Soft cationic nanoparticles for drug delivery: production and cytotoxicity of solid lipid nanoparticles (SLNs)

The surface properties of nanoparticles have decisive influence on their interaction with biological barriers (i.e., living cells), being the concentration and type of surfactant factors to have into account. As a result of different molecular structure, charge, and degree of lipophilicity, different surfactants may interact differently with the cell membrane exhibiting different degrees of cytotoxicity. In this work, the cytotoxicity of two cationic solid lipid nanoparticles (SLNs), differing in the cationic lipids used as surfactants CTAB (cetyltrimethylammonium bromide) or DDAB (dimethyldioctadecylammonium bromide), referred as CTAB-SLNs and DDAB-SLNs, respectively, was assessed against five different human cell lines (Caco-2, HepG2, MCF-7, SV-80, and Y-79). Results showed that the cationic lipids used in SLN production highly influenced the cytotoxic profile of the particles, with CTAB-SLNs being highly cytotoxic even at low concentrations (IC50 < 10 µg/mL, expressed as CTAB amount). DDAB-SLNs produced much lower cytotoxicity, even at longer exposure time (IC50 from 284.06 ± 17.01 µg/mL (SV-80) to 869.88 ± 62.45 µg/mL (MCF-7), at 48 h). To the best of our knowledge, this is the first report that compares the cytotoxic profile of CTAB-SLNs and DDAB-SLNs based on the concentration and time of exposure, using different cell lines. In conclusion, the choice of the right surfactant for biological applications influences the biocompatibility of the nanoparticles. Regardless the type of drug delivery system, not only the cytotoxicity of the drug-loaded nanoparticles should be assessed, but also the blank (non-loaded) nanoparticles as their surface properties play a decisive role both in vitro and in vivo.This research was funded by the Portuguese Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) through national funds, and co-financed by FEDER, under the project references M-ERA-NET/0004/2015 (PAIRED) and UID/AGR/04033/2019 (CITAB), co-financed by FEDER, under the Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio

Development and characterization of biointeractive gelatin wound dressing based on extract of Punica granatum Linn

Punica granatum Linn (pomegranate) extracts have been proposed for wound healing due to their antimicrobial, antioxidant, and anti-inflammatory properties. In this work, we designed biointeractive membranes that contain standard extracts of P. granatum for the purpose of wound healing. The used standard extract contained 32.24 mg/g of gallic acid and 41.67 mg/g of ellagic acid, and it showed high antioxidant activity (the concentration of the extract that produces 50% scavenging (IC50) 1.715 µg/mL). Compared to the gelatin-based membranes (GEL), membranes containing P. granatum extracts (GELPG) presented a higher maximal tension (p=0.021) and swelling index (p=0.033) and lower water vapor permeability (p=0.003). However, no difference was observed in the elongation and elastic modulus of the two types of membranes (p > 0.05). Our wound-healing assay showed that a GELPG-treated group experienced a significant increase compared to that of the control group in their wound contraction rates on days 3 (p < 0.01), 7 (p < 0.001), and on day 14 (p < 0.001). The GELPG membranes promoted major histological changes in the dynamics of wound healing, such as improvements in the formation of granular tissue, better collagen deposition and arrangement, and earlier development of cutaneous appendages. Our results suggest that a biointeractive gelatin-based membrane containing P. granatum extracts has a promising potential application for dressings that are used to treat wounds.The research was funded by FAPITEC/SE (Fundação de Apoio à Pesquisa e Inovação Tecnológica do Estado de Sergipe) and by the Brazilian Bureau of Research. T. Pashirova received the financial support from the government assignment for the FRC Kazan Scientific Center of Russian Academy of Sciences. E.B. Souto received the support from the projects M-ERA-NET-0004/2015-PAIRED and UIDB/04469/2020, granted by the Portuguese Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) through national funds and co-financed by FEDER under the Partnership Agreement PT2020.info:eu-repo/semantics/publishedVersio

Novel self-assembling system based on resorcinarene and cationic surfactant

Mixed association of calix[4]resorcinarene with ethyl sulfonate groups on the lower rim and dimethylaminomethyl groups on the upper rim (CR) and cationic surfactant 4-aza-1-hexadecyl-azoniabicyclo[2.2.2]octane bromide (DABCO-16) is studied by methods of tensiometry, conductometry, potentiometry and NMR spectroscopy at fixed CR concentration and varied surfactant concentration. Beyond ca. 0.4 mM of DABCO-16, mixed aggregates enriched by CR are proved to be formed due to electrostatic forces, while beyond ca. 5 mM, aggregates enriched by surfactant occur due to the hydrophobic effect. Spectrophotometry monitoring of the solubilization of a hydrophobic dye, Orange OT, demonstrated that only the second type of mixed aggregate enriched by DABCO-16 is capable of binding the organic probe, while the mixed system where the surfactant is a minor component shows no binding capacity towards Orange OT. This finding can be used for the design of nanocontainers with controllable binding/release properties.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Nontoxic antimicrobial micellar systems based on mono- and di-cationic Dabco-surfactants and furazolidone: Structure-solubilization properties relationships

Supplementary data to this article can be found online at https://doi.org/10.1016/j.molliq.2019.112062.Self-assembly and solubilization properties of amphiphilic mono- and bisquaternized derivatives of 1,4-diazabicyclo[2.2.2]octane (mono-CS-n and di-CS-n, where CS cationic surfactant, n=12, 14, 16, 18) was investigated by nuclear magnetic resonance with magnetic field pulse gradient. The influence of Dabco-surfactant structure (head group and length of alkyl chains) on critical micelle concentration and aggregation number of micelles was studied. The CMC of mono-CS-n are lower than CMC of di-CS-n. The aggregation numbers of mono-CS-n micelles are higher than for di-CS-n micelles. The solubilization capacity of mono-CS-n is higher than di-CS-n. The solubilization capacity of mono-CS-16 is 2.5 times higher than CTAB in the case of Orange OT as a solute, and it is close to CTAB in the case of Sudan I. The solubility of a poorly water-soluble antibacterial drug furazolidone was improved by micellar solubilization based on mono- and di-Dabco-surfactants. Mono-CS-n is the best solubilizing agents toward furazolidone. The use of mixed composition mono-Dabco-16-furazolidone provides a significant increase in antimicrobial activity (2 times against bacteria and 8 times against fungi) and reduces 2 times the dose of each of the components in combination formulation and causes <2% haemolysis of human red blood cells at the active dose.The report study was funded by Russian Foundation for Basic Research according to the research project № 18-43-160015. The authors gratefully acknowledge the CSF-SAC FRC KSC RAS.info:eu-repo/semantics/publishedVersio

Nanoparticle delivery systems in the treatment of diabetes complications

Diabetes mellitus, an incurable metabolic disease, is characterized by changes in the homeostasis of blood sugar levels, being the subcutaneous injection of insulin the first line treatment. This administration route is however associated with limited patients compliance, due to the risk of pain, discomfort and local infection. Nanoparticles have been proposed as insulin carriers to make possible the administration of the peptide via friendlier pathways without the need of injection, i.e., via oral or nasal routes. Nanoparticles stand for particles in the nanometer range that can be obtained from different materials (e.g., polysaccharides, synthetic polymers, lipid) and are commonly used with the aim to improve the physicochemical stability of the loaded drug and thereby its bioavailability. This review discusses the use of different types of nanoparticles (e.g., polymeric and lipid nanoparticles, liposomes, dendrimers, niosomes, micelles, nanoemulsions and also drug nanosuspensions) for improved delivery of different oral hypoglycemic agents in comparison to conventional therapies.The authors acknowledge the financial support received from Portuguese Science and Technology Foundation (FCT/MCT) and from European Funds (PRODER/COMPETE) under the project reference M-ERA-NET/0004/2015-PAIRED, co-financed by FEDER, under the Partnership Agreement PT2020. The authors also acknowledge the support of the research project: “Nutraceutica come supporto nutrizionale nel paziente oncologico”, CUP: B83D18000140007.info:eu-repo/semantics/publishedVersio

Cationic surfactants: self-assembly, structure-activity correlation and their biological applications

The development of biotechnological protocols based on cationic surfactants is a modern trend focusing on the fabrication of antimicrobial and bioimaging agents, supramolecular catalysts, stabilizers of nanoparticles, and especially drug and gene nanocarriers. The main emphasis given to the design of novel ecologically friendly and biocompatible cationic surfactants makes it possible to avoid the drawbacks of nanoformulations preventing their entry to clinical trials. To solve the problem of toxicity various ways are proposed, including the use of mixed composition with nontoxic nonionic surfactants and/or hydrotropic agents, design of amphiphilic compounds bearing natural or cleavable fragments. Essential advantages of cationic surfactants are the structural diversity of their head groups allowing of chemical modification and introduction of desirable moiety to answer the green chemistry criteria. The latter can be exemplified by the design of novel families of ecological friendly cleavable surfactants, with improved biodegradability, amphiphiles with natural fragments, and geminis with low aggregation threshold. Importantly, the development of amphiphilic nanocarriers for drug delivery allows understanding the correlation between the chemical structure of surfactants, their aggregation behavior, and their functional activity. This review focuses on several aspects related to the synthesis of innovative cationic surfactants and their broad biological applications including antimicrobial activity, solubilization of hydrophobic drugs, complexation with DNA, and catalytic effect toward important biochemical reaction.Russian Science Foundation; grant No. 19-73-30012, and from the Portuguese Science and Technology Foundation (FCT) no. SFRH/BPD/101650/2014 granted to SD, SFRH/BD/130555/2017 granted to ARF, and project reference M-ERA-NET/0004/2015 (PAIRED)info:eu-repo/semantics/publishedVersio

Surface modification of pralidoxime chloride-loaded solid lipid nanoparticles for enhanced brain reactivation of organophosphorus-inhibited AChE: pharmacokinetics in rat

The nanotechnological approach is an innovative strategy of high potential to achieve reactivation of organophosphorus-inhibited acetylcholinesterase in central nervous system. It was previously shown that pralidoxime chloride-loaded solid lipid nanoparticles (2-PAM-SLNs) are able to protect the brain against pesticide (paraoxon) central toxicity. In the present work, we increased brain AChE reactivation efficacy by PEGylation of 2-PAM-SLNs using PEG-lipid N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt) (DSPE-PEG2000) as a surface-modifier of SLNs. To perform pharmacokinetic study, a simple, sensitive (LLOQ 1.0ng/ml) high-performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization by multiple reaction monitoring mode (HPLC-APCI-MS) was developed. The method was compared to mass spectrometry with electrospray ionization. The method was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. Acetophenone oxime was used as the internal standard for the quantification of 2-PAM in rat plasma and brain tissue after intravenous administration. 2-PAM-DSPE-PEG2000-SLNs of mean size about 80nm (PDI=0.26), zeta-potential of 55mV and of high in vitro stability, prolonged the elimination phase of 2-PAM from the bloodstream more than 3 times compared to free 2-PAM. An increase in reactivation of POX-inhibited human brain acetylcholinesterase up to 36.08±4.3% after intravenous administration of 2-PAM-DSPE-PEG2000-SLNs (dose of 2-PAM is 5mg/kg) was achieved. The result is one of the first examples where this level of brain acetylcholinesterase reactivation was achieved. Thus, the implementation of different approaches for targeting and modifying nanoparticles surface gives hope for improving the antidotal treatment of organophosphorus poisoning by marketed reactivators.This research (the HPLC-MS part of this work) was carried out using facilities of the CSF-SAC FRC KSC RAS was financial support from the government assignment for FRC Kazan Scientific Center of Russian Academy of Sciences to D.N.B., I.Kh.R, V.M.B. This work (the part preparation, characterization, and stability, release analysis, reactivation of brain AChE in vivo of 2-PAM-DSPE-PEG2000-SLNs) was supported by Russian Science Foundation (project N◦ 19-73-30012) to T.N. P., E.A.B., I.V.Z., K.A.P. The authors are indebted to Prof. L.Ya. Zakharova who initiated this work. They express to her their thanks for her interest and constant support. The authors are indebted to Prof. Patrick Masson (KFU, Kazan) for his critical reading and editing of the manuscript. The authors are grateful to Dr. Sofya V. Lushchekina (Emanuel Institute RAS, Moscow) for her assistanceinfo:eu-repo/semantics/publishedVersio

Nanoscale isoindigo-carriers: self-assembly and tunable properties

Over the last decade isoindigo derivatives have attracted much attention due to their high potential in pharmacy and in the chemistry of materials. In addition, isoindigo derivatives can be modified to form supramolecular structures with tunable morphologies for the use in drug delivery. Amphiphilic long-chain dialkylated isoindigos have the ability to form stable solid nanoparticles via a simple nanoprecipitation technique. Their self-assembly was investigated using tensiometry, dynamic light scattering, spectrophotometry, and fluorometry. The critical association concentrations and aggregate sizes were measured. The hydrophilic–lipophilic balance of alkylated isoindigo derivatives strongly influences aggregate morphology. In the case of short-chain dialkylated isoindigo derivatives, supramolecular polymers of 200 to 700 nm were formed. For long-chain dialkylated isoindigo derivatives, micellar aggregates of 100 to 200 nm were observed. Using micellar surfactant water-soluble forms of monosubstituted 1-hexadecylisoindigo as well as 1,1′-dimethylisoindigo were prepared for the first time. The formation of mixed micellar structures of different types in micellar anionic surfactant solutions (sodium dodecyl sulfate) was determined. These findings are of practical importance and are of potential interest for the design of drug delivery systems and new nanomaterials

Rational Design 2-Hydroxypropylphosphonium Salts as Cancer Cell Mitochondria-Targeted Vectors: Synthesis, Structure, and Biological Properties

It has been shown for a wide range of epoxy compounds that their interaction with triphenylphosphonium triflate occurs with a high chemoselectivity and leads to the formation of (2-hydroxypropyl)triphenylphosphonium triflates 3 substituted in the 3-position with an alkoxy, alkylcarboxyl group, or halogen, which were isolated in a high yield. Using the methodology for the disclosure of epichlorohydrin with alcohols in the presence of boron trifluoride etherate, followed by the substitution of iodine for chlorine and treatment with triphenylphosphine, 2-hydroxypropyltriphenylphosphonium iodides 4 were also obtained. The molecular and supramolecular structure of the obtained phosphonium salts was established, and their high antitumor activity was revealed in relation to duodenal adenocarcinoma. The formation of liposomal systems based on phosphonium salt 3 and L-α-phosphatidylcholine (PC) was employed for improving the bioavailability and reducing the toxicity. They were produced by the thin film rehydration method and exhibited cytotoxic properties. This rational design of phosphonium salts 3 and 4 has promising potential of new vectors for targeted delivery into mitochondria of tumor cells