Cocrystallization-like strategy for the codelivery of hydrophobic and hydrophilic drugs in a single carrier material formulation

Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer. However, traditional drug carriers are typically characterized by low drug payload, limiting their treatment efficacy. Using nanocrystals of insoluble drug as carriers, a carrier free platform was developed previously to deliver a second insoluble drug for codelivery. To extend the concept, we hypothesized, herein, that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy. To obtain proof-of-concept, paclitaxel (PTX), an insoluble chemotherapeutic agent, and dichloroacetic acid (DCA), a water-soluble inhibitor of pyruvate dehydrogenase kinase, were utilized as model drugs. PTX-DCA hybrid nanocrystals (PTX-DCA NCs) were prepared by anti-solvent precipitation and characterized. Their in vitro antitumor activity against cancer cells was evaluated. PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rod-shape morphology and possessed encapsulated efficacy of approximately 30% for DCA. The use of the hybrid crystals enabled synergy to kill cancer cells, in particular in PTX-resistant cells in a dose-dependent pattern. In conclusion, by using a cocrystalization-like strategy, a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.     

Strategic approaches for improving entrapment of hydrophilic peptide drugs by lipid nanoparticles

In order to introduce hydrophilic peptide drugs into solid lipid nanoparticles (SLN), a technique of combining hydrophobic ion pairing (HIP) and non-aqueous oil-in-oil (O/O) emulsion-evaporation was developed. Leuprolide (LR) was selected as the model drug, while sodium stearate (SA-Na) was used as the negative charged ion pairing material. The formation of leuprolide-sodium stearate (LR-SA-Na) complex was confirmed by differential scanning calorimetry (DSC). It was observed that when the molar ratio of SA-Na/LR reached 2/1, ca 88.5% LR was incorporated into the hydrophobic ion complexes with SA-Na. Compared with the conventional method of solvent diffusion in an aqueous system, the efficiency of LR drug entrapment with SLN increased from 28.0% to 74.6% by the combined technique of HIP and O/O emulsion-evaporation. In vitro drug release tests revealed that employing technique of HIP obviously reduced the burst release and slowed down the rate of drug release. At meanwhile, applying the method of non-aqueous O/O emulsion-evaporation, the longer time of drug release but relatively higher drug burst release ratio was observed in comparison with those by the solvent diffusion method in an aqueous system. The drug entrapment and release behaviors of LR-SA-Na SLN prepared by the O/O emulsion-evaporation method suggested that it could potentially be exploited as an oral delivery system for leuprolide.     

Thermo-sensitive core-shell nanoparticles as potential drug carrier

Using fluorescence spectrometry, it was found pyrene begins to partition into the core of poly(ε-caprolactone)/poly(N-isopropylacrylamide) (PCL/PNIPAM) core-shell nanoparticles at a low nanoparticle concentration (0.001 mg/mL). The partition coefficient for pyrene partitioning between water and the nanoparticles is around 10⁴. The rate for pyrene partitioning into PCL core is very quick, depending on the relative PCL core weight. And the distinct on-off property of the nanoparticle with temperature was revealed: pyrene molecules enter into PCL core freely when temperature is less than 34 °C; while it becomes difficult when temperature rises to 37 °C. In addition, a new procedure to accurately determine the loading capacity of nanoparticle core for hydrophobic compound using UV-vis spectrometry was developed.     

A polymeric composite carrier for oral delivery of peptide drugs: Bilaminated hydrogel film loaded with nanoparticles

A smart polymeric composite carrier consisting of carboxylated chitosan grafted nanoparticles (CCGN) and bilaminated films with one alginate-Ca²⁺ mucoadhesive layer and one hydrophobic backing layer was developed as a novel carrier for peptide. Calcein, hydrophilic and hydrolytic degradative, was entrapped into CCGN as a model peptide and its release behavior was investigated. Morphology study showed a uniform distribution of CCGN in the homogeneous and porous hydrogel. CCGN was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), particle size measurement, and ζ potential measurement. The composite carrier was characterized by differential scanning calorimetry (DSC), scanning electron microscope (SEM) and fluorescence microscopy. The carrier exhibited high mucoadhesive force and pH-sensitivity, in that release of the nanoparticles and the model peptide calcein were both restricted in acidic environment while a fast and complete release was achieved in neutral medium. Therefore, this novel carrier would be a promising candidate for hydrophilic peptide drugs via oral administration.     

Copper carbonate nanoparticles as an effective biomineralized carrier to load macromolecular drugs for multimodal therapy

Macromolecular drugs have attracted great interest as biotherapy to cure previously untreatable diseases.For clinical translation, biomacromolecules encounter several common druggability difficulties, such as in vivo instability and poor penetration to cross physiologic barriers, thus requiring sophisticated systems for drug delivery. Inspired by the natural biomineralization via interaction between inorganic ions and biomacromolecules, herein we rationally screened biocompatible transition meta...     

Cross-linked poly(vinyl alcohol) as permanent hydrophilic column coating for capillary electrophoresis.

A fast method for the generation of permanent hydrophilic capillary coatings for capillary electrophoresis (CE) is presented. Such interior coating is effected by treating the surface to be coated with a solution of glutaraldehyde as cross-linking agent followed by a solution of poly(vinyl alcohol) (PVA), which results in an immobilization of the polymer on the capillary surface. Applied for capillary zone electrophoresis (CZE) such capillaries coated with cross-linked PVA exhibit excellent separation performance of adsorptive analytes like basic proteins due to the reduction of analyte-wall interactions. The long-term stability of cross-linked PVA coatings could be proved in very long series of CZE separations. More than 1000 repetitive CE separations of basic proteins were performed with stable absolute migration times relative standard deviation (RSD > 1.2%) and without loss of separation efficiency. Cross-linked PVA coatings exhibit a suppressed electroosmotic flow and excellent stability over a wide pH range.     

A biospecific polymeric carrier for polypeptide drugs

Polymeric systems for targeting polypeptide medicinal drugs onto the wall of the small intestine after oral administration were synthesized. These systems are composed of particles of ovomucoid-modified polyacrylamide hydrogel with insulin physically immobilized in its bulk. In vitro experiments have demonstrated the enhanced stability of the immobilized polypeptide against proteolysis and the affinity of polymeric particles to lectin-containing surfaces. The efficiency of the systems obtained was demonstrated in experiments with animals and diabetes patients. The effrct of these systems upon oral administration was qualitatevely similar to that of subcutaneously administered native insulin.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2504–2509, November, 2004.     

A potential bacterial carrier for bioremediation

One of the limiting factors to the effectiveness of biostimulation and bioremediation is the loss of inoculated material from the site. This can occur by a number of pathways, but is particularly problematic in open water systems where the inoculated material is simply lost in the water. It is desirable to develop new material, a matrix, within which bacteria and/or biostimulants can be incorporated. We have investigated the basic physical properties of insoluble potato starch to eventually evaluate its use as such a matrix. Insoluble starch fibers were prepared from white potato (Solanum tuberosum) and sweet potato (Ipomoea batatas) and were compared for their melting temperature by DSC and their ability to bind/aggregate bacteria. The DSC curves for white and sweet potato showed that the melting temperature is 127.34 and 133.05°C for white and sweet potato fibers, respectively. The TG curves for white and sweet potato starches exhibited one main mass loss step corresponding to the DTG peak temperature at 323.39 and 346.93°C, respectively. The two types of fibers, however, showed different binding/aggregation capacities for bacteria, with white potato approximately twice as many cells of Burkholderia cepacia (22.6 billion/g) as cells of Pseudomonas putida. The reverse was true for fibers from sweet potato, binding twice as many cells of Pseudomonas putida (23 billion/g) as cells of Burkholderia cepacia.     

Methylene blue-containing silica-coated magnetic particles: a potential magnetic carrier for photodynamic therapy

We present the preparation and characterization of methylene blue-containing silica-coated magnetic particles. The entrapment of methylene blue (MB), a photodynamic therapy drug under study in our group, in the silica matrix took place during the growth of a silica layer over a magnetic core composed of magnetite nanoparticles. The resulting material was characterized by transmission electron microscopy (TEM), light scattering, and X-ray diffraction. It is composed of approximately 30 nm silica spheres containing magnetic particles of 11 +/- 2 nm and methylene blue entrapped in the silica matrix. The immobilized drug can generate singlet oxygen, which was detected by its characteristic phosphorescence decay curve in the near-infrared and by a chemical method using 1,3-diphenylisobenzofuran to trap singlet oxygen. The lifetime of singlet oxygen was determined to be 52 micros (in acetonitrile) and 3 micros (in water), with both values being in good agreement with those in the literature. The release of singlet oxygen (etaDelta) was affected by the encapsulation of MB in the silica matrix, which caused a reduction to 6% of the quantum yield of MB free in solution. The magnetization curve confirmed the superparamagnetic behavior with a reduced saturation magnetization in respect to uncoated magnetic nanoparticles, which is consistent with the presence of a diamagnetic component over the magnetite surface. The result is a single particle platform that combines therapy (photosensitizer) and diagnostic (MRI contrast agent) possibilities at the same time, as well as drug targeting.     

Stimuli‐responsive zein‐based nanoparticles as a potential carrier for ellipticine: Synthesis,release, and in vitro delivery

In the present research, we have investigated a drug delivery system based on the pH‐responsive behaviors of zein colloidal nanoparticles coated with sodium caseinate (SC) and poly ethylene imine (PEI). These systematically designed nanoparticles were used as nanocarriers for encapsulation of ellipticine (EPT), as an anticancer drug. SC and PEI coatings were applied through electrostatic adsorption, leading to the increased size and improved polydispersity index of nanoparticles as well as sustained release of drug. Physicochemical characteristics such as hydrodynamic diameter, size distribution, zeta potential and morphology of nanoparticles prepared using different formulations and conditions were also determined. Based on the results, EPT was encapsulated into the prepared nanoparticles with a high drug loading capacity (5.06%) and encapsulation efficiency (94.8%) under optimal conditions. in vitro experiments demonstrated that the release of EPT from zein‐based nanoparticles was pH sensitive. When the pH level decreased from 7.4 to 5.5, the rate of drug release was considerably enhanced. The mechanism of pH‐responsive complexation in the drug encapsulation and release processes was extensively investigated. The pH‐dependent electrostatic interactions and drug state were hypothesized to affect the release profiles. Compared to the EPT‐loaded zein/PEI nanoparticles, the EPT‐loaded zein/SC nanoparticles exhibited a better drug sustained‐release profile, with a smaller initial burst release and longer release period. According to the results of in vitro cytotoxicity experiments, drug‐free nanoparticles were associated with a negligible cytotoxicity, whereas the EPT‐loaded nanoparticles displayed a high toxicity for the cancer cell line, A549. Our findings indicate that these pH‐sensitive protein‐based nanoparticles can be used as novel nanotherapeutic tools and potential antineoplastic drug carriers for cancer chemotherapy with controlled release.     

Tunable self-assembled stereocomplexed-polylactic acid nanoparticles as a drug carrier

In this study, a model hydrophilic drug (porphyrin) was encapsulated within hydrophobic polylactic acid (PLA) nanoparticles (NPs) with different crystallinity and the relevant release behaviors were investigated. The crystalline modification was done using a modified nanoprecipitation method, where homo and stereocomplexed PLA NPs with different average diameters based on varying polymer concentrations and solvent/nonsolvent ratios (S/N) were prepared. Entrapment efficiency and drug release of sterocomplexed-PLA NPs were compared with neat poly(l -lactic acid) (PLLA) NPs. Furthermore, to get the more sustained release, porphyrin-loaded NPs were immobilized within electrospun poly(d ,l -lactide-co-glycolide (PLGA) nanofibers (NFs). Outcomes revealed that solution concentration and solvent/nonsolvent ratio play significant roles in the formation of homo and stereocomplexed NPs. On the other hand, it was found that the formation of stereocrystals did not significantly affect the size and morphology of NPs compared with neat NPs. With regard to the entrapment efficiency and drug content, stereocomplexd-PLA NPs behave relatively the same as neat PLLA NPs while the more sustained release was observed for stereocomplexed NPs. Also, it was observed that electrospinning of PLGA solution loaded by NPs led to the uniform distribution of NPs into PLGA fibers. Encapsulating the drug-loaded NPs into nanofibers decreased the rate of drug release by 50% after 24 h, compared with direct loading of drug into PLGA NFs. We conclude that it is possible to tune the entrapment efficiency and modify the release rate of the drug by giving small changes in the process parameters without altering the physical properties of the original drug substance and polymer.     

Composite materials for medical purposes based on polyvinylpyrrolidone modified with ketoprofen and silver nanoparticles

A method for obtaining composite medical materials based on polyvinylpyrrolidone (PVP K15) modified with ketoprofen in a medium of supercritical carbon dioxide and with Ag nanoparticles prepared by metal vapor synthesis is developed. A system in which ketoprofen and Ag nanoparticles with an average size of ∼16 nm are uniformly distributed over the bulk of PVP is obtained. It is found that the yield of ketoprofen from the composite in the physiological solution is higher than that for an analogous system obtained by mechanical mixing of the components.     

Cross-linked block copolymer micelles: functional nanostructures of great potential and versatility

Supramolecular self assembly techniques have provided a versatile means by which to selectively assemble polymer molecules into well-defined three dimensional core-shell nanostructures. The covalent stabilisation and tailoring of these dynamic nanostructures can be achieved using a range of chemistries within the assembly to afford robust functional nanoparticles. Many examples of the stabilisation, functionalisation and decoration of these nanoparticles have been reported in the literature and this tutorial review will focus on these recent developments and highlight their potential applications.     

Thermosensitive core-shell particles as carrier systems for metallic nanoparticles

We present a new system that allows us to modulate the catalytic activity of metal nanoparticles (Ag) by a thermodynamic transition that takes place within the carrier system. Thermosensitive core-shell particles have been used as the carrier system in which the core consists of poly(styrene) (PS), whereas the shell consists of a poly(N-isopropylacrylamide) (PNIPA) network cross-linked by N,N'-methylenebisacrylamide (BIS). Immersed in water, the shell of these particles is swollen. Heating the suspension above 32 degrees C leads to a volume transition within the shell that is followed by a marked shrinking of the network of the shell. The maximum degree of swelling can be adjusted by the degree of cross-linking. Silver nanoparticles with diameters ranging from 6.5 to 8.5 nm have been embedded into thermosensitive PNIPA networks with different cross-linking densities. The Ag nanoparticles do not influence the swelling and the shrinking of the network in the shell. The surface plasmon absorption band of the nanoparticles is shifted to higher wavelengths with temperature. This is traced back to the varying distance of the nanoparticles caused by the swelling and the shrinking of the shell. The catalytic activity is investigated by monitoring photometrically the reduction of 4-nitrophenol by an excess of NaBH4 in the presence of the silver nanocomposite particles. The rate constant kapp was found to be strictly proportional to the total surface of the nanoparticles in the system. Moreover, kapp is first decreasing with increasing temperature when approaching the volume transition. This is due to the strong shrinking of the network. Only at temperatures above the volume transition is the normal Arrhenius-type dependence of kapp found again. In this way, catalytic activity of the metal nanoparticles enclosed in a "nanoreactor" can be modulated by volume transition over a wide range.     

Preparation of chitosan nanoparticles as carrier for immobilized enzyme

This work investigated the preparation of chitosan nanoparticles used as carriers for immobilized enzyme. The morphologic characterization of chitosan nanoparticles was evaluated by scanning electron microscope. The various preparation methods of chitosan nanoparticles were discussed and chosen. The effect of factors such as molecular weight of chitosan, chitosan concentration, TPP concentration, and solution pH on the size of chitosan nanoparticles was studied. Based on these results, response surface methodology was emploved. The results showed that solution pH, TPP concentration, and chitosan concentration significantly affected the size of chitosan nanoparticles. The adequacy of the predictive model equation for predicting the magnitude orders of the size of chitosan nanoparticles was verified effectively by the validation data. Immobilization conditions were investigated as well. The minimum particles size was about 42±5 nm under the optimized conditions. The optimal conditions of immobilization were as follow: one milligram of neutral proteinase was immobilized on chitosan nanoparticles for about 15 min at 40°C. Under the optimized conditions, the enzyme activity yield was 84.3%.     

Novel nanoparticles composed of chitosan and β-cyclodextrin derivatives as potential insoluble drug carrier

This research was aim to develop novel cyclodextrin/chitosan(CD/CS) nanocarriers for insoluble drug delivery through the mild ionic gelation method previously developed by our lab. A series of different bcyclodextrin(β-CD) derivatives were incorporated into CS nanoparticles including hydroxypropyl-bcyclodextrin(HP-β-CD), sulphobutylether-β-cyclodextrin(SB-β-CD), and 2,6-di-O-methy-β-cyclodextrin(DM-β-CD). Various process parameters for nanoparticle preparation and their effects on physicochemical properties of CD/CS nanoparticles were investigated, such as the type of CD derivatives,CD and CS concentrations, the mass ratio of CS to TPP(CS/TPP), and p H values. In the optimal condition,CD/CS nanoparticles were obtained in the size range of 215–276 nm and with the zeta potential from30.22 m V to 35.79 m V. Moreover, the stability study showed that the incorporation of CD rendered the CD/CS nanocarriers more stable than CS nanoparticles in PBS buffer at p H 6.8. For their easy preparation and adjustable parameters in nanoparticle formation as well as the diversified hydrophobic core of CD derivatives, the novel CD/CS nanoparticles developed herein might represent an interesting and versatile drug delivery platform for a variety of poorly water-soluble drugs with different physicochemical properties.     

Ceramic-based nanoparticles entrapping water-insoluble photosensitizing anticancer drugs: a novel drug-carrier system for photodynamic therapy

A novel nanoparticle-based drug carrier for photodynamic therapy is reported which can provide stable aqueous dispersion of hydrophobic photosensitizers, yet preserve the key step of photogeneration of singlet oxygen, necessary for photodynamic action. A multidisciplinary approach is utilized which involves (i) nanochemistry in micellar cavity to produce these carriers, (ii) spectroscopy to confirm singlet oxygen production, and (iii) in vitro studies using tumor cells to investigate drug-carrier uptake and destruction of cancer cells by photodynamic action. Ultrafine organically modified silica-based nanoparticles (diameter approximately 30 nm), entrapping water-insoluble photosensitizing anticancer drug 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide, have been synthesized in the nonpolar core of micelles by hydrolysis of triethoxyvinylsilane. The resulting drug-doped nanoparticles are spherical, highly monodispersed, and stable in aqueous system. The entrapped drug is more fluorescent in aqueous medium than the free drug, permitting use of fluorescence bioimaging studies. Irradiation of the photosensitizing drug entrapped in nanoparticles with light of suitable wavelength results in efficient generation of singlet oxygen, which is made possible by the inherent porosity of the nanoparticles. In vitro studies have demonstrated the active uptake of drug-doped nanoparticles into the cytosol of tumor cells. Significant damage to such impregnated tumor cells was observed upon irradiation with light of wavelength 650 nm. Thus, the potential of using ceramic-based nanoparticles as drug carriers for photodynamic therapy has been demonstrated.     

PEI-PEG接枝壳聚糖对于细胞SMMC7721转染效率的研究

本文通过聚乙二醇化的聚乙烯亚胺与壳聚糖反应,得到了水溶性良好的聚乙二醇化聚乙烯亚胺接枝的壳聚糖( mPEG-O-CS-PEI)。研究表明,纳米mPEG-O-CS-PEI对细胞SMMC7721的转染效率为7．1%。     

Cross-linked polynorbornene-coated gold nanoparticles: dependence of particle stability on cross-linking position and cross-linker structure

This paper describes the preparation of cross-linked polynorbornene coated gold nanoparticles. The polymer was grown radially from the particle surface using a ring opening metathesis polymerization of norbornene and an electrophilic norbornene ester, which was cross-linked using a variety of diamines. The stability of the cross-linked nanoparticles toward oxidative etching by cyanide was evaluated. The rate of etching decreases as diamines with fewer degrees of conformational freedom are used as cross-linkers. The distance of the cross-linking block from the nanoparticle surface was systematically varied. Nanoparticles with the cross-linked block furthest from the surface were etched most slowly. This is suggested to arise as a result of the polymers adopting a mushroom conformation when the cross-linking block is close to the particle surface, while more distal cross-linking results in more rigid polymer chains that are less permeable to the cyanide etchant. These results provide new insight into how fine-tuning the polymer cross-linking architecture can modulate nanoparticle stability.     

Self-assembling peptide as a potential carrier of hydrophobic compounds

Microcrystals of a hydrophobic cargo were stabilized by EAK16 II, a self-assembling oligopeptide, and suspended in aqueous solution. Pyrene was used as a model hydrophobic compound. Egg phosphatidylcholine (EPC) vesicles were prepared to mimic a cell membrane. Pyrene was released from its EAK16 II coating into EPC vesicles. The excimer decay profiles were acquired. They showed that pyrene is present in the crystalline form when stabilized by EAK16 II, it is molecularly dispersed in EPC vesicles, and it is completely released from its EAK16 II coating into the membrane bilayers. The release of pyrene from the microcrystals coated with EAK16 II into the EPC membrane was followed by fluorescence as a function of time. The amount of pyrene released into the EPC vesicles at a given time was quantified using a calibration curve. The concentration of pyrene released was determined as a function of time, and the concentration-versus-time profile was fitted with one exponential. The rate of pyrene release was found to depend on the peptide-to-pyrene molecular ratio. Higher peptide-to-pyrene ratios lead to slower transfer of pyrene to the lipophilic environment. Scanning electron micrographs demonstrated that a thicker coating on the pyrene crystals results in a slower release. The data presented in this work demonstrate that the self-assembling EAK16 II can stabilize a hydrophobic cargo in aqueous solution and deliver it into a lipophilic environment, and that the rate of transfer can be adjusted by tuning the peptide-to-pyrene ratio.