Antineoplastics Encapsulated in Nanostructured Lipid Carriers

Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer.     

A Mini-Review on Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Topical Delivery of Phytochemicals for the Treatment of Acne Vulgaris

Acne vulgaris (acne) is one of the most common dermatological problems affecting adolescents and young adults. Although acne may not lead to serious medical complications, its psychosocial effects are tremendous and scientifically proven. The first-line treatment for acne is topical medications composed of synthetic compounds, which usually cause skin irritation, dryness and itch. Therefore, naturally occurring constituents from plants (phytochemicals), which are generally regarded as safe, have received much attention as an alternative source of treatment. However, the degradation of phytochemicals under high temperature, light and oxygen, and their poor penetration across the skin barrier limit their application in dermatology. Encapsulation in lipid nanoparticles is one of the strategies commonly used to deliver drugs and phytochemicals because it allows appropriate concentrations of these substances to be delivered to the site of action with minimal side effects. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising delivery systems developed from the combination of lipid and emulsifier. They have numerous advantages that include biocompatibility and biodegradability of lipid materials, enhancement of drug solubility and stability, ease of modulation of drug release, ease of scale-up, feasibility of incorporation of both hydrophilic and lipophilic drugs and occlusive moisturization, which make them very attractive carriers for delivery of bioactive compounds for treating skin ailments such as acne. In this review, the concepts of SLNs and NLCs, methods of preparation, characterization, and their application in the encapsulation of anti-acne phytochemicals will be discussed.     

Cannabidiol as Self-Assembly Inducer for Anticancer Drug-Based Nanoparticles

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N-desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI₅₀ values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B, confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism     

Solid Lipid Nanoparticles Produced via a Coacervation Method as Promising Carriers for Controlled Release of Quercetin

Quercetin is a poorly water-soluble flavonoid with many benefits to human health. Besides the natural food resources that may provide Quercetin, the interest in delivery systems that could enhance its bioavailability in the human body has seen growth in recent years. Promising delivery system candidates are represented by Solid Lipid Nanoparticles (SLNs) which are composed of well-tolerated compounds and provide a relatively high encapsulation efficiency and suitable controlled release. In this study, Quercetin-loaded and negatively charged Solid Lipid Nanoparticles were synthesized based on a coacervation method, using stearic acid as a core lipid and Arabic Gum as a stabilizer. Samples were qualitatively characterized by Dynamic light scattering (DLS), Zeta Potential, Surface infrared spectroscopy (FTIR-ATR), and Time of flight secondary ion mass spectrometry (ToF-SIMS). Encapsulation efficiency, drug release, and antioxidant effect against ABTS^•+ were evaluated in vitro by UV–VIS spectrophotometry.     

Docetaxel Loaded in Copaiba Oil-Nanostructured Lipid Carriers as a Promising DDS for Breast Cancer Treatment

Breast cancer is the neoplasia of highest incidence in women worldwide. Docetaxel (DTX), a taxoid used to treat breast cancer, is a BCS-class-IV compound (low oral bioavailability, solubility and intestinal permeability). Nanotechnological strategies can improve chemotherapy effectiveness by promoting sustained release and reducing systemic toxicity. Nanostructured lipid carriers (NLC) encapsulate hydrophobic drugs in their blend-of-lipids matrix, and imperfections prevent drug expulsion during storage. This work describes the preparation, by design of experiments (2³ factorial design) of a novel NLC formulation containing copaiba oil (CO) as a functional excipient. The optimized formulation (NLC_DTX) showed approximately 100% DTX encapsulation efficiency and was characterized by different techniques (DLS, NTA, TEM/FE-SEM, DSC and XRD) and was stable for 12 months of storage, at 25 °C. Incorporation into the NLC prolonged drug release for 54 h, compared to commercial DTX (10 h). In vitro cytotoxicity tests revealed the antiproliferative effect of CO and NLC_DTX, by reducing the cell viability of breast cancer (4T1/MCF-7) and healthy (NIH-3T3) cells more than commercial DTX. NLC_DTX thus emerges as a promising drug delivery system of remarkable anticancer effect, (strengthened by CO) and sustained release that, in clinics, may decrease systemic toxicity at lower DTX doses.     

Perspectives and Prospective on Solid Lipid Nanoparticles as Drug Delivery Systems

Combating multiple drug resistance necessitates the delivery of drug molecules at the cellular level. Novel drug delivery formulations have made it possible to improve the therapeutic effects of drugs and have opened up new possibilities for research. Solid lipid nanoparticles (SLNs), a class of colloidal drug carriers made of lipids, have emerged as potentially effective drug delivery systems. The use of SLNs is associated with numerous advantages such as low toxicity, high bioavailability of drugs, versatility in the incorporation of hydrophilic and lipophilic drugs, and the potential for production of large quantities of the carrier systems. The SLNs and nanostructured lipid carriers (NLCs) are the two most frequently used types of nanoparticles. These types of nanoparticles can be adjusted to deliver medications in specific dosages to specific tissues, while minimizing leakage and binding to non-target tissues.     

Central Composite Design for Formulation and Optimization of Solid Lipid Nanoparticles to Enhance Oral Bioavailability of Acyclovir

Treatment of herpes simplex infection requires high and frequent doses of oral acyclovir to attain its maximum therapeutic effect. The current therapeutic regimen of acyclovir is known to cause unwarranted dose-related adverse effects, including acute kidney injury. For this reason, a suitable delivery system for acyclovir was developed to improve the pharmacokinetic limitations and ultimately administer the drug at a lower dose and/or less frequently. In this study, solid lipid nanoparticles were designed to improve the oral bioavailability of acyclovir. The central composite design was applied to investigate the influence of the materials on the physicochemical properties of the solid lipid nanoparticles, and the optimized formulation was further characterized. Solid lipid nanoparticles formulated from Compritol 888 ATO resulted in a particle size of 108.67 ± 1.03 nm with an entrapment efficiency of 91.05 ± 0.75%. The analyses showed that the optimum combination of surfactant and solid lipid produced solid lipid nanoparticles of good quality with controlled release property and was stable at refrigerated and room temperature for at least 3 months. A five-fold increase in oral bioavailability of acyclovir-loaded solid lipid nanoparticles was observed in rats compared to commercial acyclovir suspension. This study has presented promising results that solid lipid nanoparticles could potentially be used as an oral drug delivery vehicle for acyclovir due to their excellent properties.     

制备温度对硫辛酸脂质纳米粒的影响

通过脂质和乳化剂筛选实验得到适合于硫辛酸(ALA)负载的脂质基体和乳化剂,在此基础上分别在55℃和65℃下用高压均质法(HPH)制备了硫辛酸脂质纳米粒(ALA-NLC)。通过高效液相色谱(HPLC)、动态光散射(DLS)、原子力显微镜(AFM)、微差示扫描量热(micro-DSC)研究制备温度和保存时间对ALA-NLC性质如ALA的负载量、粒径、稳定性及形貌的影响。结果表明,制备温度和保存时间对粒径、zeta电位及ALA负载量均有较大影响。Micro-DSC结果表明,55℃和65℃下制备的ALA-NLC都可能存在过冷态现象,但是55℃制备的样品更稳定,所得配方在ALA膳食补给上具有潜在的应用价值。     

Design of Nanotechnological Carriers for Ocular Delivery of Mangiferin: Preformulation Study

(1) Background: Mangiferin (MGN) is a natural compound, showing anti-inflammatory and antioxidant activities for the potential treatment of eye diseases. The poor physicochemical features of MGN (low solubility and high instability) justify its nanoencapsulation into nanostructured lipid carriers (NLC) to improve its ocular bioavailability. (2) Methods: Firstly, MGN-NLC were prepared by the high shear homogenization coupled with the ultrasound (HSH−US) method. Finally, unloaded and MGN-loaded NLC were analyzed in terms of ocular tolerance. (3) Results: MGN-NLC showed good technological parameters suitable for ocular administration (particle size below 200 nm). The ORAC assay was performed to quantify the antioxidant activity of MGN, showing that the antioxidant activity of MGN-NLC (6494 ± 186 μM TE/g) was higher than that of the free compound (3521 ± 271 μM TE/g). This confirmed that the encapsulation of the drug was able to preserve and increase its activity. In ovo studies (HET-CAM) revealed that the formulation can be considered nonirritant. (4) Conclusions: Therefore, NLC systems are a promising approach for the ocular delivery of MGN.     

包封多酸化合物的固体脂质纳米粒的合成及生物活性研究

The solid lipid nanoparticles encapsulated polyoxometalate K₆[γ-(CpTi)₂SiW₁₀O₃₈] (abbreviated as (CpTi)₂SiW₁₀ Cp=η⁵-C₅H₅) have been prepared and structurally characterized by elemental ananlysis, IR, UV spectroscopy and TEM. The result showed that the polyoxometalate retained the parent structure after being encapsulated and the encapsulation increased the antitumoral activity of the polyoxometalate.     

Lipid Nanosystems in Topical PUVA Therapy

8-Methoxsalen was vehicled in nanoemulsion and in solid lipid nanoparticles (SLN) prepared by the hot homogenization technique in order to be used in topical psoralen UVA (PUVA) therapy. Drug entrapment efficiency in nanoparticles was improved by choosing the appropriate lipid matrix. The use of α-tocopherol in the lipid phase reduces 8-methoxsalen induced photooxidation of porcine skin, which was evaluated in vitro by a malondialdehyde (MDA) test: This result is promising to reduce in vivo human skin irritation after PUVA therapy, which can be attributed to skin photooxidation.     

Nanostructured Lipid Carriers Can Enhance Oral Absorption of Khellin,a Natural Pleiotropic Molecule

A novel formulation based on nanostructured lipid carriers (NLCs) was developed to increase solubility and intestinal absorption of khellin. K-NLCs were prepared with stearic acid, hempseed oil, Brij S20, and Labrafil M 1944 CS, using the emulsification-ultrasonication method. Developed nanoparticles were chemically and physically characterized by liquid chromatography, light scattering techniques, and electron microscopy. The size, about 200 nm, was optimal for oral delivery, and the polydispersity index (around 0.26), indicated high sample homogeneity. Additionally, K-NLCs showed a spherical morphology without aggregation by microscopic analysis. The encapsulation efficiency of khellin was about 55%. In vitro release studies were carried out in media with different pH to mimic physiological conditions. K-NLCs were found to be physically stable in the simulated gastric and intestinal fluids, and they preserved about 70% of khellin after 6 h incubation. K-NLCs were also successfully lyophilized testing different lyoprotectants, and obtained freeze-dried K-NLCs demonstrated good shelf life over a month. Lastly, permeability studies on Caco-2 cells were performed to predict khellin passive diffusion across the intestinal epithelium, demonstrating that nanoparticles increased khellin permeability by more than two orders of magnitude. Accordingly, developed NLCs loaded with khellin represent a versatile formulation with good biopharmaceutical properties for oral administration, possibly enhancing khellin’s bioavailability and therapeutic effects.     

Square Wave Voltammetry: An Alternative Technique to Determinate Piroxicam Release Profiles from Nanostructured Lipid Carriers

A new, simple, and fast electrochemical (EC) method has been developed to determine the release profile of piroxicam, a nonsteroidal anti‐inflammatory drug, loaded in a drug delivery system based on nanostructured lipid carriers (NLCs). For the first time, the samples were analyzed by using square wave voltammetry, a sensitive EC technique. The piroxicam EC responses allow us to propose a model that explains the experimental results and to subsequently determine the amount of drug loaded into the NLCs formulation as a function of time. In vitro drug release studies showed prolonged drug release (up to 5 days), releasing 60 % of the incorporated drug. The proposed method is a promising and stable alternative for the study of different drug delivery systems.     

Nanostructured Lipid Carriers-Hydrogels System for Drug Delivery: Nanohybrid Technology Perspective

Advanced hybrid component development in nanotechnology provides superior functionality in the application of scientific knowledge for the drug delivery industry. The purpose of this paper is to review important nanohybrid perspectives in drug delivery between nanostructured lipid carriers (NLC) and hydrogel systems. The hybrid system may result in the enhancement of each component’s synergistic properties in the mechanical strength of the hydrogel and concomitantly decrease aggregation of the NLC. The significant progress in nanostructured lipid carriers–hydrogels is reviewed here, with an emphasis on their preparation, potential applications, advantages, and underlying issues associated with these exciting materials.     

In Vivo Effect of Resveratrol-Loaded Solid Lipid Nanoparticles to Relieve Physical Fatigue for Sports Nutrition Supplements

Resveratrol (RSV) is a natural flavonoid polyphenol compound extracted from the plants which shows various biological activities. However, the clinical application of RSV is limited by its poor aqueous solubility, rapid metabolism and poor bioavailability. In this study, resveratrol-loaded solid lipid nanoparticles (RSV- SLNs) was design as a nano-antioxidant against the physical fatigue. The resultant RSV-SLNs were characterized by photon correlation spectroscopy (PCS), transmission electron micrographs (TEM), zeta potential, differential scanning calorimetry (DSC) and Raman spectroscopy pattern. Furthermore, the in vivo anti-fatigue effect assays showed that RSV-SLNs prolonged the mice exhausted time and running distance. The biochemical parameters of blood related to fatigue suggested that RSV-SLNs have potential applications to improve the antioxidant defense of the mice after extensive exercise and confer anti-fatigue capability. Furthermore, the molecular mechanisms of antioxidant by RSV-SLNs supplementation was investigated through the analysis of silent information regulator 2 homolog 1 (SIRT1) protein expression, which demonstrated that it could downregulate the expression of SIRT1 and increase autophagy markers, microtubule-associated protein 1 light chain 3-II (LC3-II) and sequestosome-1 (SQSTM1/p62). These results reveal that the RSV-SLNs may have great potential used as a novel anti-fatigue sports nutritional supplement.     

乳化剂对阳离子乳液聚合及乳胶粒性能的影响

以苯乙烯、丙烯酸丁酯为非离子单体,甲基丙烯酰氧乙基三甲基氯化铵（DMC）为阳离子单体,偶氮二异丁基脒盐酸盐（AIBA）为引发剂,十六烷基三甲基氯化铵（CTAC）和乙撑基双（十六烷基二甲基氯化铵）（G16—2—16）为乳化剂,采用半连续种子乳液聚合法进行阳离子乳液聚合。探讨了乳化剂的分子结构和用量对反应速率、单体转化率以及乳胶粒粒径、Zeta电位等的影响。结果表明：乳化剂的用量越大,反应速率越大,单体转化率越高,而乳胶粒粒径越小;使用G16—2—16作乳化剂时,单体转化率较高,乳胶粒粒径较大,Zeta电位较高。     

Formulation,Characterization, and Evaluation of Eudragit-Coated Saxagliptin Nanoparticles Using 3 Factorial Design Modules

Background and Introduction: Saxagliptin is a hypoglycemic drug that acts as a dipeptidyl peptidase-4 (DPP-4) inhibitor and is preferably used in the treatment of Type 2 Diabetes Mellitus (T2DM). It is safe and tolerable; however, the major disadvantage associated with it is its low bioavailability. Aim: The present research aimed to enhance the bioavailability of the drug by enteric coating with a polymer that controls the rate of drug delivery, and it was prepared as Solid Lipid Nanoparticles (SLNs). Methodology: In the current study, various SLN formulations were developed using a central composite design (CCD) module using Design Expert-11 software. A modified solvent injection technique was used to prepare Saxagliptin nanoparticles coated with Eudragit RS100. The CCD was used to determine the independent variables and their effect on dependent variables at varied levels. Evaluation studies such as particle size analysis, Zeta potential, polydispersity index (PDI), drug loading, entrapment efficiency, in-vitro drug release studies, and in vivo pharmacokinetic studies were performed for the optimized SLN formulation. The reversed-phase HPLC method was developed and validated for the estimation of the pharmacokinetic parameters of the pure drug and prepared SLNs. Results: The effect of independent variables (A1: amount of lipid, A2: amount of polymer, A3: surfactant concentration, and A4: homogenization speed) on dependent variables (R1: particle size, and R2: entrapment efficiency) was established in great detail. Observed responses of the prepared and optimized Saxagliptin SLN were close to the predicted values by the CCD. The prepared SLNs depicted particle sizes in the range of 212–442 nm. The particle size analysis results showed that an increase in the lipid concentration led to an increase in particle size. The developed bioanalytical method was noted to be very specific and robust. The method accuracy varied from 99.16% to 101.95% for intraday, and 96.08% to 103.12% for inter day operation at low (5 mcg/mL), moderate (10 mcg/mL), and higher (15 mcg/mL) drug concentrations. The observed Zeta potential values for the prepared SLNs were in the range of −41.09 ± 0.11 to 30.86 ± 0.63 mV suggesting quite good stability of the SLNs without any aggregation. Moreover, the polydispersity indices were in the range of 0.26 ± 0.051 to 0.45 ± 0.017, indicative of uniformity of sizes among the prepared SLNs. In vivo study outcomes proved that Saxagliptin oral bioavailability significantly enhanced in male Albino Wistar Rats via SLN formulation and Eudragit RS100 coating approach. Conclusions: The developed and optimized Saxagliptin SLNs revealed enhanced Saxagliptin bioavailability in comparison to the native drug. Thus, this formulation strategy can be of great importance and can be implied as a promising approach to enhance the Saxagliptin bioavailability for facilitated T2DM therapy.     

固体脂质纳米粒作为药物载体

固体脂质纳米粒是一种新型的纳米给药系统.本文综述了固体脂质纳米粒作为药物载体的研究进展,包括固体脂质纳米粒的组分选择、制备方法、表面修饰,并且对物化性质分析、给药途径以及载药和释放进行了讨论.     

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460–1047 nm) and entrapment efficiency ranging from 36.4–44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan^®). Observed bacterial suppression was detected in rabbit’s eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.     

脂质体类药物载体的微流控制备

脂质体在药物输送、人造细胞等许多领域有着巨大的应用前景。作为药物载体,脂质体可以保护药物、提高药效、减小药物对机体的毒性、使药物具有靶向性,因此发展或改进脂质体制备方法有着重要的意义。然而,传统的脂质体制备存在耗时长、设备贵、制备条件易变、前后处理步骤多、粒径不均一以及难重复等问题,基于此,脂质体的微流控制备技术逐渐发展起来。研究表明微流控技术在脂质体制备方面有着独特的优势,包括精确地控制脂质体的大小和尺寸分布。本文综述了近年来基于微流控技术的几种脂质体制备方法的研究进展,并对比了几种方法制备的脂质体的性质;进一步分析和探讨了当前微流控技术制备脂质体存在的问题,并展望了其发展趋势和方向。