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.     

Effect of solid lipid’s structure on nanostructured lipid carriers encapsulated with sun filter: characterisation,photo-stability and in vitro release

Three series of solid lipid are formulated in nanostructured lipid carriers (NLC) system, which encapsulated with sun filter to evaluate the effect on the physicochemical properties of the nanocarriers. Production is performed by ultrasonication–homogenisation, analysis by particle size, zeta potential (ZP), transmission electron microscope, Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD). Moreover, the encapsulation efficiency, ultraviolet performance and in vitro release are also investigated. The particle sizes of NLCs are between 185 and 225?nm and the polydispersity index is lower than 0.4, ZP from ?56.4 to ?78.6?mV, and the particles are spherical and in homogenous shading. All prepared NCLs encapsulated the sun filter and the EE are higher than 73%. DSC analysis revealed α- to β-polymorphic modification existed in the system of fatty alcohol and fatty acid. However, α, β and β′-polymorphic modifications are exist in the system of cetyl palmitate (PC). Compared with conventional emulsion, all NLCs displayed perfect photo-protective property, especially for the alcohol system. The photo-stability studies showed that the all NLCs have the ability to improve the photo-stability of sunscreens. The in vitro release study suggested all three NLCs displayed sustained release profile and they were fit well with Higuchi equation.     

Which one performs better for targeted lung cancer combination therapy: pre- or post-bombesin-decorated nanostructured lipid carriers?

Abstract

Purpose: The co-delivery of gene and drugs has the potential to treat cancer. The aim of this study was to compare post-bombesin decorated nanostructured lipid carriers (NLC) carrying both doxorubicin (DOX) and DNA with pre-bombesin decorated NLC for lung cancer therapy.

Methods: Post-bombesin decorated NLC were prepared by two steps. First, DOX and DNA-loaded NLC (DOX-DNA-NLC) was prepared. Second, Bombesin-NH₂ (BN-NH₂) was added into DOX-DNA-NLC to react with stearic acid-polyethylene glycol-COOH (SA-PEG-COOH) loaded in NLC. Pre-bombesin decorated NLC were prepared by two steps. First, Bombesin (BN)-conjugated ligands were synthesized. Second, DOX and DNA were loaded into BN decorated NLC. Their average size, zeta potential, drug and gene loading were evaluated. NCl-H460 human non-small lung cancer cells (NCl-H460 cells) were used for the testing of in vitro transfection efficiency and in vitro cytotoxicity. In vivo transfection efficiency and anti-tumor effect of NLC were evaluated on mice bearing NCl-H460 cells model.

Results: Post-bombesin decorated NLC has a particle size of 128?nm, DOX encapsulation efficiency (EE) of 85% and DNA EE of 91%. Pre-bombesin decorated NLC has a particle size of 101?nm, DOX EE of 86% and DNA EE of 92%. Post-bombesin decorated NLC displayed more stable and remarkably higher transfection efficiency and better anti-tumor ability than pre-bombesin decorated NLC both in vitro and in vivo.

Conclusion: Post-bombesin decorated NLC could function as better carriers to improve the cell targeting and nuclear targeting ability. The resulting nanomedicine could be a promising active targeting drug/gene therapeutic system for lung cancer therapy.     

Antioxidant activity of idebenone-loaded neutral and cationic solid–lipid nanoparticles

Abstract

Idebenone (IDE) is a lipophilic benzoquinone electron carrier synthetic analogue of coenzyme Q10, which behaves as an antioxidant and free radical scavenging molecule. Recently, the therapeutic application of IDE in Leber’s hereditary optic neuropathy has been discussed. This work was aimed at evaluating the encapsulation of IDE in solid–lipid nanoparticles (SLN). In particular, we tested the possibility of adapting the quasi-emulsion solvent diffusion technique, already proposed to produce polymeric nanoparticles, to prepare positively charged SLN with different compositions. Such a charge, due to the addition of a cationic lipid, would facilitate the interaction with the negatively charged eye surface epithelium, with a consequent longer pre-corneal residence time of the colloidal systems. In a preliminary evaluation of the produced IDE-loaded SLN, the antioxidant activity of the drug was demonstrated using an oxygen radical absorbance capacity assay. Encapsulation of the drug in the nanocarrier systems seems able to protect IDE from degradation and prolong its antioxidant potential.     

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.     

β-carotene and α-tocopherol coencapsulated in nanostructured lipid carriers of murumuru (Astrocaryum murumuru) butter produced by phase inversion temperature method: characterisation,dynamic in vitro digestion and cell viability study

Hydrophobic bioactives can be more easily incorporated into food and have their bioavailability enhanced if nanostructured lipid carriers (NLC) are used as carriers. In the present study, beta-carotene-loaded NLC were produced by low emulsification using murumuru butter and a mixture of Span 80 and Cremophor RH40 as surfactants. Their average diameter was 35?nm and alpha-tocopherol was required to protect the encapsulated β-carotene. Besides the evaluation of their physicochemical stability, NLC were submitted to dynamic in vitro digestion and cell viability assays with Caco-2 and HEPG cells. The bioaccessibility of beta-carotene in the dynamic system was about 42%. Regarding cell viability, results indicated NLC were toxic to the cell cultures tested. Such high toxicity is probably related to the type of surfactant used and to the extremely reduced particle size, which may have led to an intense and fast permeation of the NLC through the cells.     

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.     

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.     

Stealth lipid polymer hybrid nanoparticles loaded with rutin for effective brain delivery – comparative study with the gold standard (Tween 80): optimization,characterization and biodistribution

The blood–brain barrier is considered the leading physiological obstacle hindering the transport of neurotherapeutics to brain cells. The application of nanotechnology coupled with surfactant coating is one of the efficacious tactics overcoming this barrier. The aim of this study was to develop lipid polymer hybrid nanoparticles (LPHNPs), composed of a polymeric core and a phospholipid shell entangled, for the first time, with PEG-based surfactants (SAA) viz. TPGS or Solutol HS 15 in comparison with the gold standard Tween 80, aiming to enhance brain delivery and escape opsonization. LPHNPs were successfully prepared using modified single-step nanoprecipitation technique, loaded with the flavonoid rutin (RU), extracted from the flowers of Calendula officinalis L., and recently proved as a promising anti-Alzheimer. The effect of the critical process parameters (CPP) viz. PLGA amount, W_lecithin/W_PLGA ratio, and Tween 80 concentration on critical quality attributes (CQA); entrapment, size and size distribution, was statistically analyzed via design of experiments, and optimized using the desirability function. The optimized CPP were maintained while substituting Tween 80 with other PEG-SAA. All hybrid particles exhibited spherical shape with perceptible lipid shells. The biocompatibility of the prepared NPs was confirmed by hemolysis test. The pharmacokinetic assessments, post-intravenous administration to rats, revealed a significant higher RU bioavailability for NPs relative to drug solution. Biodistribution studies proved non-significant differences in RU accumulation within brain, but altered phagocytic uptake among various LPHNPs. The present study endorses the successful development of LPHNPs using PEG-SAA, and confirms the prospective applicability of TPGS and Solutol in enhancing brain delivery.     

Economic evaluations during early (phase II) drug development: a role for clinical trial simulations?

Faced with increasing demands on demonstrating cost effectiveness, pharmaceutical companies are required to conduct pharmacoeconomic evaluations throughout the drug development programme. At present, there is particular emphasis in the literature on burden-of-illness studies and on economic evaluations conducted alongside phase III clinical trials but not on those conducted during phase II clinical trials. This article describes modelling techniques, namely clinical trial simulations (CTS), which are gaining popularity in the clinical research community, but which might also prove to be beneficial during the conduct of these early pharmacoeconomic evaluations. The basic concepts and structure of CTS are described by using published examples of simulations of antipsychotic and anticancer drugs. With the use of an illustrative example of a hypothetical cholinesterase inhibitor for Alzheimer's disease, an integrated CTS-based pharmacoeconomic evaluation is presented. The results demonstrate how the modelling may be of value in 'go/no-go' decisions during the drug development programme.     

Cholesterol–PEG comodified poly (N-butyl) cyanoacrylate nanoparticles for brain delivery: in vitro and in vivo evaluations

This study investigated cholesterol–polyethylene glycol (PEG) comodified poly (ethyleneglycol)-poly (lactide) nanoparticles (CLS-PEG NPs) as a novel, biodegradable brain drug delivery system and included an evaluation of its in vitro and in vivo properties. To this end, coumarin-6 (C6), a fluorescent probe, was encapsulated into CLS-PEG NPs by an emulsion polymerization method. We reported that the use of CLS-PEG NPs led to a sustained drug release in vitro. Additionally, cell viability experiments confirmed their safety. The uptake and transport of CLS-PEG NPs, by bEnd.3 cells (an immortalized mouse brain endothelial cell line), was significantly higher than that of a control C6 solution. An investigation of the uptake mechanisms of different NP formulations demonstrated that cholesterol modifications may be the primary way to improve the efficiency of cellular uptake, wherein macropinocytosis may be the most important endocytic pathway in this process. An investigation of the transport mechanisms of CLS-PEG NPs also implicated macropinocytosis, energy and cholesterol in bEnd.3 cells lines. Following an intravenous (IV) administration to rats, pharmacokinetic experiments indicated that C6-loaded CLS-PEG NPs achieved sustained release for up to 12?h. In addition, IV delivery of CLS-PEG NPs appeared to significantly improve the ability of C6 to pass through the blood–brain barrier: the concentration of C6 found in the brain increased nearly 14.2-fold when C6 CLS-PEG NPs were used rather than a C6 solution. These in vitro and in vivo results strongly suggest that CLS-PEG NPs are a promising drug delivery system for targeting the brain, with low toxicity.     

‘More of an art than a science’? The development,design and mechanics of the Delphi Technique

The Delphi Technique is a group judgement method which is typically used to reach agreement from a group of people with expertise in a particular area. It is an iterative process where panel members complete questionnaires over several rounds, often rating their agreement/disagreement against a statement, with changes made in later rounds based on the feedback received. It has been used widely in pharmacy-related studies relevant to education, research and practice. This paper provides a critical analysis of the various design choices which researchers may consider when planning a Delphi namely the panel of participants, the use of the Likert scale, the effect of feedback, what constitutes consensus and the number of rounds. It also gives an overview of the development and origins of the Delphi, and discusses the advantages and disadvantages of the technique. Advantages include that the Delphi can be conducted with panel members in different geographical locations in their own time, however the technique can therefore take longer to conduct and lacks face-to-face discussion. Patient experts may be less comfortable participating in a relatively complex survey, however the anonymous nature of the process can be more inclusive in allowing participants to feedback candidly. This paper shows the importance of careful planning of the design choices to ensure the reliability and validity of the Delphi.     

Peptide-drug conjugates(PDCs): a novel trend of research and development on targeted therapy,hype or hope?

Peptide-drug conjugates(PDCs) are the next generation of targeted therapeutics drug after antibody-drug conjugates(ADCs), with the core benefits of enhanced cellular permeability and improved drug selectivity. Two drugs are now approved for market by US Food and Drug Administration(FDA), and in the last two years, the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer, coronavirus disease 2019(COVID-19), metabolic diseases, and so on.The therapeutic ...     

Preparation and in vitro–in vivo evaluation of surface-modified poly(lactide-co-glycolide) nanoparticles as controlled release carriers for flutamide delivery

Abstract

This investigation explores the use of methoxy polyethylene glycol (mPEG) functionalised poly(d,l-lactide-co-glycolide) (PLGA) nanocrystals of flutamide (FLT) with enhanced solubility, bioavailability and blood circulation time for targeting prostate cancer. FLT had Log P 3.27, short half life 5–6?h, low water solubility, permeability and bioavailability with extensive first-pass metabolism. FLT-loaded nanocrystals were prepared using nanoprecipitation method with surface coating by mPEG and characterised through differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray powder diffraction, scanning electronic microscopy, particle size, zeta potential, percent entrapment efficiency (% EE), in vitro dissolution, haemolysis, sterility, bioavailability and stability studies. The percent cumulative drug release and % EE of optimised formulation was found to be 95.21?±?1.18 and 88.36?±?1.20, respectively, for 48?h. In addition, FLT-loaded PEGylated PLGA nanocrystals exhibited significantly delayed blood clearance with drug level of about 766.71?ng/mL at 48?h. In conclusion, PEGylated PLGA FLT nanocrystals could be demonstrated as a novel approach to enhance solubility, bioavailability and blood circulation time.     

Tris(2-aminoethyl)amine-based α-branched fatty acid amides – Synthesis of lipids and comparative study of transfection efficiency of their lipid formulations

The synthesis of a new class of cationic lipids, tris(2-aminoethyl)amine-based α-branched fatty acid amides, is described resulting in a series of lipids with specific variations in the lipophilic as well as the hydrophilic part of the lipids. In-vitro structure/transfection relationships were established by application of complexes of these lipids with plasmid DNA (pDNA) to different cell lines. The α-branched fatty acid amide bearing two tetradecyl chains and two lysine molecules (T14diLys) in mixture with the co-lipid 1,2-di-[(9Z)-octadec-9-enoyl]-sn-glycero-3-phosphoethanolamine (DOPE) (1/2, n/n) exhibits effective pDNA transfer in three different cell lines, namely Hep-G2, A549, and COS-7. The presence of 10% serum during lipoplex incubation of the cells did not affect the transfection efficiency. Based on that, detailed investigations of the complexation of pDNA with the lipid formulation T14diLys/DOPE 1/2 (n/n) were carried out with respect to particle size and charge using dynamic light scattering (DLS), ζ-potential measurements, and transmission electron microscopy (TEM). Additionally, the lipoplex uptake was investigated by confocal laser scanning microscopy (CLSM). Overall, lipoplexes prepared from T14diLys/DOPE 1/2 (n/n) offer large potential as lipid-based polynucleotide carriers and further justify advanced examinations.     

Is there penetration of titania nanoparticles in sunscreens through skin? A comparative electron and ion microscopy study

We report on a comparative study by Transmission Electron Microscopy (HRTEM) and Scanning Transmission Ion Microscopy (STIM) combined with Rutherford Backscattering Spectrometry (RBS) and Particle Induced X-Ray Emission (PIXE) on ultra-thin and thin cross-sections, respectively, of various skin samples (porcine skin, healthy human skin, human skin grafted on a severe combined immuno-deficient mouse model) to which we applied topically various formulations containing titanium dioxide (TiO₂) nanoparticles with primary particle sizes in the range from 20–100 nm. Whereas the HRTEM and STIM/PIXE images reveal clear differences – mainly related to the different thickness of the cross-sections – they unambiguously show that penetration of TiO₂ nanoparticles is restricted to the topmost 3–5 corneocyte layers of the stratum corneum (SC).     

In the absence of hard data,Is soft data better than no data at all?

Where total anonymity and confidentiality were previously respected in drug research, a tendency towards the provision of “hard” data such as verifiable personal details seriously disadvantages researchers working with “hidden groups” who use drugs in a relatively problem free way. This particularly applies to those who use substances generally regarded as highly addictive and problematic, such as heroin. Funding for a follow-up to an earlier research project was sought; the original investigated non-problematic heroin users, whereas the chief aim of the follow-up was to examine “resilience” to the problems commonly associated with the use of heroin. An illustration of attempting to put the gathering of “hard” verifiable data into action is presented here along with the immediate consequences. Unsurprisingly, the response of potential participants to the idea of providing personal details was largely negative, as the perceived consequences of being “outed” as a heroin user were generally regarded as worse than any of the issues associated with the use of the drug itself. An irony of the situation is that this “resilience” may be due to participant refusal to compromise their anonymity. This raises some obvious ethical issues. A number of potential longer term consequences on substance use/misuse research are also discussed.