Thermosensitive poly(N-isopropylacrylamide)-b-poly(ε-caprolactone) nanoparticles for efficient drug delivery system

To investigate thermosensitive polymeric nanoparticle, amphiphilic block copolymers of poly(N-isopropylacrylamice)-b-poly(ε-caprolactone) (PNPCL) with different PCL block lengths were synthesized by hydroxy-terminated poly(N-isopropyoacrylamide) (PNiPAAm) initiated ring opening polymerization of ε-caprolactone. Owing to their amphiphilic characteristics, the block copolymers formed self-assembled polymeric nanoparticles in aqueous milieus with thermosensitive PNiPAAm shell compartment. The characterizations of the nanoparticles revealed that the PNPCL nanoparticles showed PCL block length dependent physicochemical characters such as particle sizes, critical aggregation concentrations, and core hydrophobicities. Moreover, the thermosensitive PNiPAAm shells conferred unique temperature responsive properties such as phase transitions with temperature elevation over its lower critical solution temperature (LCST). The temperature induced phase transition resulted in the formation of PNiPAAm hydrogel layer on the PNPCL nanoparticle surface. The drug release tests revealed that the formation of thermosensitive hydrogel layer resulted in the enhanced sustained drug release patterns by acting as an additional diffusion barriers. Therefore, the introduction of thermosensitive polymers on polymeric nanoparticles might be a potential approaches to modulate drug release behaviors.     

Collagen-based hydrogel films as drug-delivery devices with antimicrobial properties

Collagen (coll)-containing hydrogel films were prepared by mixing degraded collagen with monomers such as acrylamide (AAm), and 2-hydroxy ethylmethacrylate (HEMA) before the polymerization/cross-linking of composites as p(coll-co-AAm), and p(coll-co-HEMA), respectively. These materials were used as drug-delivery devices for potential wound dressing materials by loading and releasing of model drugs such as gallic acid (GA) and naproxen (NP). A linear release profile was obtained up to 32-h release from GA-loaded p(coll-co-AAm) interpenetrating polymeric networks films, and 36-h linear release profile of NP for p(coll-co-HEMA). Furthermore, metal nanoparticles such as Ag and Cu prepared within these hydrogel films offered antimicrobial characteristic against known common bacteria such as Escherichia coli, Bacillus subtilis, and Staphylococcus aureus.     

Dual stimuli-responsive supramolecular polymeric nanoparticles based on poly(<Emphasis Type="Italic">α</Emphasis>-cyclodextrin) and acetal-modified <Emphasis Type="Italic">β</Emphasis>-cyclodextrin-azobenzene

To aim at pH environment in tumor tissue and light-controlled drug release, UV and pH dual-responsive supramolecular polymeric nanoparticles mediated by host-guest interactions of poly(α-cyclodextrin) and acetal-modified β-cyclodextrin-azobenzene were developed in this work. The host molecule was poly(α-cyclodextrin) and the guest molecule was composed of acetal-modified β-cyclodextrin with one azobenzene linked. The inclusion of α-cyclodextrin and azobenzene leaded to amphiphilic supramolecular polymer, which further self-assembled to form supramolecular polymeric nanoparticles in aqueous medium. UV and pH responsiveness of supramolecular polymeric nanoparticles attributed to azobenzene and acetal, respectively. Supramolecular polymeric nanoparticles based on poly(α-cyclodextrin) and acetal-modified β-cyclodextrin-azobenzene with the average diameter of sub-100 nm were controllable to release the drugs regulated by pH and UV.     

A Novel Docetaxel-Loaded Poly (ε-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment

Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ε-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere^® in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere^® (p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.     

Nanoparticles composed of PLGA and hyperbranched poly (amine-ester) as a drug carrier

A new hyperbranched poly (amine-ester)-poly (lactide-co-glycolide) (HPAE-co-PLGA) copolymer was synthesized by ring-opening polymerization of D, L-lactide, glycolide and a fourth generation branched poly (amine-ester) (HPAE-OHs4) with Sn(Oct)₂ as catalyst. The chemical structures of copolymers were determined by FT-IR, ¹H-NMR (¹³C NMR), TGA and their molecular weights were determined by gel permeation chromatography (GPC). Two methods, double emulsion (DE) and nanoprecipitation (NP), were employed to fabricate the polymeric nanoparticles. Isoniazid (INH) was loaded as a model antitubercular drug. Influence of the preparation conditions on the nanoparticles size, encapsulation efficiency and release profile in vitro was investigated. Their entrapment efficiency (EE) to INH could reach 96% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The results showed that the HPAE-co-PLGA copolymer nanoparticles have a promising potential in hydrophilic drug delivery system.     

Nanoparticles based on β‐conglycinin and chitosan: Self‐assembly,characterization, and drug delivery

The purpose of this study was to fabricate and evaluate nanoparticles based on β‐conglycinin (7S) and chitosan (CS) to deliver 5‐fluorouracil (5‐FU). The nanoparticles were prepared with a self‐assembly method. Turbidity measurements performed at 600 nm were used to investigate the formation of the nanoparticles as a function of the pH, 7S‐to‐CS mass ratio, and total concentration of 7S and CS. The optimum conditions for the preparation of the nanoparticles were a pH of 5.5, a 7S‐to‐CS mass ratio of 4 : 1, and total concentration of 7S and CS of 9 mg/mL. Under these conditions, the nanoparticles in solution had a high turbidity and good stability. Fourier transform infrared spectroscopy revealed that the nanoparticles were formed mainly through electrostatic interactions between the amine groups (? NH₃⁺) of CS and the carboxyl groups (? COO^?) of 7S. Scanning electron microscopy micrographs and dynamic light scattering analysis showed that the nanoparticles had an approximately spherical morphology with a smooth surface, and the mean particle size was about 120 nm with a narrow size distribution. The release of 5‐FU showed an initial burst release followed by a sustained release, and the release was pH‐dependent. The release mechanism of 5‐FU was Fickian diffusion according to the Ritger–Peppas model. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41963.     

Development of Biodegradable Nanocarriers Loaded with a Monoclonal Antibody

Treatments utilizing monoclonal antibody therapeutics against intracellular protein-protein interactions in cancer cells have been hampered by several factors, including poor intracellular uptake and rapid lysosomal degradation. Our current work examines the feasibility of encapsulating monoclonal antibodies within poly(lactic-co-glycolic acid) (PLGA) nanoparticles using a water/oil/water double emulsion solvent evaporation technique. This method can be used to prepare protective polymeric nanoparticles for transporting functional antibodies to the cytoplasmic compartment of cancer cells. Nanoparticles were formulated and then characterized using a number of physical and biological parameters. The average nanoparticle size ranged from 221 to 252 nm with a low polydispersity index. Encapsulation efficiency of 16%–22% and antibody loading of 0.3%–1.12% were observed. The antibody molecules were released from the nanoparticles in a sustained manner and upon release maintained functionality. Our studies achieved successful formulation of antibody loaded polymeric nanoparticles, thus indicating that a PLGA-based antibody nanoformulation is a promising intracellular delivery vehicle for a large number of new intracellular antibody targets in cancer cells.     

Effect of non-uniform initial drug concentration distribution on the kinetics of drug release from glassy hydrogel matrices

The effect of non-uniform initial drug concentration distribution, on the kinetics of drug release from polymer matrices has been examined theoretically. The results indicate that a constant-rate of drug release can be achieved, via a specific sigmoidal drug concentration distribution without the need to have a saturated drug reservoir as in a membrane-reservoir system. To test this concept, a novel approach has been developed, which utilizes the non-Fickian swelling behaviour in glassy hydrogels to develop an inflection-point containing drug concentration profile, followed by a freeze-drying step to rapidly remove the swelling solvent and immobilize in-situ the desired sigmoidal drug concentration distribution. The drug release from such a system generally exhibits a characteristic time-lag and a constant-rate release region similar to that of a membrane-reservoir system. The applicability of the present concept and process has been demonstrated experimentally with the release of oxprenolol HCl from hydrogel beads; based on 2-hydroxyethyl methacrylate polymerized with a polymeric crosslinking agent.     

Synthesis and characterization of fluoroquinolone-imprinted polymeric nanoparticles

Molecularly imprinted polymeric nanoparticles have been prepared by means of the precipitation polymerization method using a fluoroquinolone, levofloxacin, as a template, methacrylic acid as a functional monomer and 2-ethyl-2-(hydroxymethyl)propane-l,3-diol as a crosslinker. The synthesized polymers have been characterized using scanning electron microscopy that revealed that the produced systems are sub-micrometer-sized particles with a diameter ranging from 50 to 100 nm. The study of the interactions of these polymers with selected fluoroquinolones (levofloxacin, ofloxacin, and ciprofloxacin), acetaminophen, diclofenac, aspirin, and sulfamethoxazole has been carried out in acetonitrile and water. It is demonstrated that the amounts of levofloxacin and its structural analogues (ofloxacin and ciprofloxacin) bound to the molecularly imprinted polymeric nanoparticles are higher than those bound to the non-imprinted nanoparticles both in acetonitrile and in water; the binding of acetaminophen, diclofenac, aspirin and sulfamethoxazole onto both the imprinted and non-imprinted nanoparticles are shown to be significantly lower. In water, it has been shown that even if decreased, the imprinted nanoparticles retain a relevant selectivity for the studied fluoroquinolones, and the binding of other studied pharmaceuticals are not enhanced significantly (e.g. acetaminophen) or even suppressed (e.g. diclofenac sodium, aspirin and sulfamethoxazole) by the molecular imprinting.     

Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from Curcuma longa, acts as an NF-κB inhibitor with anti-inflammatory properties. In this work, highly proliferating osteosarcoma cells were used to study the ability of curcumin to reduce the supportive effect of MSCs when stimulated by acidosis. Due to the poor solubility of curcumin in biological fluids, we used spherical polymeric nanoparticles as carriers (SPN-curc) to optimize its uptake by MSCs. We showed that SPN-curc inhibited the release of inflammatory cytokines (IL6 and IL8) by acidity-stimulated MSCs at a higher extent than by free curcumin. SPN-curc treatment was also successful in blocking tumor stemness, migration, and invasion that were driven by the secretome of acid-stressed MSCs. Overall, these data encourage the use of lipid–polymeric nanoparticles encapsulating NF-κB inhibitors such as curcumin to treat cancers whose progression is stimulated by an activated mesenchymal stroma.     

Conjugated polyelectrolyte-cisplatin complex nanoparticles for simultaneous in vivo imaging and drug tracking

A molecular brush based on conjugated polyelectrolyte (CPE) grafted with dense poly(ethylene glycol) (PEG) chains was successfully complexed with an anticancer agent, cisplatin, to form cisplatin-loaded nanoparticles (CPE-PEG-Pt). The obtained nanoparticles have high far-red/near-infrared fluorescence and are able to release the drug in a continuous and slow manner. These nanoparticles have not only been used to visualize HepG2 cancer cells, but also served as an in vivo fluorescent imaging probe that simultaneously tracks the in vivo drug distribution in nude mice upon intravenous administration.     

Stimuli‐Responsive Polymeric Nanoparticles for Nanomedicine

Nature continues to be the ultimate in nanotechnology, where polymeric nanometer‐scale architectures play a central role in biological systems. Inspired by the way nature forms functional supramolecular assemblies, researchers are trying to make nanostructures and to incorporate these into macrostructures as nature does. Recent advances and progress in nanoscience have demonstrated the great potential that nanomaterials have for applications in healthcare. In the realm of drug delivery, nanomaterials have been used in vivo to protect the drug entity in the systemic circulation, ensuring reproducible absorption of bioactive molecules that do not naturally penetrate biological barriers, restricting drug access to specific target sites. Several building blocks have been used in the formulation of nanoparticles. Thus, stability, drug release, and targeting can be tailored by surface modification. Herein the state of the art of stimuli‐responsive polymeric nanoparticles are reviewed. Such systems are able to control drug release by reacting to naturally occurring or external applied stimuli. Special attention is paid to the design and nanoparticle formulation of these so‐called smart drug‐delivery systems. Future strategies for further developments of a promising controlled drug delivery responsive system are also outlined.     

Dual responsive polymeric bionanocomposite gel beads for controlled drug release systems

Scientists are searching potential solutions for cancer treatments as well as ways to avoid the side effects of anti‐cancer agents, via targeted drug delivery. The aim of this research is to propose dual responsive beads based on sodium alginate (SA), methylcellulose (MC), and magnetic iron oxide nanoparticles (MIONs) for controlled release of 5‐Fluorouracil (5‐FU) as model drug. The beads were prepared by the dual crosslinking of SA and MC in the presence of MIONs. The structural, thermal, morphological, magnetic characteristics as well as the release profile of 5‐FU were studied. The characterization results showed that the drug molecules and MIONs were well dispersed in the polymeric matrix. The cumulative release percentage was ca. 80% at pH = 4.2 and 40% at pH = 7.2 after 6 h. Thus, the sensitivity of beads on the pH value was verified. Moreover, the release profile exhibited reduction with an increase in the concentration of MIONs under an external magnetic field. The obtained results confirmed the dual sensitive release of 5‐FU (i.e., PH/magnetic) that can be used for the targeted and controlled drug delivery systems. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45143.     

Influence of the solvent and the end groups on the morphology of cross-linked amphiphilic poly(1,2-butadiene)-b-poly(ethylene oxide) nanoparticles

The phase diagrams of nanoparticles based on self-assembled amphiphilic poly(1,2-butadiene)-b-poly(ethylene oxide) diblock copolymers (PB-b-PEO) and subsequent intra-micellar cross-linking in methanol and water show that the obtained morphology of the nanoparticles depends on: (i) the block ratio; (ii) the block length; (iii) the solvent; and (iv) the PEO-sided end group. Depending on these parameters, spherical, cylindrical and vesicle-like nanoparticles are synthesized. The PEO-sided end group is found to have an influence on the morphology of the nanoparticles and in addition, it has an impact on the characteristic dimension of the polymeric nanoparticles.     

Electron Beam Synthesis and Characterization of Poly Vinyl Alcohol/Poly Acrylic Acid Embedded Ni and Ag Nanoparticles

Electron beam irradiation was applied to prepare poly (vinyl alcohol) and poly (acrylic acid) P (PVA/AAc) containing nickel and silver nanoparticles. The prepared P (PVA/AAc)–Ni and P (PVA/AAc)–Ag nanoparticles were characterized by Fourier-transform infrared, UV–Visible spectroscopy, X-ray diffraction (XRD) and transmission electron microscope (TEM). The electrical conductivity and thermal gravimetrical analysis (TGA) have been investigated. Bacterial sensitivity toward nickel and silver nanoparticles was studied. The XRD and TEM confirmed that by increasing the Ni or Ag contents from 10 to 150?mmol in the copolymers, the metal particle size increases from 27.6 to 45.6?nm for Ni and from 14.8 to 37.4?nm for Ag. Meanwhile, the mean size particle increases from 33.02 to 45.05?nm for Ni and from 15.5 to 44.03?nm for Ag. The electrical conductivity of the polymer containing Ag is higher than that of Ni and it increased by increasing the metal content. The TGA studies confirmed that, the thermal stability increase by the introduction of metal into polymeric complex. Bacterial sensitivity to metal nanoparticles was found to vary depending on the microbial species. Disc diffusion studies with P. aeruginosa, E. coli and K. pneumoniae revealed greater effectiveness of the silver nanoparticles compared to the nickel nanoparticles, S. aureus depicted the highest sensitivity to nanoparticles compared to the other strains and was more adversely affected by the nickel nanoparticles.     

可生物降解纳米粒子制备研究进展

可生物降解纳米粒子作为纳米级药物载体，在蛋白质、多肽、疫苗、基因等药物控制释放方面具有广阔的应用前景。它的优点不仅在于其能有效地降低药物毒性，屏蔽药物不良气味并对药物控制释放，纳米粒子超微小的粒径能够有效地穿越组织间隙被细胞吸收，可通过人体的毛细血管甚至血脑屏障(BBB)来发挥药效。本文重点介绍近年来国内外可生物降解纳米粒子制备方法的进展情况，同时概述了各种影响因素和条件，并对可生物降解纳米粒子的发展做出展望。     

Magnetite/poly(D,L-lactide-co-glycolide) and hydroxyapatite/poly(D,L-lactide-co-glycolide) prepared by W/O/W emulsion technique for drug carrier: Evaluation of in vitro release of dexamethasone from composite nanoparticles

Biocompatible polymeric carriers containing inorganic materials for delivering therapeutic agents to a targeted site are promising candidate for drug delivery. Two nanocomposite nanoparticles, magnetite/poly(D,L-lactide-co-glycolide) and hydroxyapatite/poly(D,L-lactide-co-glycolide) (Fe₃O₄/PLGA and HAp/PLGA, respectively), with different weight ratios of inorganics to polymer and different polymer molecular weights were prepared by water-in-oil-in-water (W/O/W) emulsion technique to determine incorporation and in vitro release profile of the small molecule drugs water-insoluble dexamethasone acetate (DEX-Ac) and water-soluble dexamethasone phosphate (DEX-P). The in vitro release for DEX-Ac nanoparticles showed an initial burst release followed by a continuous slower release, whereas DEX-P nanoparticles showed only rapid initial release behavior.     

Quaternary and pentanary mesoporous bioactive glass nanoparticles as novel nanocarriers for gallic acid: Characterisation,drug release and antibacterial activity

Mesoporous bioactive glass nanoparticles (MBGNs) have gained considerable attention as multifunctional platforms for simultaneously releasing ions and phytotherapeutic compounds. Thus, in the first part of this study, MBGNs based on the 53SiO₂–4P₂O₅–20CaO–23Na₂O (wt %) (S53P4) composition were synthesized by a microemulsion assisted sol-gel method. More precisely, P₂O₅ was substituted with B₂O₃ and Na₂O with MgO and/or ZnO. For B containing MBGNs all ions were successfully incorporated into the borosilicate structure without inducing crystallisation. In contrast, for S53P4 a poorly crystalline hydroxyapatite phase was identified. All MBGNs had a typical spherical shape with an internal radial network of mesopores. Additionally, for S53P4 a second fraction of particles with a smaller size and compact core was observed. Secondly, the feasibility of MBGNs as nanocarriers for gallic acid (GA) was evaluated. All drug-loaded samples showed a similar in vitro release profile which can be divided into three main phases: burst release, slow release and sustained release. Among the different compositions, S53P4 exhibited the highest cumulative release, whereas B and Mg containing particles exhibited the opposite. The presence of Zn in the MBGN compositions improved their antibacterial effect against both E. coli and S. aureus. Moreover, it was shown that depending on the MBGNs’ composition, the antibacterial activity of GA loaded MBGNs can be enhanced. Thus, the results proved that MBGNs can be used as controlled drug delivery system and, by tailoring the composition, a synergistic antibacterial effect can be achieved, considering that GA and biologically active ions are simultaneously released.     

PLGA Biodegradable Nanoparticles Containing Perphenazine or Chlorpromazine Hydrochloride: Effect of Formulation and Release

In our study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles loaded with perphenazine (PPH) and chlorpromazine hydrochloride (CPZ-HCl) were formulated by emulsion solvent evaporation technique. The effect of various processing variables, including PLGA concentration, theoretical drug loading, poly(vinyl alcohol) (PVA) concentration and the power of sonication were assessed systematically to obtain higher encapsulation efficiency and to minimize the nanoparticles size. By the optimization formulation process, the nanoparticles were obtained in submicron size from 325.5 ± 32.4 to 374.3 ± 10.1 nm for nanoparticles loaded with PPH and CPZ-HCl, respectively. Nanoparticles observed by scanning electron microscopy (SEM) presented smooth surface and spherical shape. The encapsulation efficiency of nanoparticles loaded with PPH and CPZ-HCl were 83.9% and 71.0%, respectively. The drug loading were 51.1% and 39.4% for PPH and CPZ-HCl, respectively. Lyophilized nanoparticles with different PLGA concentration 0.8%, 1.3% and 1.6% (w/v) in formulation process were evaluated for in vitro release in phosphate buffered saline (pH = 7.4) by using dialysis bags. The release profile for both drugs have shown that the rate of PPH and CPZ-HCl release were dependent on a size and amount of drugs in the nanoparticles.     

(S)-Reutericyclin: Susceptibility Testing and In Vivo Effect on Murine Fecal Microbiome and Volatile Organic Compounds

We aimed to assess the in vitro antimicrobial activity and the in vivo effect on the murine fecal microbiome and volatile organic compound (VOC) profile of (S)-reutericyclin. The antimicrobial activity of (S)-reutericyclin was tested against Clostridium difficile, Listeria monocytogenes, Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Staphylococcus (S.) epidermidis, Streptococcus agalactiae, Pseudomonas aeruginosa and Propionibacterium acnes. Reutericyclin or water were gavage fed to male BALBc mice for 7 weeks. Thereafter stool samples underwent 16S based microbiome analysis and VOC analysis by gas chromatography mass spectrometry (GC-MS). (S)-reutericyclin inhibited growth of S. epidermidis only. Oral (S)-reutericyclin treatment caused a trend towards reduced alpha diversity. Beta diversity was significantly influenced by reutericyclin. Linear discriminant analysis Effect Size (LEfSe) analysis showed an increase of Streptococcus and Muribaculum as well as a decrease of butyrate producing Ruminoclostridium, Roseburia and Eubacterium in the reutericyclin group. VOC analysis revealed significant increases of pentane and heptane and decreases of 2,3-butanedione and 2-heptanone in reutericyclin animals. The antimicrobial activity of (S)-reutericyclin differs from reports of (R)-reutericyclin with inhibitory effects on a multitude of Gram-positive bacteria reported in the literature. In vivo (S)-reutericyclin treatment led to a microbiome shift towards dysbiosis and distinct alterations of the fecal VOC profile.