveals the time scale of particle formation as well as incorporation of small molecule guests and the role of solvent mixing.     

Recent advances in stimuli-responsive degradable block copolymer micelles: synthesis and controlled drug delivery applications

(Bio)degradation in response to external stimuli (stimuli-responsive degradation, SRD) is a desired property in constructing novel nanostructured materials. For polymer-based multifunctional drug delivery applications, the degradation enables fast and controlled release of encapsulated therapeutic drugs from delivery vehicles in targeted cells. It also ensures the clearance of the empty device after drugs are delivered to the body. This review summarizes recent development of various strategies to the design and synthesis of self-assembled micellar aggregates based on novel amphiphilic block copolymers having different numbers of stimuli-responsive cleavable elements at various locations. These cleavable linkages including disulfide, acid-labile, and photo-cleavable linkages are incorporated into micelles, and then are cleaved in response to cellular triggers such as reductive reaction, light, and low acid. The well-designed SRD micelles have been explored as controlled/enhanced delivery vehicles of drugs and genes. For future design and development of effective stimuli-responsive degradable micelles toward tumor-targeting delivery applications in vivo, a high degree of control over degradation for tunable release of encapsulated anticancer drugs as well as bioconjugation for active tumor-targeting is required.     

pH/Temperature-responsive behavior of amphiphilic block copolymer micelles prepared using two different methods

The pH- and temperature-responsive behavior of amphiphilic block copolymer poly(L-lactide)-b-poly(2-(dimethylamino)ethyl methacrylate) (PLLA-b-PDMAEMA) in aqueous solutions is investigated using static and dynamic light scattering. Electrostatic force, hydrophobic interaction, and hydrogen bonding coexist in the system. Micelles with different structures are prepared using water addition (WA) and direct dissolution (DD) methods. The aggregation from loose micelles into large micellar clusters is observed above the transition temperature under basic conditions. Only micellar clusters from the DD method could disaggregate when temperature was decreased to 24.3 °C after heating. The behavior of the micelles prepared with the DD method indicates that only the outer parts of the PLLA-b-PDMAEMA chains in the corona are solvated.     

Effect of hydrophobicity inside PEO-PPO-PEO block copolymer micelles on the stabilization of gold nanoparticles: experiments

In this paper we present the effect of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer micelles and their hydrophobicity on the stabilization of gold nanoparticles. Gold nanoparticles were prepared by a method developed by Sakai et al. (Sakai, T.; Alexandridis, P. Langmuir 2004, 20, 8426). An absorption centered at 300-400 nm in time-dependent UV spectra provided evidence that the very first step of the synthesis was to form primary gold clusters. Then the gold clusters grew in size and were stabilized by block copolymer micelles. The stabilization capacities of the micelles were modulated by tuning the block copolymer concentration and composition and by adding salts. With good stabilization, gold particles were spherical and uniform in size with a diameter of 5-10 nm. Otherwise they were aggregates with irregular shapes such as triangular, hexagonal, and rodlike. The presence of a small amount of NaF significantly increased the stabilization capacity of the micelles and consequently modified the quality of the gold particles. Using FTIR and 1H NMR spectroscopy, micellization of the block copolymers and hydrophobicity of the micelles were proven very important for the stabilization. A higher hydrophobicity of the micelle cores was expected to favor the entrapment of primary gold clusters and the stabilization of gold nanoparticles.     

Aggregation behavior of star-like PEO-PPO-PEO block copolymer in aqueous solution

The aggregation behavior of a star-like amphiphilic block copolymer (denoted as AP432, which was synthesized via anionic polymerization), in aqueous solutions was investigated by surface tension, steady-state fluorescence, dynamic light scattering (DLS) and transmission electron microscopy (TEM). For comparison, a commercially available linear amphiphilic PEO-PPO-PEO block copolymer, Pluronics L64, which has a similar PEO fraction to AP432, was also studied. It is found that the different molecular structure of AP432 and L64 leads to a significant difference on their behavior both at the air/water interface and in bulk aqueous solutions. The results of surface tension measurements indicate that the surface activity of AP432 is much more pronounced than that of L64. The formation of AP432 and L64 aggregates are identified by DLS, fluorescence and TEM measurement.     

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined p H-responsive poly(ε-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers(PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization(ATRP),ring opening polymerization(ROP) and "click" chemistry.Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy(FTIR),proton nuclear magnetic resonance(1H-NMR),and gel permeation chromatography(GPC).Then,the polymers could selfassemble into micelles in aqueous solution,which was demonstrated by dynamic light scattering(DLS) and transmission electron microscopy(TEM).The p H-responsive self-assembly behavior of these copolymers in water was investigated at different p H values of 7.4 and 5.0 for controlled doxorubicin(DOX) release,and these results revealed that the release rate of DOX could be effectively controlled by altering the p H,and the release of drug loading efficiency(DLE) was up to 88%(W/W).CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility,whereas the DOX-loaded micelles remained with high cytotoxicity for He La cells.Moreover,confocal laser scanning microscopy(CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect.The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX.These results successfully indicated that p H-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.     

Phosphocreatine immobilization of the surface of silica and magnetite nanoparticles for targeted drug delivery

Russian Chemical Bulletin - A method is proposed for immobilization of anti-ischemic drug phosphocreatine on the surface of aminated silica and magnetite nanoparticles of similar size and shape....     

Structural characterization of novel phospholipid lipid nanoparticles for controlled drug delivery

Drug-phospholipid lipid nanoparticles (DPLNs) are prepared by incorporating drug-phospholipid complexes (DPCs) with a liquid lipid. DPLNs demonstrated interesting properties including increased encapsulation capacity, improved stability and controlled drug release profile. A comprehensive characterization of DPLNs was presented and then a schematic model was suggested according to the characterization results. Transmission electron microscopy and scanning electron microscope measurements showed the morphology of DPLNs. X-ray diffraction exhibited a predominantly amorphous structure for DPCs and totally amorphous for DPLNs. Laser confocal scanning microscopy revealed the relative position of DPCs and liquid lipid, showing that DPLNs formed a homogeneous system. Fluorescence spectra and electron spin resonance further confirmed the chemical environment inside the DPLNs in a non-invasive way.     

Acrylic acid copolymer nanoparticles for drug delivery: structural characterization of nanoparticles by small-angle x-ray scattering

Nanoparticles are possible carriers for drug delivery. Copolymer nanoparticles of acrylic acid, acrylic amide, acrylic butylester, and methacrylic methylester (CAA) dispersed in water and in 0.15 M NaCl-solution were investigated by small-angle x-ray scattering (SAXS) experiments. The particles were characterized in terms of parameters relevant for the in vivo distribution: particle shape and diameter, size distribution, surface structure, and their organization within tight systems.The CAA-nanoparticles exist in at least three populations of spheres with two minor subpopulations having radii of about 32 and 66 nm and the main moiety around 45 nm. The degree of polydispersity isR _w/R _N=1.05. The subpopulations possess different hydrophobic areas on their surfaces, leading to different recognition by opsonins in vivo and different organ distribution and clearance velocity. The particles are compact without channels and holes, which is proved by low internal hydrationw=0.22 g H₂O/g polymer. Drugs and coating surfactants will interact mainly with the outer surface and not tunnel into the carriers. The surface of the nanoparticles is fractal with a dimensionD=2.3. Probe-molecules with dimensions less than 11.4 nm in diameter will find a larger contact area than expected from the sphere radius. Adsorption rate and position of the arrival of surfactants, and possibly opsonins, may be affected thereby. The negative charges on the CAA-nanoparticle surface are nearly completely screened in physiological NaCl-solutions by counter-ions. Therefore, surface charges hamper carrier-cell interaction at short distances only and do not prevent specific recognition and clearance by the reticuloendothelial system (RES).     

Dual-responsive controlled drug delivery based on ionically assembled nanoparticles

Ionically assembled nanoparticles (INPs) have been formed from poly(ionic liquid-co-N-isopropylacrylamide) with deoxycholic acid through electrostatic interaction. The structure and properties of the INPs were investigated by using (1)H NMR, Fourier transform infrared (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS), and so on. Due to pH-responsive deoxycholic acid (pK(a) = 6.2) and thermo responsive N-isopropylacrylamide included in the ionic complex, the INPs exhibit highly pH and thermal dual-responsive properties. The potential practical applications as drug delivery carriers were demonstrated using doxorubicin (DOX) as a model drug. With a lower pH (pH 5.2) and higher temperature (above 37 °C), structural collapse of the INPs occurred as well as release of DOX owing to protonated DA departure from the INPs and a lower LCST (lower critical solution temperature) at the pathological conditions. The result shows that 80% of DOX molecules were released from INPs within 48 h at pH 5.2, 43 °C, but only 30% of the drug was released within 48 h at 37 °C and pH 7.4. Moreover, drug-loaded INPs exhibit an inhibitory effect on cell growth.     

Hydrothermal synthesis of ZnO nanobundles controlled by PEO-PPO-PEO block copolymers

Homocentric ZnO nanobundles with pyramidlike and hexagonal prism shapes were synthesized in colloidal systems formed by PEO-PPO-PEO amphiphilic block copolymers. The prism- and pyramidlike ZnO crystals were produced by L64 and F68, respectively, which may be attributed to the different growth rates of various crystal facets. It was proposed that the two processes for crystallization, including nucleation and crystal growth, happened in the macromolecular micelles under hydrothermal conditions. The room-temperature photoluminescence spectra of the ZnO products showed sharp ultraviolet emission located around 390 nm originating from the radiative recombination of free excitons. The sharp emission, with a half-maximum of about 8 nm, gave a powerful attestation that the sample was of high crystal quality, which was consistent with the SEM and TEM observations. The single ultraviolet emission is important for the application of ZnO-based materials in the electronic and photonic realms.     

in vitro biological evaluation of folate-functionalized block copolymer micelles for selective anti-cancer drug delivery

The main objective of this study was to evaluate the ability of folic acid-functionalized diblock copolymer micelles to improve the delivery and uptake of two poorly water-soluble anti-tumor drugs, tamoxifen and paclitaxel, to cancer cells through folate receptor targeting. The diblock copolymer used in this study comprised a hydrophilic poly[2-(methacryloyloxy)ethyl phosphorylcholine] (MPC) block, carrying at the chain end the folate targeting moiety, and a pH-sensitive hydrophobic poly[2-(diisopropylamino)ethyl methacrylate] (DPA) block (FA-MPC-DPA). The drug-loading capacities of tamoxifen- and paclitaxel-loaded micelles were determined by high performance liquid chromatography and the micelle dimensions were determined by dynamic light scattering and transmission electron microscopy. Cell viability studies were carried out on human chronic myelogenous leukaemia (K-562) and colon carcinoma cell lines (Caco-2) in order to demonstrate that drug-loaded FA-MPC-DPA micelles exhibited higher cytotoxicities toward cancer cells than unfunctionalized MPC-DPA micelles. Uptake studies confirmed that folate-conjugated micelles led to increased drug uptake within cancer cells, demonstrating the expected selectivity toward these tumor cells.     

Mixed Co/Fe oxide nanoparticles in block copolymer micelles

Small iron oxide and Co-doped iron oxide nanoparticles (NPs) were synthesized in a commercial amphiphilic block copolymer, poly(ethylene oxide)-b-poly(methacrylic acid) (PEO 68-b-PMAA8), in aqueous solutions. The structure and composition of the micelles containing guest molecules (metal salts) or NPs (metal oxides) were studied using transmission electron microscopy, dynamic light scattering, X-ray photoelectron spectroscopy, and X-ray powder diffraction. The enlarged micelle cores after incorporation of metal salts are believed to be formed by both PMAA blocks containing metal species and penetrating PEO chains. The nanoparticle size distributions in PEO 68-b-PMAA8 were determined using small-angle X-ray scattering (SAXS) in bulk. Two independent methods for SAXS data interpretation for comprehensive analysis of volume distributions of metal oxide NPs showed presence of both small particles and larger entities containing metal species which are ascribed to organization of block copolymer micelles in bulk. The magnetometry measurements revealed that the NPs are superparamagnetic and their characteristics depend on the method of the NP synthesis. The important advantage of the PEO 68-b-PMAA8 stabilized magnetic nanoparticles described in this paper is their remarkable solubility and stability in water and buffers.     

Study on surfactant coating of polymeric nanoparticles for controlled delivery of anticancer drug

Biodegradable nanoparticles loaded with anticancer drug paclitaxel and appropriately coated with polyvinyl alcohol (PVA), polyethylene glycol (PEG) as well as d--tocopheryl polyethylene glycol 1000 succinate (TPGS) were produced and characterised by various analysis techniques such as laser light scattering (LLS) for particle size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for particle morphology, X-ray photoelectron spectroscopy (XPS) and Fourier Transform Infrared-Photoacoustic Spectroscopy (FTIR-PAS) for surface chemistry, and high performance liquid chromatography (HPLC) for drug encapsulation efficiency (EE) and in vitro release kinetics. The emphasis was given to the possible effects of surface coating on the physicochemical and pharmaceutical properties of paclitaxel loaded nanoparticles. It was found that the type and amount of the surfactant could significantly affect the drug EE in the nanoparticles, the particles characteristics and their in vitro release behaviour. The surfactants dominated on the nanoparticles surface and the coated nanoparticles displayed in spherical shape with relative smooth surface within the resolution scope of the equipment. The particle size and size distribution showed close relation to the surface coating, which may also be responsible for the drug encapsulation efficiency and the in vitro release kinetics. A favourable formulation of drug loaded nanoparticles of desired properties could be obtained by optimising the fabrication parameters.     

Redox-responsive polymer prodrug/AgNPs hybrid nanoparticles for drug delivery

The redox-responsive hybrid nanoparticles of P(MACPTS-co-MAGP)@AgNPs is developed for drug delivery and fluorescence monitoring of the drug release by applying the NSET-based strategy.     

Chitosan/cyclodextrin nanoparticles as drug delivery system

One of the most attractive areas of research in drug delivery is the design of nanomedicines consisting of nanosystems that are able to deliver drugs to the right place, at appropriate time. Natural polysaccharides, due to their outstanding merits, have received more and more attention in the field of drug delivery systems. In particular, polysaccharides seem to be the most promising materials in the preparation of nanometric carriers. The main goal of the present study was to investigate the potential of a recent generation of hybrid polysaccharide nanocarriers, composed of chitosan (CS) and an anionic cyclodextrin, carboxymethyl-β-cyclodextrin (CM-β-CD), for the encapsulation of a model drug, sulindac. CS and CM-β-CD were processed to nanoparticles (NPs) via the ionotropic gelation technique. The stoichiometric ratio between these two polymers was found to influence particle size and zeta potential. Decreasing CS:CM-β-CD ratio led to an increase in particle size and decrease in zeta potential. DSC and FTIR analyses confirmed formation of NPs and encapsulation of sulindac inside them. Release profiles indicate a continuous release of the drug throughout 24?h. However, the rate of release was more rapid during the first hours; about 55–90% of the drug being released after 3?h.     

The effects of irradiation on controlled drug delivery/controlled drug release systems

The research of radiation effects on drugs over the past 60 years has mainly dealt with radiation sterilization of individual active pharmaceutical ingredients (APIs) in the form of pure substances or injectable solutions. However, the emergence of novel systems for drug administration and targeting via controlled drug delivery (CDD) and/or controlled drug release (CDR) has extended the use of irradiation with respect to pharmaceuticals: the capacity of radiation to act as an initiator of crosslinking has been used in the manufacturing and modification of a number of polymeric carriers with an added advantage of reducing the microbial load of products at the same time. The application of irradiation to these novel systems requires the understanding of radiation action not only on APIs alone but also on drug carriers and on the functioning of the integral CDD/CDR systems. In this paper, the significance of CDD/CDR systems is considered with a special emphasis on the role of irradiation for sterilization and crosslinking in the developments over the past 15 years. Radiation sterilization, crosslinking and degradation of the principal forms of drug carrier systems and the effects of irradiation on the release kinetics of APIs are discussed in light of radiation chemical principles. Regulatory aspects pertaining to radiation sterilization of drugs are also considered. Relevant results are summarized in tabular form.