Development of intravenous lipid emulsion of vinorelbine based on drug–phospholipid complex technique

In order to reduce the severe venous toxicity, we developed an intravenous lipid emulsion of vinorelbine and investigated its preclinical stability, toxicity and antitumor efficacy. Vinorelbine–phospholipid complex was prepared to enhance the lipophilicity of vinorelbine thus facilitating the encapsulation into lipid emulsion. After complexation more than 70% of vinorelbine was encapsulated into the oil phase. Meanwhile, the lipid emulsion showed good stability without drug leakage. Local irritation after injection of the lipid emulsion was investigated in rabbits and compared with Navelbine^® (the commercial product). The antitumor therapeutic efficacies were evaluated in tumor-bearing mouse models inoculated with A549 human lung cancer cells and BCAP-37 human breast cancer cells and compared as well. Results showed that the lipid emulsion significantly reduced the injection irritation compared with that of Navelbine^®, while maintained the antitumor activity in A549 and BCAP-37 cells xenograft tumor mouse models. Taken together, lipid emulsion loaded with vinorelbine–phospholipid complex is a promising vinorelbine intravenous injection with reduced venous irritation.     

Development and characterization of different low methoxy pectin microcapsules by an emulsion–interface reaction technique

In the controlled release area, biodegradable microcapsules are one of the most useful devices to deliver materials in an effective, prolonged and safe manner. A new charged film microcapsular carrier system, using three different pectins, is described. The study utilized pectin microcapsules prepared by two encapsulation mechanisms of interfacial reaction explored through interaction of charged droplet–oil-anionic surfactant-calcium or oil-cationic surfactant with negatively charged pectin. A method for drug encapsulation was developed based on the type of pectin, surfactants and emulsification technique. Both types of surfactant, anionic sodium dodecyl sulphate (SDS) and cationic benzalkonium chloride (BzACl) promoted polymer film formation on the oil droplet surfaces, probably through cross-linking and electrostatic interaction, respectively. Microcapsules consisting of pectin as shell and hydrophobic oil as core were characterized. The resulting microcapsules were relatively small particles (d<3?µm), had high total particle number, specific surface area and drug encapsulation efficiency. They also demonstrated good stability with minimum particle aggregation. Correlation between physicochemical and drug release kinetic parameters were investigated with regard to the effect of pectin macromolecular structure and nature of surfactant used as a counterion in the manufacturing of microcapsules. The release rate of the encapsulated material (prednisolone) in three microcapsules can be controlled by manipulating the conformational flexibility of pectins in the presence of different counterions. As a result, biodegradable pectin microcapsules offer a novel approach for developing sustained release drug delivery systems that have potential for colonic drug delivery.     

Solid lipid nanoparticles carrying chemotherapeutic drug across the blood–brain barrier through insulin receptor-mediated pathway

Abstract

Carmustine (BCNU)-loaded solid lipid nanoparticles (SLNs) were grafted with 83–14 monoclonal antibody (MAb) (83–14 MAb/BCNU-SLNs) and applied to the brain-targeting delivery. Human brain-microvascular endothelial cells (HBMECs) incubated with 83–14 MAb/BCNU-SLNs were stained to demonstrate the interaction between the nanocarriers and expressed insulin receptors (IRs). The results revealed that the particle size of 83–14 MAb/BCNU-SLNs decreased with an increasing weight percentage of Dynasan 114 (DYN). Storage at 4?°C for 6 weeks slightly deformed the colloidal morphology. In addition, poloxamer 407 on 83–14 MAb/BCNU-SLNs induced cytotoxicity to RAW264.7 cells and inhibited phagocytosis by RAW264.7 cells. An increase in the weight percentage of DYN from 0% to 67% slightly reduced the viability of RAW264.7 cells and promoted phagocytosis. Moreover, the transport ability of 83–14 MAb/BCNU-SLNs across the blood–brain barrier (BBB) in vitro enhanced with an increasing weight percentage of Tween 80. 83–14 MAb on MAb/BCNU-SLNs stimulated endocytosis by HBMECs via IRs and enhanced the permeability of BCNU across the BBB. 83–14 MAb/BCNU-SLNs can be a promising antitumor drug delivery system for transporting BCNU to the brain.     

Effects of typical and atypical antipsychotics on glucose–insulin homeostasis and lipid metabolism in first-episode schizophrenia

Rationale Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.Objectives The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.Materials and methods One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.Results After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.Conclusions This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.     

Solid lipid nanoparticles for transdermal delivery of diclofenac sodium: preparation, characterization and in vitro studies

The aim of this study was to prepare diclofenac sodium (DNa) solid lipid nanoparticles (SLNs) by a modified emulsion/solvent evaporation method for transdermal delivery. Five independent processing parameters including the lipid matrix, emulsifiers, co-emulsifiers, water-dispersed phase and organic phase were assessed systematically to enhance the entrapment of DNa. The SLNs produced by optimal formulation were submicrometre size with low polydispersity index, the entrapment efficiency was about 89% and the drug loading was about 9.5%. Shape and surface morphology were determined by transmission electron microscopy, which revealed the fairly spherical and core-shell shapes of the SLNs. The in?vitro release of SLNs showed a two-step release pattern: one initial burst release followed by a second slow-release phase. In the in?vitro cutaneous permeation studies, value of flux obtained for DNa solution was higher than that of SLNs suspension. SLNs had also been shown to improve the dermal localization of DNa.     

Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose–insulin homeostasis and lipid metabolism

Rationale With the antipsychotic drugs available today, especially with some of the newer, atypical antipsychotics, metabolic side effects, such as weight gain, diabetes mellitus and lipid abnormalities, have become a complication to the drug therapy that have to be recognized and treated.Objective The aim of this article is to suggest guidelines for prevention and treatment of adverse effects of antipsychotics on glucose–insulin homeostasis and lipid metabolism, whereas strategies for management of antipsychotic-induced weight gain are summarized elsewhere.Method The guidelines are based on results of experimental and clinical studies presented in the article, as well as on a recently published review of 180 articles in the field.Results Both conventional and atypical antipsychotics can indirectly, by causing obesity, promote development of insulin resistance and type-2 diabetes. In addition, some atypical agents probably directly induce hyperinsulinemia, followed by weight gain, insulin resistance and drug-induced, sometimes insulin-dependent, diabetes.Conclusion In this article, guidelines for the management of adverse metabolic effects of antipsychotics are described.     

Chitosan–ceramide coating on gold nanorod to improve its physiological stability and reduce the lipid surface-related toxicity

Gold nanoparticles are promising materials for many applications that include imaging, drug delivery, and photothermal therapy. However, AuNPs can be unstable and/or toxic. We purposed to improve the stability and reduce toxicity of gold nanorods (AuNR) upon coating with biocompatible polymer, chitosan–ceramide (CS–CE), without replacing the original layer, CTAB. CS–CE-coated AuNR was prepared by simple mixing for 24 h and purified by centrifugation. The coating was confirmed by UV–Vis absorption analysis and surface charge and size measurement. We prepared nanorods with CS or CS–CE coating at two different concentrations (5 and 10% AuNR), the resulting in larger nanorods with a more positive surface-charge than that of AuNR. We investigated the UV-absorption and protein adsorption of the polymer coated nanorods. Based on the protein adsorption, AuNR-CS–CE was found to be more stable under physiological conditions than AuNR-CS. The cell internalization assay revealed that Hela cells internalized higher amounts of AuNR-CS–CE than that of AuNR-CS. Cytotoxicity study revealed that AuNR-CS–CE has lower toxicity than AuNR against HeLa cells. The CS–CE coating improved the stability of AuNR under physiological conditions via the hydrophobic interactions between the AuNR lipid surface and the ceramide anchor in the CS backbone as well as.     

Nanostructured lipid carriers,solid lipid nanoparticles,and polymeric nanoparticles: which kind of drug delivery system is better for glioblastoma chemotherapy?

Context: Glioblastoma is a malignant brain tumor originating in the central nervous system. Successfully therapy of this disease required the efficient delivery of therapeutic agents to the tumor cells and tissues. Delivery of anticancer drugs using novel nanocarriers is promising in glioma treatment.

Objective: Polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were constructed for the delivery of temozolomide (TMZ). The anti-tumor effects of the three kinds of nanocarriers were compared to provide the optimum choice for gliomatosis cerebri treatment.

Methods: TMZ-loaded PNPs (T-PNPs), SLNs (T-SLNs), and NLCs (T-NLCs) were formulated. Their particle size, zeta potential, drug encapsulation efficiency (EE), and drug loading (DL) capacity were evaluated. Anti-tumor efficacies of the three kinds of nanocarriers were evaluated on U87 malignant glioma cells (U87?MG cells) and mice-bearing malignant glioma model.

Results: T-NLCs displayed the best anti-tumor activity than other formulations in vivo and in vitro. The most significantly glioma inhibition was observed on NLCs formulations than PNPs and SLNs.

Conclusion: This work demonstrates that NLCs can deliver TMZ into U87MG cells more efficiently, with higher inhibition efficacy than PNPs and SLNs. T-NLCs could be an excellent drug delivery system for glioblastoma chemotherapy.     

Development of the SoloSTAR® insulin pen device: design verification and validation

Background: SoloSTAR^® (SOL; sanofi-aventis, Deutschland, GmbH) is a new, disposable insulin injection pen device for use by people with type 1 or type 2 diabetes to administer long- or short-acting insulin. Objectives: To discuss factors that have underlined the design process of the SOL device. In addition, to highlight the studies that shaped the direction of its development, such as addressing the unmet needs of people with diabetes, which included a need for better differentiation features and a lower injection force compared with existing prefilled disposable pen devices. Results: The development of the SOL pen device was an iterative process involving both patients and the design team, which has lead to a manufacturable, tailor-made pen device. Patients' needs have been taken into account in the pen design; there are numerous differentiators on the device, which avoids confusion between insulin types. Furthermore, the SOL device has a lower injection force compared with other marketed pen devices. Finally, studies have shown that the SOL device is more accurate, easier to use and is preferred by patients over other pens on the market. Conclusions: The SOL device has undergone rigorous user and laboratory testing, which has captured evolving improvements to better meet the needs of people with diabetes.     

Preparation and characterization of recombinant human growth hormone–Zn2+-dextran nanoparticles using aqueous phase–aqueous phase emulsion

An effective and simple method was developed to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)–Zn²⁺-dextran nanoparticles (NPs) for a variety of delivery applications of the delicate protein. The results showed that the prepared rhGH-Zn²⁺-dextran particles were spherical, glassy, and uniform in size. rhGH recovered from the NPs maintained its structural integrity and its bioactivity well, as suggested by the Nb₂-11 cell proliferation assay. Using polyethylene glycol and polysaccharide to mediate Zn²⁺-induced precipitation has proved to be a promising method to prepare spherical protein-loaded NPs with desired sizes and preserved protein stability.From the Clinical EditorThis basic science paper discusses a simple yet effective method to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)-Zn²⁺-dextran nanoparticles for a variety of delivery applications.     

Effects of stilbenes on glucose and lipid metabolism in insulin resistant HepG2 cells北大核心CSCD

Aim To explore the effect of four stilbenes including rhaponticin, desoxyrhaponticin, rhapontigenin and resveratrol on glucose and lipid metabolism in insulin-resistant HepG2 cells induced by high glucose and high fat. Methods The model of insulin resistance was established by incubating HepG2 cells with a complex of glucose and oleic acid. MTT assay was used to detect cell viability. The intracellular triglyceride (TG) and glucose levels were measured by the kit method. The lipid production was observed by oil red O staining, and the cell morphology and uptake of 2-NBDG were observed by confocal microscope. The PPAR signaling pathway and PI3K/Akt insulin signaling pathway related proteins were determined by Western blot to evaluate the effect of stilbenes on glycolipid metabolism in IR-HepG2 cells. Results The complex containing 50 mmol • L-1 glucose and 0.5 mmol • L-1 oleic acid induced a successful insulin resistance model in HepG2 cells for 48 hours. Compared with the model group, all the four compounds could reduce the content of TG and lipid accumulation, and increase the ability of glucose uptake. These compounds could significantly inhibit the expression level of peroxisome proliferatorsactivated receptor (PPAR-) lipid metabolism-related proteins, and up-regulate the expression of phosphoinositide 3 -kinase (PI3 K) glycometabolism-related proteins, among which rhaponticin and resveratrol had the most significant effect. Conclusions The four stilbenes may alleviate insulin resistance in HepG2 cells by regulation of glucose and lipid metabolism disorder, especially rhaponticin and resveratrol. The mechanism may be related to the regulation of PPAR signaling pathway and the activation of PI3 K/AKT/mTORl pathway to reduce lipid production and promote glucose uptake. © 2023 Publication Centre of Anhui Medical University. All rights reserved.     

Development,characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington’s disease

Abstract

Objective: The objective of the present study was to investigate the potential use of solid lipid nanoparticles (SLNs) as a drug delivery system to enhance the brain-targeting efficiency of rosmarinic acid (RA) following intranasal (i.n.) administration.

Materials and methods: The RA-loaded SLNs was prepared by the hot homogenization technique, in which glycerol monostearate (GMS) as lipid, tween 80 and soya lecithin were used as surfactant along with hydrogenated soya phosphatidyl choline (HSPC) as a stabilizer, and were characterized for particle size, zeta potential (ZP), in vitro study. Nasal delivery of the developed formulation followed by the study of behavioral (locomotor, narrow beam, body weight) and biochemical parameters (glutathione, lipid peroxidation, catalase and nitrite) in wistar rat was carried out.

Results: Optimized RA-loaded SLNs using tween 80 (SLNPRT) have the mean size of (149.2?±?3.2?nm), ZP (?38.27?mV) entrapment efficiency (61.9?±?2.2%). 3-NP-treated rat significantly increased behavioral alterations, oxidative damage as compared with the control group. SLNPRT treatment significantly improved behavioral abnormalities and attenuated the oxidative stress in 3NP-treated rats. However, the nasal delivery of SLNPRT produced significant therapeutic action as compared to intravenous application. In the organ distribution study, brain drug concentration was found to be 5.69?µg, in pharmacokinetic study C_max, t_max, t_1/2, AUC values were found to be 0.284?µg/ml, 1.5?h, 3.17?h, and 1.505?µg/ml/h, respectively.

Conclusion: The encouraging results confirmed the developed optimized RA-loaded SLNs formulation following the non-invasive nose-to-brain drug delivery that is a promising therapeutic approach for the effective management in Huntington disease.     

General overview of lipid–polymer hybrid nanoparticles,dendrimers, micelles,liposomes, spongosomes and cubosomes

Introduction: In recent years, the wider use of nanotechnology has attracted greater attention from scientists in multi-disciplinary fields. Nanotechnological research has come a long way in the past decade, with major advances being made, both in terms of diagnostic and therapeutic potential of nanoparticles.

Areas covered: Some of the prominently discussed nanoparticles in this day and age are polymeric micelles, liposomes, lipid–polymer hybrid nanoparticles, dendrimers, spongosomes and cubosomes. This review attempts to focus on the conventional advantages and exemplary features that these particles possess, thus making them some of the most ideal vehicles for drug delivery.

Expert opinion: Particulate systems, which have been extensively studied in this article, have been employed to enhance the pharmacokinetic and pharmacodynamic characteristics of various hydrophobic and hydrophilic drug moieties, thus attempting to prolong the blood circulation times and increase their efficacy over unmodified drug molecules. These modification techniques have enabled these drug molecules to be delivered to the pharmacological sites of action at an optimised controlled rate, thus trying to minimise the potential for any toxicity resulting from the non-specific distribution of drug to various organs.     

Inflammation–coagulation response and thrombotic effects induced by silica nanoparticles in zebrafish embryos

Nowadays, nanotechnology environmental health and safety (nanoEHS) is gaining attention. We previously found that silica nanoparticles (SiNPs) could induce vascular endothelial damage. However, the subsequent toxicologic response to SiNPs-induced endothelial damage was still largely unknown. In this study, we explored the inflammation–coagulation response and thrombotic effects of SiNPs in endothelial cells and zebrafish embryos. For in vitro study, swollen mitochondria and autophagosome were observed in ultrastructural analysis. The cytoskeleton organization was disrupted by SiNPs in vascular endothelial cells. The release of proinflammatory and procoagulant cytokines including IL-6, IL-8, MCP-1, PECAM-1, TF and vWF, were markedly elevated in a dose-dependent manner. For in vivo study, based on the NOAEL for dosimetry selection, and using two transgenic zebrafish, Tg(mpo:GFP) and Tg(fli-1:EGFP), SiNPs-induced neutrophil-mediated inflammation and impaired vascular endothelial cells. With the dosage higher than NOAEL, SiNPs significantly decreased blood flow and velocity, exhibiting a blood hypercoagulable state in zebrafish embryos. The thrombotic effect was assessed by o-dianisidine staining, showed that an increasing of erythrocyte aggregation occurred in SiNPs-treated zebrafish. Microarray analysis was used to screen the possible genes for inflammation–coagulation response to SiNPs in zebrafish, and the JAK1/TF signaling pathway was further verified by qRT-PCR and Western blot assays. For in-deepth study, il6st was knocked down with specific morpholinos. The whole-mount in situ hybridization and qRT-PCR analysis showed that the expression jak1 and f3b were attenuated in il6st knockdown groups. In summary, our data demonstrated that SiNPs could induce inflammation–coagulation response and thrombotic effects via JAK1/TF signaling pathway.     

Solid lipid nanoparticles as drug carriers. I. Incorporation and retention of the lipophilic prodrug 3′-azido-3′-deoxythymidine palmitate

Solid lipid nanoparticles (SLN) were prepared with trilaurin (TL) as the SLN solid core and dipalmitoylphosphatidylcholine (DPPC) or a mixture of DPPC and dimyristoylphosphatidylglycerol (DMPG) to produce neutral and negatively charged SLNs. The ester prodrug of 3′-azido-3′-deoxythimidine (Zidovudine®, AZT) with palmitic acid, AZT palmitate (AZT-P), was synthesized and its incorporation and retention in SLNs determined. The incorporation of hydrophilic AZT in SLNs was minimal; however the incorporation of AZT-P increased with increasing phospholipid (PL) content and was independent of the amount of TL used. The incorporation of AZT-P was greater in negatively charged SLNs than in neutral SLNs. The in vitro release of AZT-P from different SLNs formulation was studied at 37°C using a bulk-equilibrium reverse dialysis sac technique. Increased drug release was observed in SLNs formulated with PLs having a transition temperature below 37°C. The results obtained indicate that the highly packed TL core of the SLN is not compatible with lipophilic molecules such as AZT-P. The incorporation and subsequent retention of AZT-P appears to be dependent on the PL coating on the SLNs surface and is independent of the TL solid core.     

Formulation,in vitro evaluation and kinetic analysis of chitosan–gelatin bilayer muco-adhesive buccal patches of insulin nanoparticles

The present study was performed to optimise the formulation of a muco-adhesive buccal patch for insulin nanoparticles (NPs) delivery. Insulin NPs were synthesised by an ionic gelation technique using N-di methyl ethyl chitosan cysteine (DMEC-Cys) as permeation enhancer biopolymer, tripolyphosphate (TPP) and insulin. Buccal patches were developed by solvent-casting technique using chitosan and gelatine as muco-adhesive polymers. Optimised patches were embedded with 3?mg of insulin-loaded NPs with a homogeneous distribution of NPs in the muco-adhesive matrix, which displayed adequate physico-mechanical properties. The drug release characteristics, release mechanism and kinetics were investigated. Data fitting to Peppas equation with a correlation coefficient indicated that the mechanism of drug release followed an anomalous transport that means drug release was afforded through drug diffusion along with polymer erosion. In vitro drug release, release kinetics, physical and mechanical studies for all patch formulations reflected the ideal characteristics of this buccal patch for the delivery of insulin NPs.     

Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

Aim:

Arterial function is significantly influenced by bupivacaine at both clinically relevant concentrations and toxic concentrations, but the underlying mechanisms are not fully understood. In the present study we investigated the role of α₁-adrenoceptors in bupivacaine effects on isolated rat aortas.

Methods:

Isolated aortic rings were prepared from rats and suspended in an organ bath. Phenylephrine (Phe)-induced vasoconstriction and acetylcholine (ACh)-induced vasodilation were recorded through an isometric force transducer connected to a data acquisition system.

Results:

Administration of bupivacaine (30–300 μmol/L) produced mild vasoconstriction, and this response declined with repeated administrations. Treatment of the aortic rings with bupivacaine (3–30 μmol/L) for 20 min enhanced Phe-induced vasoconstriction, while treatment for 40 min suppressed Phe-induced vasoconstriction. Both the short- and long-term bupivacaine treatment suppressed ACh-induced vasodilation. Incubation of the aortic rings with 0.2%–0.6% lipid emulsion (LE) for 100 min significantly increased the pD₂ and E_max values of Phe-induced vasoconstriction, and incubation with 0.4% LE for 100 min reversed the inhibition of bupivacaine on vasoconstriction induced by Phe (30 μmol/L). In contrast, incubation with LE suppressed ACh-induced vasodilation, even at a lower concentration and with a 5-min incubation.

Conclusion:

Bupivacaine exerts dual effects on α₁-adrenoceptor-mediated vasoconstriction of isolated rat aortic rings: short-term treatment enhances the response, while long-term treatment inhibits it; the inhibition may be reversed via long-term incubation with LE.