PLGA–lecithin–PEG core–shell nanoparticles for controlled drug delivery

Current approaches to encapsulate and deliver therapeutic compounds have focused on developing liposomal and biodegradable polymeric nanoparticles (NPs), resulting in clinically approved therapeutics such as Doxil/Caelyx and Genexol-PM, respectively. Our group recently reported the development of biodegradable core–shell NP systems that combined the beneficial properties of liposomal and polymeric NPs for controlled drug delivery. Herein we report the parameters that alter the biological and physicochemical characteristics, stability, drug release properties and cytotoxicity of these core–shell NPs. We further define scalable processes for the formulation of these NPs in a reproducible manner. These core–shell NPs consist of (i) a poly(d,l-lactide-co-glycolide) hydrophobic core, (ii) a soybean lecithin monolayer, and (iii) a poly(ethylene glycol) shell, and were synthesized by a modified nanoprecipitation method combined with self-assembly. Preparation of the NPs showed that various formulation parameters such as the lipid/polymer mass ratio and lipid/lipid–PEG molar ratio controlled NP physical stability and size. We encapsulated a model chemotherapy drug, docetaxel, in the NPs and showed that the amount of lipid coverage affected its drug release kinetics. Next, we demonstrated a potentially scalable process for the formulation, purification, and storage of NPs. Finally, we tested the cytotoxicity using MTT assays on two model human cell lines, HeLa and HepG2, and demonstrated the biocompatibility of these particles in vitro. Our data suggest that the PLGA–lecithin–PEG core–shell NPs may be a useful new controlled release drug delivery system.     

Fabrication and characterization of monodisperse PLGA–alginate core–shell microspheres with monodisperse size and homogeneous shells for controlled drug release

Monodisperse PLGA–alginate core–shell microspheres with controlled size and homogeneous shells were first fabricated using capillary microfluidic devices for the purpose of controlling drug release kinetics. Sizes of PLGA cores were readily controlled by the geometries of microfluidic devices and the fluid flow rates. PLGA microspheres with sizes ranging from 15 to 50 μm were fabricated to investigate the influence of the core size on the release kinetics. Rifampicin was loaded into both monodisperse PLGA microspheres and PLGA–alginate core–shell microspheres as a model drug for the release kinetics studies. The in vitro release of rifampicin showed that the PLGA core of all sizes exhibited sigmoid release patterns, although smaller PLGA cores had a higher release rate and a shorter lag phase. The shell could modulate the drug release kinetics as a buffer layer and a near-zero-order release pattern was observed when the drug release rate of the PLGA core was high enough. The biocompatibility of PLGA–alginate core–shell microspheres was assessed by MTT assay on L929 mouse fibroblasts cell line and no obvious cytotoxicity was found. This technique provides a convenient method to control the drug release kinetics of the PLGA microsphere by delicately controlling the microstructures. The obtained monodisperse PLGA–alginate core–shell microspheres with monodisperse size and homogeneous shells could be a promising device for controlled drug release.     

Preparation and characterization of OSA/CS core–shell microgel: in vitro drug release and degradation properties

Cationic polymers have been widely used as drug delivery systems. Herein, an oxidized sodium alginate/chitosan (OSA/CS) core–shell microgel was prepared via water-in-oil emulsion method. Morphological properties of the resulting microgel were determined by transmission electron microscopy, hydrodynamic diameter of the microgel was characterized by dynamic light scattering. The objective of this work was to achieve the colon-specific delivery of an antiulcerative colitis drug using a fully nontoxic carrier. 5-aminosalicylic acid (5-ASA) was chosen as a model drug, which is rapidly absorbed before entering the colon, thus it is necessary to develop a colon-specific delivery system for it. The in vitro drug release profile was established in buffer solutions with 0.1?M HCl/NaCl (pH 1.2) and 0.1?M phosphate buffered saline (pH 7.4) at 37?°C. The results indicated that this OSA/CS core–shell microgel inhibited the release of 5-ASA in stomach to a certain extent and is degradable in physiological conditions. Due to the excellent biocompatible nature of CS and OSA, this core–shell microgel has good biocompatibility and may have potential applications in oral controlled drug delivery systems.     

Photostable water-dispersible NIR-emitting CdTe/CdS/ZnS core–shell–shell quantum dots for high-resolution tumor targeting

Near-infrared (NIR, 700–900 nm) fluorescent quantum dots are highly promising as NIR bioprobes for high-resolution and high-sensitivity bioimaging applications. In this article, we present a class of NIR-emitting CdTe/CdS/ZnS core–shell–shell quantum dots (QDs), which are directly prepared in aqueous phase via a facile microwave synthesis. Significantly, the prepared NIR-emitting QDs possess excellent aqueous dispersibility, strong photoluminescence, favorable biocompatibility, robust storage-, chemical-, and photo-stability, and finely tunable emission in the NIR range (700–800 nm). The QDs are readily functionalized with antibodies for use in immunofluorescent bioimaging, yielding highly spectrally and spatially resolved emission for in vitro and in vivo imaging. In comparison to the large size of 15–30 nm of the conventional NIR QDs, the extremely small size (∼4.2 nm or 7.5 nm measured by TEM or DLS, respectively) of our QDs offers great opportunities for high-efficiency and high-sensitivity targeted imaging in cells and animals.     

A magnetic,luminescent and mesoporous core–shell structured composite material as drug carrier

In this paper, hydrothermal synthesized Fe₃O₄ microspheres have been encapsulated with nonporous silica and a further layer of ordered mesoporous silica through a simple sol–gel process. The surface of the outer silica shell was further functionalized by the deposition of YVO₄:Eu³⁺ phosphors, realizing a sandwich structured material with mesoporous, magnetic and luminescent properties. The multifunctional system was used as drug carrier to investigate the storage and release properties using ibuprofen (IBU) as model drug by the surface modification. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectra (XPS), Fourier transform infrared spectroscopy (FT-IR), N₂ adsorption/desorption, photoluminescence (PL) spectra, and superconducting quantum interference device (SQUID) were used to characterized the samples. The results reveal that the material shows typical ordered mesoporous characteristics, and have monodisperse spherical morphology with smooth surface and narrow size distribution. Additionally, the multifunctional system shows the characteristic emission of Eu³⁺ (⁵D₀–⁷F_1–4) even after the loading of drug molecules. Magnetism measurement reveals the superparamagnetic feature of the samples. Drug release test indicates that the multifunctional system shows drug sustained properties. Moreover, the emission intensities of Eu³⁺ in the drug carrier system increase with the released amount of drug, thus making the drug release be easily tracked and monitored by the change of the luminescence intensity.     

Drug co-loading and pH-sensitive release core–shell nanoparticles via layer-by-layer assembly

Multifunctional core–shell nanoparticles are widely used for biomedical and catalytic applications. In this work, bilayers of chitosan (Cs) and phosphorylated polyvinyl alcohol (PPVA) were sequentially deposited on 3-Aminopropyltri-ethoxysilane-modified SiO₂ nanoparticles via layer-by-layer electrostatic self-assembly. The good spherical shape and size distribution were observed by DLS and transmission electron microscope analysis. 7-Hydroxycoumarin (7-HC) and rhodamine B (RhB) as model drugs were loaded in the core and shell of the nanoparticles separately. Confocal laser scanning microscopy shows the core–shell structure of HC-SiO₂(PPVA/Cs)_n-RhB nanoparticles and the embedded location of 7-HC and RhB. The pH-sensitive release investigation of RhB indicates that the release profiles of RhB from HC-SiO₂(PPVA/Cs)₃PPVA-RhB core–shell nanoparticles are totally different at pH values of 2.0, 7.4, and 9.2. These results predict that the multifunctional nanoparticle SiO₂(PPVA/Cs)_n has a great potential for drug delivery.     

Synthesis and characterization of thermoresponsive polyamidoamine–polyethylene glycol–poly(d,l-lactide) core–shell nanoparticles

This work describes the synthesis and characterization of novel thermoresponsive highly branched polyamidoamine–polyethylene glycol–poly(d,l-lactide) (PAMAM–PEG–PDLLA) core–shell nanoparticles. A series of dendritic PEG–PDLLA nanoparticles were synthesized through conjugation of PEG of various chain lengths (1500, 6000 and 12,000 g mol^?1) to polyamidoamine (PAMAM) dendrimer G3.0 and subsequent ring-opening polymerization of DLLA. The ninhydrin assay, ¹H NMR, Fourier transform infrared spectroscopy, dynamic light scattering and atomic force microscopy were used to characterize the structure and compositions of dendritic PEG–PDLLA nanoparticles. The sol–gel phase transition of aqueous dendritic PEG–PDLLA solutions was measured using UV–visual spectroscopy. According to our results dendritic PEG–PDLLA nanoparticles in aqueous solution can self-assemble into sub-micron/micron aggregates, the size of which is dependent on temperature and PEG–PDLLA chain length. Further, dendritic PEG–PDLLA solutions exhibit a sol–gel phase transition with increasing temperature. The constructed dendritic PEG–PDLLA nanoparticles possessed high cytocompatibility, which was significantly improved compared with PAMAM dendrimers. The potential of dendritic PEG–PDLLA nanoparticles for encapsulation of water-insoluble drugs such as camptothecin was demonstrated. The dendritic PEG–PDLLA nanoparticles we developed offer greater structural flexibility and provide a novel nanostructured thermoresponsive carrier for drug delivery.     

Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core–shell nanoparticles

A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core–shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core–shell nanoparticles would be a promising approach for tumor targeted therapy.     

Unibody core–shell smart polymer as a theranostic nanoparticle for drug delivery and MR imaging

Developing novel multifunctional nanoparticles (NPs) with robust preparation, low cost, high stability, and flexible functionalizability is highly desirable. This study provides an innovative platform, termed unibody core–shell (UCS), for this purpose. UCS is comprised of two covalent-bonded polymers differed only by the functional groups at the core and the shell. By conjugating Gd³⁺ at the stable core and encapsulating doxorubicin (Dox) at the shell in a pH-sensitive manner, we developed a theranostic NPs (UCS-Gd-Dox) that achieved a selective drug release (75% difference between pH 7.4 and 5.5) and MR imaging (r₁ = 0.9 and 14.5 mm⁻¹ s⁻¹ at pH 7.4 and 5.5, respectively). The anti-cancer effect of UCS-Gd-Dox is significantly better than free Dox in tumor-bearing mouse models, presumably due to enhanced permeability and retention effect and pH-triggered release. To the best of our knowledge, this is the simplest approach to obtain the theranostic NPs with Gd-conjugation and Dox doping.     

The role of surface chemistry in determining in vivo biodistribution and toxicity of CdSe/ZnS core–shell quantum dots

To examine the effect of surface chemistry and surface charge on in vivo biodistribution and toxicity of CdSe/ZnS core–shell quantum dots (QDs), QDs with positive, negative, or PEG coating are used in this study for in vivo evaluation in a mouse model. The results suggest that QDs coated with cationic polydiallyldimethylammonium chloride (PDDA) preferentially deposit in the lung other than in the liver, while the negative and PEGylated QDs render abundant accumulation in the liver. At higher doses positive QDs with PDDA coating show severe acute toxicity due to pulmonary embolism. Independent of their surface coatings, all QDs cause injuries in specific tissues like liver, spleen, lung, and kidney, after acute and long-term exposure, and the degree of injuries is dominated by their surface properties. For the positively charged QDs, the acute phase toxicity is primarily contributed by the coating material PDDA, while coating on QDs may amplify both in vitro and in vivo toxicity of PDDA. PEGylated QDs display the slightest chronic injuries in the long-term toxicity examination in comparison to positive or negative ones.     

Silk fibroin–polyurethane blends: Physical properties and effect of silk fibroin content on viscoelasticity,biocompatibility and myoblast differentiation

As a way to modify both the physical and biological properties of a highly elastic and degradable polyurethane (PU), silk fibroin (SF) was blended with the PU at differing ratios. With increasing SF content, the tensile strength decreased as did the strain at break; the stiffness increased to around 35 MPa for the highest silk content. C2C12 (a mouse myoblast cell line) cells were used for in vitro experiments and showed significantly improved cell responses with increasing SF content. With increasing SF content the number of non-adherent cells was reduced at both 4 and 8 h compared to the sample with the lowest SF content. In addition, muscle marker genes were upregulated compared to the sample containing no SF, and in particular sarcomeric actin and α-actin.     

Multilayered, core/shell nanoprobes based on magnetic ferric oxide particles and quantum dots for multimodality imaging of breast cancer tumors

Multilayered, core/shell nanoprobes (MQQ-probe) based on magnetic nanoparticles (MNPs) and quantum dots (QDs) have been successfully developed for multimodality tumor imaging. This MQQ-probe contains Fe(3)O(4) MNPs, visible-fluorescent QDs (600?nm emission) and near infrared-fluorescent QDs (780?nm emission) in multiple silica layers. The fabrication of the MQQ-probe involves the synthesis of a primer Fe(3)O(4) MNPs/SiO(2) core by a reverse microemulsion method. The MQQ-probe can be used both as a fluorescent probe and a contrast reagent of magnetic resonance imaging. For breast cancer tumor imaging, anti-HER2 (human epidermal growth factor receptor 2) antibody was conjugated to the surface of the MQQ-probe. The specific binding of the antibody conjugated MQQ-probe to the surface of human breast cancer cells (KPL-4) was confirmed by fluorescence microscopy and fluorescence-activated cell sorting analysis in?vitro. Due to the high tissue permeability of near-infrared (NIR) light, NIR fluorescence imaging of the tumor mice (KPL-4 cells transplanted) was conducted by using the anti-HER2 antibody conjugated MQQ-probe. In?vivo multimodality images of breast tumors were successfully taken by NIR fluorescence and T(2)-weighted magnetic resonance. Antibody conjugated MQQ-probes have great potential to use for multimodality imaging of cancer tumors in?vitro and in?vivo.     

Gene × Environment interaction and resilience: effects of child maltreatment and serotonin, corticotropin releasing hormone, dopamine, and oxytocin genes

In this investigation, gene-environment interaction effects in predicting resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 595) were examined. A multicomponent index of resilient functioning was derived and levels of resilient functioning were identified. Variants in four genes (serotonin transporter linked polymorphic region, corticotropin releasing hormone receptor 1, dopamine receptor D4-521C/T, and oxytocin receptor) were investigated. In a series of analyses of covariance, child maltreatment demonstrated a strong negative main effect on children's resilient functioning, whereas no main effects for any of the genotypes of the respective genes were found. However, gene-environment interactions involving genotypes of each of the respective genes and maltreatment status were obtained. For each respective gene, among children with a specific genotype, the relative advantage in resilient functioning of nonmaltreated compared to maltreated children was stronger than was the case for nonmaltreated and maltreated children with other genotypes of the respective gene. Across the four genes, a composite of the genotypes that more strongly differentiated resilient functioning between nonmaltreated and maltreated children provided further evidence of genetic variations influencing resilient functioning in nonmaltreated children, whereas genetic variation had a negligible effect on promoting resilience among maltreated children. Additional effects were observed for children based on the number of subtypes of maltreatment children experienced, as well as for abuse and neglect subgroups. Finally, maltreated and nonmaltreated children with high levels of resilience differed in their average number of differentiating genotypes. These results suggest that differential resilient outcomes are based on the interaction between genes and developmental experiences.     

α-Tricalcium phosphate: synthesis, properties and biomedical applications

Nowadays, α-tricalcium phosphate (α-TCP, α-Ca₃(PO₄)₂) is receiving growing attention as a raw material for several injectable hydraulic bone cements, biodegradable bioceramics and composites for bone repair. In the phase equilibrium diagram of the CaO–P₂O₅ system, three polymorphs corresponding to the composition Ca₃(PO₄)₂ are recognized: β-TCP, α-TCP and α′-TCP. α-TCP is formed by heating the low-temperature polymorph β-TCP or by thermal crystallization of amorphous precursors with the proper composition above the transformation temperature. The α-TCP phase may be retained at room temperature in a metastable state, and its range of stability is strongly influenced by ionic substitutions. It is as biocompatible as β-TCP, but more soluble, and hydrolyses rapidly to calcium-deficient hydroxyapatite, which makes α-TCP a useful component for preparing self-setting osteotransductive bone cements and biodegradable bioceramics and composites for bone repairing. The literature published on the synthesis and properties of α-TCP is sometimes contradictory, and therefore this article focuses on reviewing and critically discussing the synthetic methods and physicochemical and biological properties of α-TCP-based biomaterials (excluding α-TCP-based bone cements).     

In situ doxorubicin–CaP shell formation on amphiphilic gelatin–iron oxide core as a multifunctional drug delivery system with improved cytocompatibility,pH-responsive drug release and MR imaging

An amphiphilic gelatin–iron oxide core/calcium phosphate shell (AGIO@CaP-DOX) nanoparticle was successfully synthesized as an efficient anti-cancer drug delivery system, where doxorubicin (DOX) as a model molecule was encapsulated by electrolytic co-deposition during CaP shell formation. The shell of CaP precipitate played a pivotal role, not only in acting as a drug depot, but also in rendering the drug release rate in a highly pH-dependent controlled manner. Together with MR imaging, highly biocompatible drug-carrying CaP shell and efficient cellular internalization, the AGIO@CaP-DOX nanoparticles developed in this study area promising multifunctional nanodevice for nanotherapeutic approaches.     

Fabrication, Characterization and In Vitro Evaluation of Aligned PLGA–PCL Nanofibers for Neural Regeneration

Electrospun nanofibrous scaffolds have received a great deal of attention in tissue engineering in recent years. Bridging larger nerve gaps between proximal and distal ends requires exogenous tubular constructs with uniaxially aligned topographical cues to promote the axonal re-growth due to the lack of fibrin cable formation. In this study, we have designed and developed a collector to obtain aligned nanofibers of PLGA-PCL. The average diameter of the fibers obtained is 230?±?63?nm and the alignment of fibers is quantified by calculating relative angle of each fiber. The tensile strength, porosity, contact angle, and biodegradation of the uniaxial PLGA-PCL nanofibers are measured and compared with the corresponding random fibers. Pore size, Young's modulus, and degradation of the aligned scaffold are significantly lesser than random fibers (p?相似文献   

Poly(ethylene glycol)-poly(lactic-co-glycolic acid) core–shell microspheres with enhanced controllability of drug encapsulation and release rate

Poly(lactic-co-glycolic acid) (PLGA) microspheres have been widely used as drug carriers for minimally invasive, local, and sustained drug delivery. However, their use is often plagued by limited controllability of encapsulation efficiency, initial burst, and release rate of drug molecules, which cause unsatisfactory outcomes and several side effects including inflammation. This study presents a new strategy of tuning the encapsulation efficiency and the release rate of protein drugs from a PLGA microsphere by filling the hollow core of the microsphere with poly(ethylene glycol) (PEG) hydrogels of varying cross-linking density. The PEG gel cores were prepared by inducing in situ cross-linking reactions of PEG monoacrylate solution within the PLGA microspheres. The resulting PEG-PLGA core–shell microspheres exhibited (1) increased encapsulation efficiency, (2) decreased initial burst, and (3) a more sustained release of protein drugs, as the cross-linking density of the PEG gel core was increased. In addition, implantation of PEG-PLGA core–shell microspheres encapsulated with vascular endothelial growth factor (VEGF) onto a chicken chorioallantoic membrane resulted in a significant increase in the number of new blood vessels at an implantation site, while minimizing inflammation. Overall, this strategy of introducing PEG gel into PLGA microspheres will be highly useful in tuning release rates and ultimately in improving the therapeutic efficacy of a wide array of protein drugs.