Characteristics of felodipine-located poly(ε-caprolactone) microspheres

Felodipine-loaded poly (ε-caprolactone) (PCL) microspheres were prepared by two methods, the conventional emulsion solvent evapouration method and the quenching method. The aim of this work was to investigate the effects of process parameters such as emulsion type, drug loading, molecular-weight of the polymer, types of emulsion stabilizer and dispersed phase solvents, as well as preparation methods. The results show that, when conventional emulsion solvent evapouration method was used, the o/w-method produced smaller mean size and higher encapsulation efficiency compared with the o/o-method. The encapsulation efficiencies increased with an increase in the molecular weight and a decrease in crystallinity of PCL. The size of microspheres varied with the type of emulsion stabilizer used, smaller microspheres with PVA and narrow size distribution with Pol 237. The water solubility of the dispersed phase solvent was one of the critical factors in controlling the encapsulation efficiency and microsphere mean size. When water-soluble solvents such as acetonitrile and ethyl formate were used, the encapsulation efficiencies decreased due to higher evapouration rate. When quenching methods were used, in contrast to the conventional emulsion solvent evapouration method, very narrowly size-distributed but bigger microspheres were obtained.     

Treatments of paclitaxel with poly(vinyl pyrrolidone) to improve drug release from poly(ɛ-caprolactone) matrix for film-based stent

Drug-loaded biodegradable films as a principal part of film-based stent were investigated for controlled drug delivery systems. In this study, solid dispersion technique, a pretreatment method of paclitaxel (PTX), was applied to prepare the PTX-loaded poly(?-caprolactone) (PCL) films. Drug dissolution rates and characteristics of the poly(vinyl pyrrolidone) (PVP)/PTX solid dispersions (SDs) and physical mixtures (PMs) were investigated to show that the PVP/PTX SDs were successfully prepared before being incorporated in biodegradable films. Afterwards, the effect of the application of SDs on improving drug release behavior, weightlessness, crystalline states, and surface and internal morphologies of the films were studied. It was found that, the films with SDs showed a higher drug release rate than the films with PMs or pure PTX. In addition, the content of PVP in the SDs also had impact on drug release behavior: the more PVP in SDs, the faster the drug was released. According to the drug release test and weightlessness study, the possible drug release mechanism was put forward for the films with SDs. The application of solid dispersion technique showed a remarkable effect on improving drug release behavior for film-based biodegradable stent drug delivery systems.     

Preparation and characterization of β-cyclodextrin and poly(acrylic acid) microspheres

Abstract

A method for the preparation of poly(acrylic acid) (PAA) microspheres cross-linked with beta-cyclodextrin (β-CD) is described. The method is based on a water-in-oil (w/o) emulsion solvent evaporation technique which facilitates a condensation reaction between PAA and β-CD. Aqueous solutions of PAA and β-CD were used as the dispersed phase and food grade olive oil was used as the continuous phase. The effect of homogenization speed (used in the preparation of the emulsion), phase volume ratio and cyclodextrin-polymer load on the particle size of the microspheres produced was investigated in a replicated factorial design. Microspheres were sized by light microscopy. The particle size of the microspheres was influenced by all three variables with two significant first order interactions between the variables being observed (homogenization speed with phase volume ratio and homogenization speed with load). A second order interaction between the three principal factors was also observed. Particle size ranged from 16 to 150m, depending on the production variables employed. The yield for the technique was 69.5 × 9.5%. Using selected conditions, microspheres of 15–25 pm size were prepared from a range of PAA with different weight average molecular weights (w). These particles were then characterized for β-CD, free carboxylic acid group content and residual oleic acid.     

Release of paeonol-β-CD complex from thermo-sensitive poly(N-isopropylacrylamide) hydrogels

By preparing an inclusion complex of paeonol (PAE) with β-cyclodextrin (β-CD), this study investigated its release behavior from thermo-sensitive poly(N-isopropylacrylamide) (PNIPAAm) hydrogels. The PAE-β-CD complex was prepared via coprecipitation. According to differential scanning calorimeter (DSC) and X-ray diffraction (XRD) results, the solid PAE-β-CD complex was found in the amorphous state, indicating that each PAE molecule was encapsulated by a β-CD molecule. The change of chemical shifts of H3 and H5 in proton nuclear magnetic resonance (H NMR) spectra indicated that PAE was inside the CD cavity. PNIPAAm hydrogels containing different cross-linker contents were then synthesized and had a similar lowest critical solution temperature (LCST) of around 33°C. Experimental results of swelling and deswelling indicated that increasing the cross-linker content of the hydrogel decreased the swelling ratio and increased the water retention. According to experimental results of PAE-β-CD complex release, the release rate at 45°C (>LCST) was higher than at 25°C (相似文献   

Formulation of highly soluble poly(ethylene glycol)‐peptide DNA condensates

Two poly(ethylene glycol) (PEG)‐peptides were synthesized and tested for their ability to bind to plasmid DNA and form soluble DNA condensates with reduced spontaneous gene expression. PEG‐vinyl sulfone or PEG‐orthopyridyl disulfide were reacted with the sulfhydryl of Cys‐Trp‐Lys₁₈ (CWK₁₈) resulting in the formation of nonreducible (PEG‐VS‐CWK₁₈) and reducible (PEG‐SS‐CWK₁₈) PEG‐ peptides. Both PEG‐peptides were prepared on a micromole scale, purified by RP‐HPLC in >80% yield, and characterized by 1H NMR and MALDI‐TOF. PEG‐peptides bound to plasmid DNA with an apparent affinity that was equivalent to alkylated (Alk)CWK₁₈, resulting in DNA condensates with a mean diameter of 80–90 nm and Z (zeta) potential of +10 mV. The particle size of PEG‐peptide DNA condensates was constant throughout the DNA concentration range of 0.05–2 mg/mL, indicating these to be approximately 20‐fold more soluble than AlkCWK₁₈ DNA condensates. The spontaneous gene transfer to HepG2 cells mediated by PEG‐VS‐CWK₁₈ DNA conden‐ sates was over two orders of magnitude lower than PEG‐SS‐CWK₁₈ DNA condensates and three orders of magnitude lower than AlkCWK₁₈ DNA condensates. PEG‐VS‐CWK₁₈ efficiently blocked in vitro gene transfer by reducing cell uptake. The results indicate that a high loading density of PEG on DNA is necessary to achieve highly soluble DNA condensates that reduce spontaneous in vitro gene transfer by blocking nonspecific uptake by HepG2 cells. These two properties are important for developing targeted gene delivery systems to be used in vivo.     

Biodegradable poly(ɛ-caprolactone)–poly(ethylene glycol) copolymers as drug delivery system

Poly(?-caprolactone)–poly(ethylene glycol) (PCL–PEG) copolymers are important synthetic biomedical materials with amphiphilicity, controlled biodegradability, and great biocompatibility. They have great potential application in the fields of nanotechnology, tissue engineering, pharmaceutics, and medicinal chemistry. This review introduced several aspects of PCL–PEG copolymers, including synthetic chemistry, PCL–PEG micro/nanoparticles, PCL–PEG hydrogels, and physicochemical and toxicological properties.     

Neuroprotective effects of poly(ADP-ribose) polymerase inhibitors in transient focal cerebral ischemia of rats

目的：研究多聚ＡＤＰ核糖多聚酶（ＰＡＲＰ）在局灶性脑缺血再灌注损伤中的作用．方法：雄性Ｗｉｓｔａｒ大鼠用插丝法阻塞大脑中动脉３５ｈ后再灌注，梗塞灶用ＴＴＣ染色显示，图象分析测量；神经功能缺损采用０－５级评分．结果：低剂量ＰＡＲＰ抑制剂３氨基苯甲酰胺（１０ｍｇ·ｋｇ－１）或尼克酰胺（２０ｍｇ·ｋｇ－１）具有明显的神经保护作用，治疗窗近６ｈ；高剂量反而加重脑损伤，特别是尼克酰胺在再灌注起始给药．选择性单ＡＤＰ核糖酰转移酶抑制剂对脑梗塞无明显作用．结论：暂时非完全性抑制ＰＡＲＰ对脑缺血再灌注损伤产生神经保护作用，然而完全抑制该酶（尤其是在再灌注期）则产生损害作用．     

Surfactant-free microspheres of Poly(ε-caprolactone)/poly (ethylene glyco I )/poly(ε-caprolactone) triblock copolymers as a protein carrier

The aim of this study is to prepare biodegradable microspheres without the use of surfactants or emulsifiers for a novel sustained delivery carriers of protein drugs. A poly(epsilon-caprolactoney poly(ethylene glycol)/poly(epsilon-caprolactone) (CEC) triblock copolymer was synthesized by the ring-opening of epsilon-caprolactone with dihydroxy poly (ethylene glycol) to prepare surfactant-free microspheres. When dichloromethane (DCM) or ethyl formate (EF) was used as a solvent, the formation of microspheres did not occur. Although the microspheres could be formed prior to lyophilization under certain conditions, the morphology of microspheres was not maintained during the filtration and lyophilization process. Surfactant-free microspheres were only formed when ethyl acetate (EA) was used as the organic solvent and showed good spherical microspheres although the surfaces appeared irregular. The content of the protein in the microsphere was lower than expected, probably because of the presence of water channels and pores. The protein release kinetics showed a burst release until 2 days and after that sustained release pattern was showed. Therefore, these observations indicated that the formation of microsphere without the use of surfactant is feasible, and, this the improved process, the protein is readily incorporated in the microsphere.     

Efficacy of methotrexate-loaded poly(ε-caprolactone) implants in Ehrlich solid tumor-bearing mice

Abstract

Context: Methotrexate (MTX) is used in the treatment of malignancies; however, its clinical application is limited by its toxic dose-related side effects. An alternative to overcome the toxicity of the MTX in healthy tissues is the design of an implantable device capable of controlling the delivery of this drug for an extended period within the tumor site.

Objective: To develop methotrexate-loaded poly(ε-caprolactone) implants (MTX PCL implants) and to demonstrate their efficacy as local drug delivery systems capable of inhibiting Ehrlich solid tumor bearing mice.

Materials and methods: MTX PCL implants were produced by the melt-molding technique and were characterized by FTIR, WAXS, DSC and SEM. The in vitro and in vivo release of MTX from the PCL implants was also evaluated. The efficacy of implants in inhibiting tumor cells in culture and the solid tumor in a murine model was revealed.

Results and discussion: The chemical and morphological integrity of the drug was preserved into the polymeric matrix. The in vitro and in vivo release processes of the MTX from the PCL implants were modulated by diffusion. MTX diffused from the implants revealed an antiproliferative effect on tumor cells. Finally, MTX controlled and sustained released from the polymeric implants efficiently reduced 42.7% of the solid tumor in mice paw.

Conclusion: These implantable devices represented a contribution to improve the efficacy and safety of chemotherapy treatments, promoting long-term local drug accumulation in the targeted site.     

Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4–6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations.The dose and generation dependence of several of these response factors are seen to well represent experimental observations at a range of time points. The model indicates that variations between responses of different cell-lines, including murine macrophages, human keratinocytes and colon cells, can be simulated and understood in terms of different intracellular antioxidant levels, and, within a given cell-line, varying responses of different cytotoxicity assays can be understood in terms of their sensitivities to different intracellular cascade events.The model serves as a tool to interpolate and visualise the range of dose and temporal dependences and elucidate the mechanisms underlying the in vitro cytotoxic response to nanoparticle exposure and describes the interaction in terms of independent nanoparticle properties and cellular parameters, based on reaction rates. Such an approach could be a valid alternative to that of effective concentrations for classification of nanotoxicity and may lay the foundation for future quantitative structure activity relationships and predictive nanotoxicity models.     

Silk coating on poly(ε-caprolactone) microspheres for the delayed release of vancomycin

The treatment of osteomyelitis remains a challenge for orthopaedic surgeons. Controlled release of vancomycin from biodegradable microspheres is a promising method for eliminating infection. However, the large initial burst release may make it difficult to maintain the local vancomycin concentration superior to minimum inhibitory concentration for several weeks. The aims of this study were to explore applications of the silk fibroin (SF) as an aqueous coating material for vancomycin-loaded poly(ε-caprolactone) (PCL) microspheres, and investigate the effects of silk coating on in vitro drug release. Examinations of particle size analyses, vancomycin content, Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and in vitro drug release were performed. The results showed that silk coating could reduce the large initial burst release and retard the vancomycin release. Therefore, we suggest that the SF could be used as an aqueous coating material for vancomycin-loaded PCL microspheres and prolonged the drug release. SF coating on vancomycin-loaded PCL microspheres may be considered as an effective approach to prolong the drug release and improve the anti-infection effects.     

Effects of 15d-PGJ₂-loaded poly(D,L-lactide-co-glycolide) nanocapsules on inflammation

BACKGROUND AND PURPOSE

The PPAR-γ agonist 15d-PGJ₂ is a potent anti-inflammatory agent but only at high doses. To improve the efficiency of 15d-PGJ₂, we used poly(D,L-lactide-co-glycolide) nanocapsules to encapsulate it, and function as a drug carrier system. The effects of these loaded nanocapsules (15d-PGJ₂-NC) on inflammation induced by different stimuli were compared with those of free 15d-PGJ₂.

EXPERIMENTAL APPROACH

Mice were pretreated (s.c.) with either 15d-PGJ₂-NC or unloaded 15d-PGJ₂ (3, 10 or 30 µg·kg⁻¹), before induction of an inflammatory response by i.p. injection of either endotoxin (LPS), carrageenan (Cg) or mBSA (immune response).

KEY RESULTS

The 15d-PGJ₂-NC complex did not display changes in physico-chemical parameters or drug association efficiency over time, and was stable for up to 60 days of storage. Neutrophil migration induced by i.p. administration of LPS, Cg or mBSA was inhibited by 15d-PGJ₂-NC, but not by unloaded 15d-PGJ₂. In the Cg model, 15d-PGJ₂-NC markedly inhibited serum levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-12p70. Importantly, 15d-PGJ₂-NC released high amounts of 15d-PGJ₂, reaching a peak between 2 and 8 h after administration. 15d-PGJ₂ was detected in mouse serum after 24 h, indicating sustained release from the carrier. When the same concentration of unloaded 15d-PGJ₂ was administered, only small amounts of 15d-PGJ₂ were found in the serum after a few hours.

CONCLUSIONS AND IMPLICATIONS

The present findings clearly indicate the potential of the novel anti-inflammatory 15d-PGJ₂ carrier formulation, administered systemically. The formulation enables the use of a much smaller drug dose, and is significantly more effective compared with unloaded 15d-PGJ₂.     

Silk coating on poly(ε-caprolactone) microspheres for the delayed release of vancomycin

The treatment of osteomyelitis remains a challenge for orthopaedic surgeons. Controlled release of vancomycin from biodegradable microspheres is a promising method for eliminating infection. However, the large initial burst release may make it difficult to maintain the local vancomycin concentration superior to minimum inhibitory concentration for several weeks. The aims of this study were to explore applications of the silk fibroin (SF) as an aqueous coating material for vancomycin-loaded poly(ε-caprolactone) (PCL) microspheres, and investigate the effects of silk coating on in vitro drug release. Examinations of particle size analyses, vancomycin content, Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and in vitro drug release were performed. The results showed that silk coating could reduce the large initial burst release and retard the vancomycin release. Therefore, we suggest that the SF could be used as an aqueous coating material for vancomycin-loaded PCL microspheres and prolonged the drug release. SF coating on vancomycin-loaded PCL microspheres may be considered as an effective approach to prolong the drug release and improve the anti-infection effects.     

Encapsulation and release of α-chymotrypsin from poly(glycerol adipate-co-ω-pentadecalactone) microparticles

Polymer-based microparticles are increasingly becoming of interest for a variety of applications including drug delivery. Recently poly(glycerol adipate) (PGA) and poly(glycol adipate-co-ω-pentadecalactone) have shown promise for delivery of dexamethasone phosphate and ibuprofen. In this paper the copolyester poly(glycol adipate-co-ω-pentadecalactone) was evaluated as a colloidal delivery system for encapsulated therapeutic proteins. Enzyme containing microparticles were prepared via the double water-in-oil-in-water (w/o/w) emulsion-solvent evaporation methodology. α-Chymotrypsin was used as a model proteolytic enzyme and its transfer was monitored during the emulsification process, in addition to in vitro release from formed particles. On average, 22.1 µg protein per 1 mg polymer was encapsulated, although gradual loss of activity of the protein, once released, was recorded. The work presented shows the potential of this polyester as a delivery system for enzymes via microparticles, with improvements to the system achievable via polymer and process optimization. The pendant hydroxyl groups on the polymer backbone provide future capacity for tailored alteration of the physical and chemical properties of the polymer, in addition to covalent attachment of various compounds.     

Design and synthesis of N-substituted indazole-3-carboxamides as poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors(†)

A group of novel N-1-substituted indazole-3-carboxamide derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy was applied to a weakly active unsubstituted 1H-indazole-3-carboxamide 2, by introducing a three carbon linker between 1H-indazole-3-carboxamide and different heterocycles, and led to compounds 4 [1-(3-(piperidine-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) =36μm] and 5 [1-(3-(2,3-dioxoindolin-1-yl)propyl)-1H-indazole-3-carboxamide, IC(50) = 6.8μm]. Compound 5 was evaluated in rats for its protective action against diabetes induced by a treatment with streptozotocin, a known diabetogenic agent. In addition to preserving the ability of the pancreas to secrete insulin, compound 5 was also able to attenuate the ensuing hyperglycemic response to a significant extent.     

Development of a docetaxel micellar formulation using poly(ethylene glycol)–polylactide–poly(ethylene glycol) (PEG–PLA–PEG) with successful reconstitution for tumor targeted drug delivery

Docetaxel (DTX)-loaded polymeric micelles (DTBM) were formulated using the triblock copolymer, poly(ethylene glycol)–polylactide–poly(ethylene glycol) (PEG–PLA–PEG), to comprehensively study their pharmaceutical application as anticancer nanomedicine. DTBM showed a stable formulation of anticancer nanomedicine that could be reconstituted after lyophilization (DTBM-R) in the presence of PEG 2000 and D-mannitol (Man) as surfactant and protectant, respectively. DTBM-R showed a particle size less than 150?nm and greater than 90% of DTX recovery after reconstitution. The robustly formed micelles might minimize systemic toxicity due to their sustained drug release and also maximize antitumor efficacy through increased accumulation and release of DTX from the micelles. From the pharmaceutical development point of view, DTBM-R showing successful reconstitution could be considered as a potent nanomedicine for tumor treatment.     

Preparation of Tacrolimus loaded micelles based on poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone)

Self-assembled polymeric micelles are widely applied in drug delivery system. In this study, Tacrolimus (FK506) loaded micelles were prepared based on biodegradable poly(?-caprolactone)-poly(ethylene glycol)-poly(?-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic characteristics. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of FK506 and PCEC. The particle size distribution and variation of obtained micelles were determined using Malvern laser particle size analyzer, while the spherical geometry was observed on transmission electron microscope (TEM), and the crystallographic assays were fulfilled by X-ray diffractometer (XRD). Besides, in vitro release profile demonstrated a significant difference between rapid release of free Tacrolimus and much slower and sustained release of FK506 loaded micelles. These results suggested that we have successfully prepared Tacrolimus loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for Tacrolimus delivery in immunosuppressive therapy.     

Nifedipine encapsulated core-shell type nanoparticles based on poly(γ-benzyl L-glutamate)/poly(ethylene glycol) diblock copolymers

The diblock copolymers based on PBLG and PEO (GE) were synthesized and characterized. Nanoparticles showed spherical shape from the observations of TEM and approved core-shell structure. Drug contents were increased with use of higher initial drug concentration and higher Mw of GE. Nifedipine (NFD) release rate was slower in longer PBLG chain length and higher NFD contents than short PBLG chain length and lower drug contents of NFD due to the hydrophobic interaction between PBLG domain and NFD.     

Concanavalin A-conjugated poly(ethylene glycol)–poly(lactic acid) nanoparticles for intranasal drug delivery to the cervical lymph nodes

Abstract

Concanavalin A (ConA)-conjugated poly(ethylene glycol)–poly(lactic acid) nanoparticles (ConA-NPs) were prepared for targeted drug delivery to the cervical lymph nodes after intranasal administration. ConA, a lectin specifically binding to α-mannose and α-glucose, was covalently conjugated on NPs without loss of its carbohydrates binding bioactivity. In vitro cellular uptake experiment demonstrated that NPs could be uptaken by Calu-3 cells in a time- and concentration-dependent manner, and conjugation of ConA on NPs could significantly increase the rate and amount of cellular uptake. ConA-NP showed no obvious toxicity to Calu-3 cells in vitro or to the nasal cilia of rats in vivo. Compared with NPs without ConA, ConA-NP is more effective in targeting drugs to the deep cervical lymph nodes, as evidenced by 1.36–2.52 times increase of targeting efficiency, demonstrating that ConA-NP is a potential carrier for targeted drug delivery to the cervical lymph nodes via nasal route.     

Transport of saquinavir across human brain-microvascular endothelial cells by poly(lactide-co-glycolide) nanoparticles with surface poly-(γ-glutamic acid)

Poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) with surface poly-(γ-glutamic acid) (γ-PGA) were applied to enhance the transport of saquinavir (SQV) across the blood-brain barrier (BBB). PLGA NPs encapsulated SQV and grafted with γ-PGA to form drug carriers (γ-PGA/SQV-PLGA NPs) for crossing through a monolayer of human brain-microvascular endothelial cells (HBMECs) regulated with human astrocytes. The results revealed that a lower molecular weight of γ-PGA yielded a higher grafting efficiency of γ-PGA on PLGA NPs. In addition, γ-PGA with a low molecular weight accelerated the dissolution of SQV from γ-PGA/SQV-PLGA NPs. A higher grafting efficiency (more didecyl dimethylammonium bromide) and a lower molecular weight of γ-PGA increased the permeability of SQV across the BBB, in general. When the grafting efficiency was 85.2% at 6 kDa of γ-PGA, γ-PGA/SQV-PLGA NPs reached about 6 times the permeability of free SQV (the maximal permeability). γ-PGA could also promote the endocytosis of NPs and expression of ornithine decarboxylase by HBMECs. γ-PGA/SQV-PLGA NPs are efficacious nanoparticulate carriers in delivering antiretroviral drug across the BBB.