Niosomes as carriers for tretinoin. II. Influence of vesicular incorporation on tretinoin photostability

In this work, we compared the chemical stability of tretinoin (TRA) in methanol and in vesicular suspensions exposed both to UV and artificial daylight conditions with the aim of evaluating the potential of niosomes as topical carriers capable of improving the stability of photosensitive drugs. Tretinoin-loaded niosomes were prepared from polyoxyethylene (4) lauryl ether (Brij^® 30), sorbitan esters (Span^® 40 and Span^®60) and a commercial mixture of octyl/decyl polyglucosides (Triton^® CG110). Liposomes made from hydrogenated (P90H) and non-hydrogenated (P90) soy phosphatidylcholines were also prepared and studied. In order to evaluate the influence of vesicle structure on the photostability of tretinoin, TRA-loaded vesicles were prepared by the film hydration method, extrusion technique and sonication. After UV irradiation, TRA dissolved in methanol degraded very quickly while the incorporation in vesicles always led to a reduction of the photodegradation process. The photoprotection offered by vesicles varied depending on the vesicle structure and composition. After fluorescent light irradiation for 21 days, not all the studied vesicular formulations improved TRA stability when compared with the free drug in methanol. Tretinoin incorporated in P90 or Span vesicles presented a half-life shorter or very close to that of the free drug. However, the inclusion of TRA in P90H liposomes and Brij^® 30 or Triton^® CG110 niosomes retarded the drug photodegradation.     

固体脂质纳米粒和纳米结构脂质载体在药物传递中的研究进展

基于固体脂质的纳米粒（Solid lipid - based nanoparticles,SLBNs）作为新型药物传递系统比常规的药物传递系统存在优势。通常,基于固体脂质的纳米粒可以分成两种形态,即固体脂质纳米粒（ Solid lipid nanoparticles, SLNs）和纳米结构脂质载体（Nanostructured lipid carriers,NLCs）。但固体脂质纳米粒与纳米结构脂质载体在基质的组成上不同,本文就基于固体脂质的纳米粒的制备技术、表征方法及应用的最新研究进展进行总结,为基于固体脂质的纳米粒进一步研究提供参考依据。     

Lipid nanocarriers as skin drug delivery systems: Properties,mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology.Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers.In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.     

粉防已碱纳米醇质体的制备、表征和抗关节炎疗效(英文)

本研究旨在探索醇质体用于改善粉防己碱局部给药治疗关节炎的可行性。用pH梯度法制备醇质体, 并对其粒径、形态和包封率进行表征。所制备的粉防己碱醇质体为球形, 平均粒径约为78 nm, 包封率为 (52.87±3.81)%。而粉防己碱脂质体具有较大的粒径 (99 nm) 和较高的包封率 (98.80±0.01)%。此外, 与粉防己碱脂质体相比, 粉防己碱醇质体显示出显著的体外透皮性能和抗大鼠关节炎疗效, 并与市售地塞米松软膏的疗效无显著性差异。结果表明, 醇质体有望成为粉防己碱皮肤局部给药的纳米载体。     

Design, synthesis and characterization of captopril prodrugs for enhanced percutaneous absorption

Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady-state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure-permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (J(m)) than the parent drug, since the increases in permeability coefficient (k(p)) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted k(p) values were synthesized and characterized, and J(m) measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In-vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with J(m) being highest for ethyl to butyl esters. Substantial first-order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.     

Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: formulation optimization,in vitro evaluation and preclinical assessment

The present investigation aimed for the development and characterization of ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery and effective treatment against vitiligo. The ethosomes were prepared by central composite design (CCD) and characterized for various quality attributes like vesicle shape, size, zeta potential, lamellarity, drug entrapment and drug leaching. The optimized ethosomes were subsequently incorporated int Carbopol® 934 gel and characterized for drug content, rheological behavior, texture profile, in vitro release, ex vivo skin permeation and retention, skin photosensitization and histopathological examination. Ethosomes were found to be spherical and multilamellar in structures having nanometric size range with narrow size distribution, and high encapsulation efficiency. Ethosomal formulations showed significant skin permeation and accumulation in the epidermal and dermal layers. The fluorescence microscopy study using 123 Rhodamine exhibited enhanced permeation of the drug-loaded ethosomes in the deeper layers of skin. Also, the developed formulation showed insignificant phototoxicity and erythema vis-à-vis the conventional cream. The results were cross-validated using histopathological examination of skin segments. In a nutshell, the ethosomes-based hydrogel formulation was found to be a promising drug delivery system demonstrating enhanced percutaneous penetration of methoxsalen with reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.     

Nanostructured lipid carriers (NLC) for the delivery of natural molecules with antimicrobial activity: production,characterisation and in vitro studies

This study describes the preparation, characterisation and in vitro activity of nanostructured lipid carriers (NLCs) encapsulating natural molecules with antimicrobial activity, such as plumbagin, hydroquinon, eugenol, alpha-asarone and alpha-tocopherol. NLCs were prepared by melt and ultrasonication method, characterised by Cryo-TEM for morphology and SdFFF for dimensional distribution and active encapsulation yields. In vitro tests were conducted on bacteria, fungi and human cell cultures. In vitro tests demonstrated that plumbagin is strongly toxic towards F. oxysporum especially when active molecules are loaded on NLC. Plumbagin was completely non toxic on cyanobacterial model strain up to a threshold over which cell viability was completely lost. NLC loaded with active molecules showed a lower toxicity as compared to their free form on human cultured cells. Although further studies need to be performed, these systems can be potentially proposed to control phytopathogenic organisms.     

Oral absorption enhancement of salmon calcitonin by using both N-trimethyl chitosan chloride and oligoarginines-modified liposomes as the carriers

Abstract

In this study both N-trimethyl chitosan chloride (TMC) and oligoarginine (Arg8) were utilized to modify liposomes as the multifunctional carriers (TMC-Arg8-Lips) for enhancing the oral absorption of salmon calcitonin. Two permeation enhancers with positive charges were sequentially adsorbed on the liposomal surface with negative charges by electrostatic interaction. Instead of salmon calcitonin, fluorescein isothiocyanate dextran (FD4) was loaded in TMC-Arg8-Lips for Caco-2 cell permeation test in vitro and penetration examination in rat intestinal tract in vivo. The results showed that the apparent permeability coefficient (P_app) of TMC-Arg8-Lips containing FD4 were 7.0-, 4.4-, 1.8- and 1.4-folds higher than FD4 solution, FD4-TMC solution, non-modified liposomes (Non-Lips) and TMC modified liposomes (TMC-Lips), respectively. A strong fluorescence was observed by confocal laser scanning microscope (CLSM) at rat intestinal wall isolated in different times after the FD4 loaded carriers were intragastrically administrated. Furthermore, the images revealed that TMC-Arg8-Lips could penetrate deeply inside the mucosal membrane. The pharmacodynamic study indicated that TMC-Arg8-Lips containing calcitonin were more efficient in enhancing the absorption and prolonging the reduction of blood calcemia in rats. The area above the plasma calcium concentration–time curve (AAC) of TMC-Arg8-Lips containing calcitonin was increased by more than 16.6- and 1.6-fold when compared to Non-Lips and TMC-Lips, respectively.     

Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy

Proteins bind the surfaces of nanoparticles, and biological materials in general, immediately upon introduction of the materials into a physiological environment. The further biological response of the body is influenced by the nanoparticle-protein complex. The nanoparticle's composition and surface chemistry dictate the extent and specificity of protein binding. Protein binding is one of the key elements that affects biodistribution of the nanoparticles throughout the body. Here we review recent research on nanoparticle physicochemical properties important for protein binding, techniques for isolation and identification of nanoparticle-bound proteins, and how these proteins can influence particle biodistribution and biocompatibility. Understanding the nanoparticle-protein complex is necessary for control and manipulation of protein binding, and allows for improved engineering of nanoparticles with favorable bioavailability and biodistribution.     

Effects of liposomes with polyisoprenoids,potential drug carriers,on the cardiovascular and excretory system in rats

BackgroundThe unpredictable side effects of a majority currently used drugs are the substantial issue, in which patients and physicians are forced to deal with. Augmenting the therapeutic efficacy of drugs may prove more fruitful than searching for the new ones. Since recent studies show that new cationic derivatives of polyisoprenoid alcohols (APrens) might exhibit augmenting properties, we intend to use them as a component of liposomal drug carriers. In this study we investigate if these compounds do not per se cause untoward effects on the living organism.MethodsMale Sprague–Dawley rats received for four weeks daily injections (0.5 ml sc) of liposomes built of dioleoyl phosphatidylethanolamine (DOPE), liposomes built of DOPE and APren-7 (ratio 10:1) or water solvent. Weekly, rats were observed in metabolic cages (24 h); blood and urine were sampled for analysis; body weight (BW) and systolic blood pressure (SBP) were determined. After chronic experiment, kidneys and heart were harvested for histological and morphometric analysis.ResultsThe 4-week BW increments were in the range of 97 ± 4 to 102 ± 4%, intergroup differences were not significant. Microalbuminuria was the lowest in the group receiving liposomes with APren-7 (0.22 ± 0.03 mg/day). Water and food intake, plasma and urine parameters were similar in all groups.ConclusionsNewly designed liposomes containing APren-7 did not affect functions of the excretory and cardiovascular systems, and renal morphology; therefore we find them suitable as a component of liposomal drug carriers.     

Sunlight-induced rapid and efficient biogenic synthesis of silver nanoparticles using aqueous leaf extract of Ocimum sanctum Linn. with enhanced antibacterial activity

Background

Nanotechnology is now regarded as a distinct field of research in modern science and technology with multifaceted areas including biomedical applications. Among the various approaches currently available for the generation of metallic nanoparticles, biogenic synthesis is of increasing demand for the purpose of green nanotechnology. Among various natural sources, plant materials are the most readily available template-directing matrix offering cost-effectiveness, eco-friendliness, and easy handling. Moreover, the inherent pharmacological potentials of these medicinal plant extracts offer added biomedical implementations of the synthesized metal nanoparticles.

Results

A robust practical method for eco-friendly synthesis of silver nanoparticles using aqueous leaf extract of Ocimum sanctum (Tulsi) as both reducing and capping agent, under the influence of direct sunlight has been developed without applying any other chemical additives. The nanoparticles were characterized with the help of UV-visible spectrophotometer and transmission electron microscopy (TEM). The prepared silver nanoparticles exhibited considerable antibacterial activity. The effects were more pronounced on non-endospore-forming Gram-positive bacteria viz., Staphylococcus aureus, Staphylococcus epidermidis, and Listeria monocytogenes than endospore-forming species Bacillus subtilis. The nanoparticles also showed prominent activity on Gram-negative human pathogenic Salmonella typhimurium, Escherichia coli, Pseudomonas aeruginosa, and plant pathogenic Pantoea ananatis. A bactericidal mode of action was observed for both Gram-positive and Gram-negative bacteria by the nanoparticles.

Conclusions

We have developed a very simple, efficient, and practical method for the synthesis of silver nanoparticles using aqueous leaf extract of O. sanctum under the influence of direct sunlight. The biosynthesis of silver nanoparticles making use of such a traditionally important medicinal plant without applying any other chemical additives, thus offers a cost-effective and environmentally benign route for their large-scale commercial production. The nanoparticles dispersed in the mother solution showed promising antibacterial efficacy.

Graphical Abstract

Open in a separate windowSunlight-induced rapid and efficient biogenic synthesis of silver nanoparticles using aqueous leaf extract of Ocimum sanctum Linn. with enhanced antibacterial activity.

Electronic supplementary material

The online version of this article (doi:10.1186/s13588-014-0018-6) contains supplementary material, which is available to authorized users.     

基于熵权的Topsis法评价不同促透剂对双氯芬酸钠的透皮吸收

目的：探讨基于熵权的Topsis法在透皮吸收促进剂促透效果综合评价中的应用。方法：以双氯芬酸钠为模型药物,使用薄荷醇、月桂氮芯 卓酮、冰片、石菖蒲挥发油为促透剂,在离体透皮吸收装置上进行透皮吸收实验,计算稳态流量、渗透系数、增渗倍数、滞后时间,运用基于熵权的Topsis法对几种促透剂的促透效果进行综合评价。结果：对双氯芬酸钠的促透作用其优劣顺序为：1%薄荷醇、1%月桂氮芯 卓酮、1%冰片联用1%薄荷醇和1%月桂氮芯 卓酮、1%冰片和1%月桂氮芯 卓酮、1%冰片、1%薄荷醇和1%月桂氮芯 卓酮、1%石菖蒲挥发油和1%月桂氮芯 卓酮、1%石菖蒲挥发油。结论：基于熵权的Topsis法使主观与客观相结合,可以用于评价促透剂的促透效果。     

Comparative study of liposomes,transfersomes and ethosomes as carriers for improving topical delivery of celecoxib

Topical administration of celecoxib proved to be an effective mean of preventing skin cancer development and improving anticancer drugs effectiveness in skin tumors treatment. The aim of this study was the development of an effective topical formulation of celecoxib, able to promote drug skin delivery, providing its in depth penetration through the skin layers. Three kinds of vesicular formulations have been investigated as drug carriers: liposomes containing a surfactant, or transfersomes and ethosomes, containing suitable edge activators. Firstly, the effect of membrane composition variations on the system performance has been evaluated for each vesicle type. Selected formulations were characterized for particle size, polydispersity index and encapsulation efficiency. The best formulations were subjected to ex vivo permeation studies through excised human skin. All vesicular formulations markedly (p < 0.001) improved the drug amount penetrated into the skin with respect to an aqueous suspension, from 2.0 to 6.5, up to 9.0 folds for liposomes, transfersomes and ethosomes, respectively. In particular, ethosomes containing Tween 20 as edge activator not only showed the best vesicle dimensions and homogeneity, and the highest encapsulation efficacy (54.4%), but also enabled the highest increase in drug penetration through the skin, probably due to the simultaneous presence in their composition of ethanol and Tween 20, both acting as permeation enhancers. Therefore, among the various vesicular formulations examined in the study, Tween 20-ethosomes can be considered the most promising one as carrier for topical celecoxib applications aimed to prevent skin cancer development and increase the anticancer drugs effectiveness against skin tumors.     

Biocompatible lidocaine and prilocaine loaded-nanoemulsion system for enhanced percutaneous absorption: QbD-based optimisation,dermatokinetics and in vivo evaluation

Abstract

Barrier properties of the skin and physicochemical properties of the drugs are the main hiccups in delivering local anaesthetic molecules topically. The present work endeavours for systematic optimisation and evaluation of nanoemulsions (NEs) of local anaesthetic drugs, lidocaine and prilocaine, employing the systematic approach of Quality by Design. A 3³ Box–Behnken design was employed for systematic optimisation of the factors obtained from screening studies employing Plackett–Burman design and risk assessment studies. The superior permeation rates, and higher concentrations of the drugs in skin layers from the optimised NE carriers, were achieved in permeation and dermatokinetic studies, when compared to marketed cream. Furthermore, rapid onset of action was demonstrated by the NE system in rabbit eye corneal reflex model and biocompatibility was confirmed from the absence of any marked skin change(s) in the normal skin histology. The developed NE systems demonstrated it as a promising carrier for topical delivery of lidocaine and prilocaine.     

Synthesis, characterization and transfection activity of new saturated and unsaturated cationic lipids

We synthesized new cationic lipids, analogue to N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) and 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethylammonium bromide (DMRIE), in order to compare those containing a dodecyl chain with those having a relatively long chain with two or five double bonds, such as squalenyl and dihydrofarnesyl derivatives, or complex saturated structures, such as squalane derivatives. The fusogenic helper lipid dioleoylphosphatidylethanolamine (DOPE) was added to cationic lipids to form a stable complex. Liposomes composed of 50:50 w/w cationic lipid/DOPE were prepared and incubated with plasmidic DNA at various charge ratios and the diameter and zeta potential of the complexes were measured. The surface charge of the DNA/lipid complexes can be controlled by adjusting the cationic lipid/DNA ratio. Finally, we tested the in vitro transfection efficiency of the cationic lipid/DNA complexes using different cell lines. The transfection efficiency was highest for the dodecyloxy derivative containing a single hydroxyethyl group in the head, followed by the dodecyloxy and the farnesyloxy trimethylammonium derivatives. Instead the C27 squalenyl and C27 squalanyl derivatives resulted inactive.     

Preparation,characterization and evaluation of liposomal doxorubicin and harmine that show synergistic activity in vitro

A combinatory therapeutic system that simultaneously targets several independent pathways is preferred for the treatment of cancer. In our study, a combinatory liposomal delivery system containing doxorubicin (Dox) and harmine (HM) was constructed by thin film dispersing method together with pH gradient method. A simple, precise and accurate spectrophotometric method for the determination of Dox and HM in liposomal formulation was established and validated. A drug HSPC ratio of 1: 20, loading time of 30 min and loading temperature of 50 °C were the optimal conditions for the preparation of drug loaded liposomes, which exhibited excellent physicochemical properties such as average particle size of ~100 nm, low polydispersity index below 0.2 and high entrapment efficiency above 93%. Sustained release of drug from liposomes at pH 7.4 showed good biological safety. The synergetic cytotoxic effect for these two drugs was evaluated in MCF-7 cells. The in vitro antitumor studies demonstrated the superior anti-proliferation activity of the liposomal Dox and HM with a combination index of 0.81, which indicated great synergistic effect and increased anti-proliferation efficiency. The experimental data suggested that combinational liposome therapy could be an effective way to develop efficient treatment of cancers.     

Enhancement of percutaneous absorption of Finasteride by cosolvents,cosurfactant and surfactants

The enhancing effects of routinely used co-solvents, propylene glycol and 2-propanol, anionic and cationic surfactants and a co-surfactant with different concentrations were evaluated on the skin permeation of Finasteride. In vitro permeation experiments with rat skin revealed that the solvent mixture is a very important factor in the penetration of Finasteride through the skin. Unexpectedly, cationic and anionic surfactants in various concentrations did not show any enhancement effect on drug transdermal absorption but co-surfactant Transcutol P increased skin penetration of Finastride significantly. Transcutol P with 0.25% and 1% showed the best enhancement in the initial and final sampling time, respectively. Transcutol P in a concentration of 0.25% increased skin absorption of the drug nearly 3.6 times in the first 15?min. The highest enhancement ratio (ER) was gained in the presence of 1% Transcutol P (ER?=?5.98). In this study, among the different topical Finastride formulations, Transcutol P 1% in combination with water, propylene glycol and 2-propanol (30, 10, and 60) showed the highest enhancement ratio.     

Synthesis, encapsulation and antitumor activity of new betulin derivatives

Novel betulin derivatives were prepared and tested for their antitumor activity. Starting from 3-O-acetyl- or 3-O-methyl-betulinic aldehyde, the synthesis of C-28 ethynyl derivatives was performed; their subsequent transformation with several 1,3-dipolarophiles afforded pyrazoles and 1,2,3-triazoles. Their screening for antitumor activity was performed in a panel of 15 human cancer cell lines by a colorimetric SRB-assay. Thereby, several compounds revealed a higher cytotoxicity than betulinic acid. In addition, the encapsulation of the lead structure 7 into liposomes was investigated. The results from a dye exclusion test and from DNA laddering experiments provided evidence for an apoptotic cell death.     

Platinum complexes of curcumin delivered by dual-responsive polymeric nanoparticles improve chemotherapeutic efficacy based on the enhanced anti-metastasis activity and reduce side effects

Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum–curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt–CUR@PSPPN) to facilitate intracellular release and synergistic anti-cancer effects. Pt–CUR@PSPPN was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both in vivo and in vitro. In addition, Pt–CUR@PSPPN blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt–CUR@PSPPN provided a novel and attractive therapeutic strategy for NSCLC.