Pharmaceutics

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Open AccessEditorial

Preclinical Evaluation of Lipid-Based Nanosystems

by Ana Catarina Silva and José Manuel Sousa Lobo

Pharmaceutics 2021, 13(5), 708; https://doi.org/10.3390/pharmaceutics13050708 - 12 May 2021

Viewed by 2111

Abstract

The use of lipid-based nanosystems, including lipid nanoparticles (solid lipid nanoparticles—SLN, and nanostructured lipid carriers—NLC), nanoemulsions, and liposomes, among others, is widespread [...] Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

Research

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19 pages, 8753 KiB

Open AccessArticle

Dexamethasone-Loaded Lipomers: Development, Characterization, and Skin Biodistribution Studies

by Eloy Pena-Rodríguez, Maria Lajarin-Reinares, Aida Mata-Ventosa, Sandra Pérez-Torras and Francisco Fernández-Campos

Pharmaceutics 2021, 13(4), 533; https://doi.org/10.3390/pharmaceutics13040533 - 11 Apr 2021

Cited by 7 | Viewed by 3698

Abstract

Follicular targeting has gained more attention in recent decades, due to the possibility of obtaining a depot effect in topical administration and its potential as a tool to treat hair follicle-related diseases. Lipid core ethyl cellulose lipomers were developed and optimized, following which [...] Read more.

Follicular targeting has gained more attention in recent decades, due to the possibility of obtaining a depot effect in topical administration and its potential as a tool to treat hair follicle-related diseases. Lipid core ethyl cellulose lipomers were developed and optimized, following which characterization of their physicochemical properties was carried out. Dexamethasone was encapsulated in the lipomers (size, 115 nm; polydispersity, 0.24; zeta-potential (Z-potential), +30 mV) and their in vitro release profiles against dexamethasone in solution were investigated by vertical diffusion Franz cells. The skin biodistribution of the fluorescent-loaded lipomers was observed using confocal microscopy, demonstrating the accumulation of both lipomers and fluorochromes in the hair follicles of pig skin. To confirm this fact, immunofluorescence of the dexamethasone-loaded lipomers was carried out in pig hair follicles. The anti-inflammatory (via TNFα) efficacy of the dexamethasone-loaded lipomers was demonstrated in vitro in an HEK001 human keratinocytes cell culture and the in vitro cytotoxicity of the nanoformulation was investigated. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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24 pages, 4278 KiB

Open AccessArticle

Clarithromycin Solid Lipid Nanoparticles for Topical Ocular Therapy: Optimization, Evaluation and In Vivo Studies

by Anroop B. Nair, Jigar Shah, Bandar E. Al-Dhubiab, Shery Jacob, Snehal S. Patel, Katharigatta N. Venugopala, Mohamed A. Morsy, Sumeet Gupta, Mahesh Attimarad, Nagaraja Sreeharsha and Pottathil Shinu

Pharmaceutics 2021, 13(4), 523; https://doi.org/10.3390/pharmaceutics13040523 - 9 Apr 2021

Cited by 62 | Viewed by 5464

Abstract

Solid lipid nanoparticles (SLNs) are being extensively exploited as topical ocular carrier systems to enhance the bioavailability of drugs. This study investigated the prospects of drug-loaded SLNs to increase the ocular permeation and improve the therapeutic potential of clarithromycin in topical ocular therapy. [...] Read more.

Solid lipid nanoparticles (SLNs) are being extensively exploited as topical ocular carrier systems to enhance the bioavailability of drugs. This study investigated the prospects of drug-loaded SLNs to increase the ocular permeation and improve the therapeutic potential of clarithromycin in topical ocular therapy. SLNs were formulated by high-speed stirring and the ultra-sonication method. Solubility studies were carried out to select stearic acid as lipid former, Tween 80 as surfactant, and Transcutol P as cosurfactant. Clarithromycin-loaded SLN were optimized by fractional factorial screening and 3² full factorial designs. Optimized SLNs (CL10) were evaluated for stability, morphology, permeation, irritation, and ocular pharmacokinetics in rabbits. Fractional factorial screening design signifies that the sonication time and amount of lipid affect the SLN formulation. A 3² full factorial design established that both factors had significant influences on particle size, percent entrapment efficiency, and percent drug loading of SLNs. The release profile of SLNs (CL9) showed ~80% drug release in 8 h and followed Weibull model kinetics. Optimized SLNs (CL10) showed significantly higher permeation (30.45 μg/cm²/h; p < 0.0001) as compared to control (solution). CL10 showed spherical shape and good stability and was found non-irritant for ocular administration. Pharmacokinetics data demonstrated significant improvement of clarithromycin bioavailability (p < 0.0001) from CL10, as evidenced by a 150% increase in C_max (~1066 ng/mL) and a 2.8-fold improvement in AUC (5736 ng h/mL) (p < 0.0001) as compared to control solution (C_max; 655 ng/mL and AUC; 2067 ng h/mL). In summary, the data observed here demonstrate the potential of developed SLNs to improve the ocular permeation and enhance the therapeutic potential of clarithromycin, and hence could be a viable drug delivery approach to treat endophthalmitis. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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27 pages, 6433 KiB

Open AccessArticle

Oligonucleotide Delivery across the Caco-2 Monolayer: The Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS)

by Jana Kubackova, Ondrej Holas, Jarmila Zbytovska, Barbora Vranikova, Guanghong Zeng, Petr Pavek and Anette Mullertz

Pharmaceutics 2021, 13(4), 459; https://doi.org/10.3390/pharmaceutics13040459 - 28 Mar 2021

Cited by 11 | Viewed by 3968

Abstract

Oligonucleotides (OND) represent a promising therapeutic approach. However, their instability and low intestinal permeability hamper oral bioavailability. Well-established for oral delivery, self-emulsifying drug delivery systems (SEDDS) can overcome the weakness of other delivery systems such as long-term instability of nanoparticles or complicated formulation [...] Read more.

Oligonucleotides (OND) represent a promising therapeutic approach. However, their instability and low intestinal permeability hamper oral bioavailability. Well-established for oral delivery, self-emulsifying drug delivery systems (SEDDS) can overcome the weakness of other delivery systems such as long-term instability of nanoparticles or complicated formulation processes. Therefore, the present study aims to prepare SEDDS for delivery of a nonspecific fluorescently labeled OND across the intestinal Caco-2 monolayer. The hydrophobic ion pairing of an OND and a cationic lipid served as an effective hydrophobization method using either dimethyldioctadecylammonium bromide (DDAB) or 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). This strategy allowed a successful loading of OND-cationic lipid complexes into both negatively charged and neutral SEDDS. Subjecting both complex-loaded SEDDS to a nuclease, the negatively charged SEDDS protected about 16% of the complexed OND in contrast to 58% protected by its neutral counterpart. Furthermore, both SEDDS containing permeation-enhancing excipients facilitated delivery of OND across the intestinal Caco-2 cell monolayer. The negatively charged SEDDS showed a more stable permeability profile over 120 min, with a permeability of about 2 × 10⁻⁷ cm/s, unlike neutral SEDDS, which displayed an increasing permeability reaching up to 7 × 10⁻⁷ cm/s. In conclusion, these novel SEDDS-based formulations provide a promising tool for OND protection and delivery across the Caco-2 cell monolayer. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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22 pages, 3510 KiB

Open AccessArticle

Cyanocobalamin Ultraflexible Lipid Vesicles: Characterization and In Vitro Evaluation of Drug-Skin Depth Profiles

by Antonio José Guillot, Enrique Jornet-Mollá, Natalia Landsberg, Carmen Milián-Guimerá, M. Carmen Montesinos, Teresa M. Garrigues and Ana Melero

Pharmaceutics 2021, 13(3), 418; https://doi.org/10.3390/pharmaceutics13030418 - 20 Mar 2021

Cited by 23 | Viewed by 3784

Abstract

Atopic dermatitis (AD) and psoriasis are the most common chronic inflammatory skin disorders, which importantly affect the quality of life of patients who suffer them. Among other causes, nitric oxide has been reported as part of the triggering factors in the pathogenesis of [...] Read more.

Atopic dermatitis (AD) and psoriasis are the most common chronic inflammatory skin disorders, which importantly affect the quality of life of patients who suffer them. Among other causes, nitric oxide has been reported as part of the triggering factors in the pathogenesis of both conditions. Cyanocobalamin (vitamin B₁₂) has shown efficacy as a nitric oxide scavenger and some clinical trials have given positive outcomes in its use for treating skin pathologies. Passive skin diffusion is possible only for drugs with low molecular weights and intermediate lipophilicity. Unfortunately, the molecular weight and hydrophilicity of vitamin B₁₂ do not predict its effective diffusion through the skin. The aim of this work was to design new lipid vesicles to encapsulate the vitamin B₁₂ to enhance its skin penetration. Nine prototypes of vesicles were generated and characterized in terms of size, polydispersity, surface charge, drug encapsulation, flexibility, and stability with positive results. Additionally, their ability to release the drug content in a controlled manner was demonstrated. Finally, we found that these lipid vesicle formulations facilitated the penetration of cyanocobalamin to the deeper layers of the skin. The present work shows a promising system to effectively administer vitamin B₁₂ topically, which could be of interest in the treatment of skin diseases such as AD and psoriasis. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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21 pages, 4992 KiB

Open AccessArticle

The Impact of Lipid Handling and Phase Distribution on the Acoustic Behavior of Microbubbles

by Simone A.G. Langeveld, Inés Beekers, Gonzalo Collado-Lara, Antonius F. W. van der Steen, Nico de Jong and Klazina Kooiman

Pharmaceutics 2021, 13(1), 119; https://doi.org/10.3390/pharmaceutics13010119 - 19 Jan 2021

Cited by 11 | Viewed by 4048

Abstract

Phospholipid-coated microbubbles are ultrasound contrast agents that can be employed for ultrasound molecular imaging and drug delivery. For safe and effective implementation, microbubbles must respond uniformly and predictably to ultrasound. Therefore, we investigated how lipid handling and phase distribution affected the variability in [...] Read more.

Phospholipid-coated microbubbles are ultrasound contrast agents that can be employed for ultrasound molecular imaging and drug delivery. For safe and effective implementation, microbubbles must respond uniformly and predictably to ultrasound. Therefore, we investigated how lipid handling and phase distribution affected the variability in the acoustic behavior of microbubbles. Cholesterol was used to modify the lateral molecular packing of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)-based microbubbles. To assess the effect of lipid handling, microbubbles were produced by a direct method, i.e., lipids directly dispersed in an aqueous medium or indirect method, i.e., lipids first dissolved in an organic solvent. The lipid phase and ligand distribution in the microbubble coating were investigated using confocal microscopy, and the acoustic response was recorded with the Brandaris 128 ultra-high-speed camera. In microbubbles with 12 mol% cholesterol, the lipids were miscible and all in the same phase, which resulted in more buckle formation, lower shell elasticity and higher shell viscosity. Indirect DSPC microbubbles had a more uniform response to ultrasound than direct DSPC and indirect DSPC-cholesterol microbubbles. The difference in lipid handling between direct and indirect DSPC microbubbles significantly affected the acoustic behavior. Indirect DSPC microbubbles are the most promising candidate for ultrasound molecular imaging and drug delivery applications. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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13 pages, 2713 KiB

Open AccessArticle

Solid Lipid Particles for Lung Metastasis Treatment

by Lourdes Valdivia, Lorena García-Hevia, Manuel Bañobre-López, Juan Gallo, Rafael Valiente and Mónica López Fanarraga

Pharmaceutics 2021, 13(1), 93; https://doi.org/10.3390/pharmaceutics13010093 - 13 Jan 2021

Cited by 11 | Viewed by 3020

Abstract

Solid lipid particles (SLPs) can sustainably encapsulate and release therapeutic agents over long periods, modifying their biodistribution, toxicity, and side effects. To date, no studies have been reported using SLPs loaded with doxorubicin chemotherapy for the treatment of metastatic cancer. This study characterizes [...] Read more.

Solid lipid particles (SLPs) can sustainably encapsulate and release therapeutic agents over long periods, modifying their biodistribution, toxicity, and side effects. To date, no studies have been reported using SLPs loaded with doxorubicin chemotherapy for the treatment of metastatic cancer. This study characterizes the effect of doxorubicin-loaded carnauba wax particles in the treatment of lung metastatic malignant melanoma in vivo. Compared with the free drug, intravenously administrated doxorubicin-loaded SLPs significantly reduce the number of pulmonary metastatic foci in mice. In vitro kinetic studies show two distinctive drug release profiles. A first chemotherapy burst-release wave occurs during the first 5 h, which accounts for approximately 30% of the entrapped drug rapidly providing therapeutic concentrations. The second wave occurs after the arrival of the particles to the final destination in the lung. This release is sustained for long periods (>40 days), providing constant levels of chemotherapy in situ that trigger the inhibition of metastatic growth. Our findings suggest that the use of chemotherapy with loaded SLPs could substantially improve the effectiveness of the drug locally, reducing side effects while improving overall survival. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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23 pages, 3799 KiB

Open AccessArticle

Oral Gel Loaded by Fluconazole‒Sesame Oil Nanotransfersomes: Development, Optimization, and Assessment of Antifungal Activity

by Hala M. Alkhalidi, Khaled M. Hosny and Waleed Y. Rizg

Pharmaceutics 2021, 13(1), 27; https://doi.org/10.3390/pharmaceutics13010027 - 25 Dec 2020

Cited by 32 | Viewed by 3643

Abstract

Candidiasis is one of the frequently encountered opportunistic infections in the oral cavity and can be found in acute and chronic presentations. The study aimed to develop fluconazole-loaded sesame oil containing nanotransfersomes (FS-NTF) by the thin-layer evaporation technique to improve the local treatment [...] Read more.

Candidiasis is one of the frequently encountered opportunistic infections in the oral cavity and can be found in acute and chronic presentations. The study aimed to develop fluconazole-loaded sesame oil containing nanotransfersomes (FS-NTF) by the thin-layer evaporation technique to improve the local treatment of oral candidiasis. Optimization of the formulation was performed using the Box‒Behnken statistical design to determine the variable parameters that influence the vesicle size, entrapment efficiency, zone of inhibition, and ulcer index. Finally, the formulated FS-NTF was embedded within the hyaluronic acid‒based hydrogel (HA-FS-NTF). The rheological behavior of the optimized HA-FS-NTF was assessed and the thixotropic behavior with the pseudoplastic flow was recorded; this is desirable for an oral application. An in vitro release study revealed the rapid release of fluconazole from the HA-FS-NTF. This was significantly higher when compared with the fluconazole suspension and hyaluronic acid hydrogel containing fluconazole. Correspondingly, the ex vivo permeation was also found to be higher in HA-FS-NTF in sheep buccal mucosa (400 μg/cm²) when compared with the fluconazole suspension (122 μg/cm²) and hyaluronic acid hydrogel (294 μg/cm²). The optimized formulation had an inhibition zone of 14.33 ± 0.76 mm and enhanced antifungal efficacy for the ulcer index (0.67 ± 0.29) in immunocompromised animals with Candida infection; these findings were superior to those of other tested formulations. Hence, it can be summarized that fluconazole can effectively be delivered for the treatment of oral candidiasis when it is entrapped in a nanotransfersome carrier and embedded into cross-linked hyaluronic acid hydrogel. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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22 pages, 4367 KiB

Open AccessArticle

Nanostructured Lipid Carriers Made of Ω-3 Polyunsaturated Fatty Acids: In Vitro Evaluation of Emerging Nanocarriers to Treat Neurodegenerative Diseases

by Sara Hernando, Enara Herran, Rosa Maria Hernandez and Manoli Igartua

Pharmaceutics 2020, 12(10), 928; https://doi.org/10.3390/pharmaceutics12100928 - 29 Sep 2020

Cited by 9 | Viewed by 3699

Abstract

Neurodegenerative diseases (ND) are one of the main problems of public health systems in the 21st century. The rise of nanotechnology-based drug delivery systems (DDS) has become in an emerging approach to target and treat these disorders related to the central nervous system [...] Read more.

Neurodegenerative diseases (ND) are one of the main problems of public health systems in the 21st century. The rise of nanotechnology-based drug delivery systems (DDS) has become in an emerging approach to target and treat these disorders related to the central nervous system (CNS). Among others, the use of nanostructured lipid carriers (NLCs) has increased in the last few years. Up to today, most of the developed NLCs have been made of a mixture of solid and liquid lipids without any active role in preventing or treating diseases. In this study, we successfully developed NLCs made of a functional lipid, such as the hydroxylated derivate of docohexaenoic acid (DHAH), named DHAH-NLCs. The newly developed nanocarriers were around 100 nm in size, with a polydispersity index (PDI) value of <0.3, and they exhibited positive zeta potential due to the successful chitosan (CS) and TAT coating. DHAH-NLCs were shown to be safe in both dopaminergic and microglia primary cell cultures. Moreover, they exhibited neuroprotective effects in dopaminergic neuron cell cultures after exposition to 6-hydroxydopamine hydrochloride (6-OHDA) neurotoxin and decreased the proinflammatory cytokine levels in microglia primary cell cultures after lipopolysaccharide (LPS) stimuli. The levels of the three tested cytokines, IL-6, IL-1β and TNF-α were decreased almost to control levels after the treatment with DHAH-NLCs. Taken together, these data suggest the suitability of DHAH-NLCs to attaining enhanced and synergistic effects for the treatment of NDs. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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22 pages, 3522 KiB

Open AccessArticle

Design, Optimization, Manufacture and Characterization of Efavirenz-Loaded Flaxseed Oil Nanoemulsions

by Priveledge Mazonde, Sandile M. M. Khamanga and Roderick B. Walker

Pharmaceutics 2020, 12(9), 797; https://doi.org/10.3390/pharmaceutics12090797 - 23 Aug 2020

Cited by 29 | Viewed by 6584

Abstract

The formation, manufacture and characterization of low energy water-in-oil (w/o) nanoemulsions prepared using cold pressed flaxseed oil containing efavirenz was investigated. Pseudo-ternary phase diagrams were constructed to identify the nanoemulsion region(s). Other potential lipid-based drug delivery phases containing flaxseed oil with 1:1 m/m [...] Read more.

The formation, manufacture and characterization of low energy water-in-oil (w/o) nanoemulsions prepared using cold pressed flaxseed oil containing efavirenz was investigated. Pseudo-ternary phase diagrams were constructed to identify the nanoemulsion region(s). Other potential lipid-based drug delivery phases containing flaxseed oil with 1:1 m/m surfactant mixture of Tween^® 80, Span^® 20 and different amounts of ethanol were tested to characterize the impact of surfactant mixture on emulsion formation. Flaxseed oil was used as the oil phase as efavirenz exhibited high solubility in the vehicle when compared to other vegetable oils tested. Optimization of surfactant mixtures was undertaken using design of experiments, specifically a D-optimal design with the flaxseed oil content set at 10% m/m. Two solutions from the desired optimization function were produced based on desirability and five nanoemulsion formulations were produced and characterized in terms of in vitro release of efavirenz, physical and chemical stability. Metastable nanoemulsions containing 10% m/m flaxseed oil were successfully manufactured and significant isotropic gel (semisolid) and o/w emulsions were observed during phase behavior studies. Droplet sizes ranged between 156 and 225 nm, zeta potential between −24 and −41 mV and all formulations were found to be monodisperse with polydispersity indices ≤ 0.487. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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17 pages, 5964 KiB

Open AccessArticle

Spontaneous In Situ Formation of Liposomes from Inert Porous Microparticles for Oral Drug Delivery

by Maryam Farzan, Gabriela Québatte, Katrin Strittmatter, Florentine Marianne Hilty, Joachim Schoelkopf, Jörg Huwyler and Maxim Puchkov

Pharmaceutics 2020, 12(8), 777; https://doi.org/10.3390/pharmaceutics12080777 - 15 Aug 2020

Cited by 6 | Viewed by 4450

Abstract

Despite the wide-spread use of liposomal drug delivery systems, application of these systems for oral purposes is limited due to their large-scale formulation and storage issues. Proliposomes are one of the formulation approaches for achieving solid powders that readily form liposomes upon hydration. [...] Read more.

Despite the wide-spread use of liposomal drug delivery systems, application of these systems for oral purposes is limited due to their large-scale formulation and storage issues. Proliposomes are one of the formulation approaches for achieving solid powders that readily form liposomes upon hydration. In this work, we investigated a dry powder formulation of a model low-soluble drug with phospholipids loaded in porous functionalized calcium carbonate microparticles. We characterized the liposome formation under conditions that mimic the different gastrointestinal stages and studied the factors that influence the dissolution rate of the model drug. The liposomes that formed upon direct contact with the simulated gastric environment had a capacity to directly encapsulate 25% of the drug in situ. The emerged liposomes allowed complete dissolution of the drug within 15 min. We identified a negative correlation between the phospholipid content and the rate of water uptake. This correlation corroborated the results obtained for the rate of dissolution and liposome encapsulation efficiency. This approach allows for the development of solid proliposomal dosage formulations, which can be scaled up with regular processes. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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24 pages, 5106 KiB

Open AccessArticle

Light-Activated Liposomes Coated with Hyaluronic Acid as a Potential Drug Delivery System

by Otto K. Kari, Shirin Tavakoli, Petteri Parkkila, Simone Baan, Roosa Savolainen, Teemu Ruoslahti, Niklas G. Johansson, Joseph Ndika, Harri Alenius, Tapani Viitala, Arto Urtti and Tatu Lajunen

Pharmaceutics 2020, 12(8), 763; https://doi.org/10.3390/pharmaceutics12080763 - 12 Aug 2020

Cited by 35 | Viewed by 6150

Abstract

Light-activated liposomes permit site and time-specific drug delivery to ocular and systemic targets. We combined a light activation technology based on indocyanine green with a hyaluronic acid (HA) coating by synthesizing HA–lipid conjugates. HA is an endogenous vitreal polysaccharide and a potential targeting [...] Read more.

Light-activated liposomes permit site and time-specific drug delivery to ocular and systemic targets. We combined a light activation technology based on indocyanine green with a hyaluronic acid (HA) coating by synthesizing HA–lipid conjugates. HA is an endogenous vitreal polysaccharide and a potential targeting moiety to cluster of differentiation 44 (CD44)-expressing cells. Light-activated drug release from 100 nm HA-coated liposomes was functional in buffer, plasma, and vitreous samples. The HA-coating improved stability in plasma compared to polyethylene glycol (PEG)-coated liposomes. Liposomal protein coronas on HA- and PEG-coated liposomes after dynamic exposure to undiluted human plasma and porcine vitreous samples were hydrophilic and negatively charged, thicker in plasma (~5 nm hard, ~10 nm soft coronas) than in vitreous (~2 nm hard, ~3 nm soft coronas) samples. Their compositions were dependent on liposome formulation and surface charge in plasma but not in vitreous samples. Compared to the PEG coating, the HA-coated liposomes bound more proteins in vitreous samples and enriched proteins related to collagen interactions, possibly explaining their slightly reduced vitreal mobility. The properties of the most abundant proteins did not correlate with liposome size or charge, but included proteins with surfactant and immune system functions in plasma and vitreous samples. The HA-coated light-activated liposomes are a functional and promising alternative for intravenous and ocular drug delivery. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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22 pages, 3781 KiB

Open AccessArticle

Porous Nanostructure, Lipid Composition, and Degree of Drug Supersaturation Modulate In Vitro Fenofibrate Solubilization in Silica-Lipid Hybrids

by Ruba Almasri, Paul Joyce, Hayley B. Schultz, Nicky Thomas, Kristen E. Bremmell and Clive A. Prestidge

Pharmaceutics 2020, 12(7), 687; https://doi.org/10.3390/pharmaceutics12070687 - 21 Jul 2020

Cited by 9 | Viewed by 3393

Abstract

The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3–22.7% w/w, (ii) lipid [...] Read more.

The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3–22.7% w/w, (ii) lipid type: medium-chain triglyceride (Captex 300) and mono and diester of caprylic acid (Capmul PG8), and (iii) silica nanostructure: spray dried fumed silica (FS) and mesoporous silica (MPS), on the in vitro dissolution, solubilization, and solid-state stability of the model drug fenofibrate (FEN). Greater FEN crystallinity was detected at higher drug loads and within the MPS formulations. Furthermore, an increased rate and extent of dissolution was achieved by FS formulations when compared to crystalline FEN (5–10-fold), a commercial product; APO-fenofibrate (2.4–4-fold) and corresponding MPS formulations (2–4-fold). Precipitation of FEN during in vitro lipolysis restricted data interpretation, however a synergistic effect between MPS and Captex 300 in enhancing FEN aqueous solubilization was attained. It was concluded that a balance between in vitro performance and drug loading is key, and the optimum drug load was determined to be between 7–16% w/w, which corresponds to (200–400% equilibrium solubility in lipid S_eq). This study provides valuable insight into the impact of key characteristics of SLHs, in constructing optimized solid-state lipid-based formulations for the oral delivery of PWSDs. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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19 pages, 6008 KiB

Open AccessArticle

Effectiveness of a Controlled 5-FU Delivery Based on FZD10 Antibody-Conjugated Liposomes in Colorectal Cancer In vitro Models

by Maria Principia Scavo, Annalisa Cutrignelli, Nicoletta Depalo, Elisabetta Fanizza, Valentino Laquintana, Giampietro Gasparini, Gianluigi Giannelli and Nunzio Denora

Pharmaceutics 2020, 12(7), 650; https://doi.org/10.3390/pharmaceutics12070650 - 10 Jul 2020

Cited by 23 | Viewed by 3689

Abstract

The use of controlled delivery therapy in colorectal cancer (CRC) reduces toxicity and side effects. Recently, we have suggested that the Frizzled 10 (FZD10) protein, a cell surface receptor belonging to the FZD protein family that is overexpressed in CRC cells, is a [...] Read more.

The use of controlled delivery therapy in colorectal cancer (CRC) reduces toxicity and side effects. Recently, we have suggested that the Frizzled 10 (FZD10) protein, a cell surface receptor belonging to the FZD protein family that is overexpressed in CRC cells, is a novel candidate for targeting and treatment of CRC. Here, the anticancer effect of novel immuno-liposomes loaded with 5-Fluorouracil (5-FU), decorated with an antibody against FZD10 (anti-FZD10/5-FU/LPs), was evaluated in vitro on two different CRC cell lines, namely metastatic CoLo-205 and nonmetastatic CaCo-2 cells, that were found to overexpress FZD10. The anti-FZD10/5-FU/LPs obtained were extensively characterized and their preclinical therapeutic efficacy was evaluated with the MTS cell proliferation assay based on reduction of tetrazolium compound, scratch test, Field Emission Scanning Electron Microscopes (FE-SEM) investigation and immunofluorescence analysis. The results highlighted that the cytotoxic activity of 5-FU was enhanced when encapsulated in the anti-FZD10 /5-FU/LPs at the lowest tested concentrations, as compared to the free 5-FU counterparts. The immuno-liposomes proposed herein possess a great potential for selective treatment of CRC because, in future clinical applications, they can be encapsulated in gastro-resistant capsules or suppositories for oral or rectal delivery, thereby successfully reaching the intestinal tract in a minimally invasive manner. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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16 pages, 2865 KiB

Open AccessArticle

N-Alkylisatin-Loaded Liposomes Target the Urokinase Plasminogen Activator System in Breast Cancer

by Lisa Belfiore, Darren N. Saunders, Marie Ranson and Kara L. Vine

Pharmaceutics 2020, 12(7), 641; https://doi.org/10.3390/pharmaceutics12070641 - 7 Jul 2020

Cited by 16 | Viewed by 2712

Abstract

The urokinase plasminogen activator and its receptor (uPA/uPAR) are biomarkers for metastasis, especially in triple-negative breast cancer. We prepared anti-mitotic N-alkylisatin (N-AI)-loaded liposomes functionalized with the uPA/uPAR targeting ligand, plasminogen activator inhibitor type 2 (PAI-2/SerpinB2), and assessed liposome uptake in [...] Read more.

The urokinase plasminogen activator and its receptor (uPA/uPAR) are biomarkers for metastasis, especially in triple-negative breast cancer. We prepared anti-mitotic N-alkylisatin (N-AI)-loaded liposomes functionalized with the uPA/uPAR targeting ligand, plasminogen activator inhibitor type 2 (PAI-2/SerpinB2), and assessed liposome uptake in vitro and in vivo. Receptor-dependent uptake of PAI-2-functionalized liposomes was significantly higher in the uPA/uPAR overexpressing MDA-MB-231 breast cancer cell line relative to the low uPAR/uPAR expressing MCF-7 breast cancer cell line. Furthermore, N-AI cytotoxicity was enhanced in a receptor-dependent manner. In vivo, PAI-2 N-AI liposomes had a plasma half-life of 5.82 h and showed an increased accumulation at the primary tumor site in an orthotopic MDA-MB-231 BALB/c-Fox1nu/Ausb xenograft mouse model, relative to the non-functionalized liposomes, up to 6 h post-injection. These findings support the further development of N-AI-loaded PAI-2-functionalized liposomes for uPA/uPAR-positive breast cancer, especially against triple-negative breast cancer, for which the prognosis is poor and treatment is limited. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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27 pages, 2919 KiB

Open AccessArticle

Double Optimization of Rivastigmine-Loaded Nanostructured Lipid Carriers (NLC) for Nose-to-Brain Delivery Using the Quality by Design (QbD) Approach: Formulation Variables and Instrumental Parameters

by Sara Cunha, Cláudia Pina Costa, Joana A. Loureiro, Jorge Alves, Andreia F. Peixoto, Ben Forbes, José Manuel Sousa Lobo and Ana Catarina Silva

Pharmaceutics 2020, 12(7), 599; https://doi.org/10.3390/pharmaceutics12070599 - 28 Jun 2020

Cited by 82 | Viewed by 8229

Abstract

Rivastigmine is a drug commonly used in the management of Alzheimer’s disease that shows bioavailability problems. To overcome this, the use of nanosystems, such as nanostructured lipid carriers (NLC), administered through alternative routes seems promising. In this work, we performed a double optimization [...] Read more.

Rivastigmine is a drug commonly used in the management of Alzheimer’s disease that shows bioavailability problems. To overcome this, the use of nanosystems, such as nanostructured lipid carriers (NLC), administered through alternative routes seems promising. In this work, we performed a double optimization of a rivastigmine-loaded NLC formulation for direct drug delivery from the nose to the brain using the quality by design (QbD) approach, whereby the quality target product profile (QTPP) was the requisite for nose to brain delivery. The experiments started with the optimization of the formulation variables (or critical material attributes—CMAs) using a central composite design. The rivastigmine-loaded NLC formulations with the best critical quality attributes (CQAs) of particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) were selected for the second optimization, which was related to the production methods (ultrasound technique and high-pressure homogenization). The most suitable instrumental parameters for the production of NLC were analyzed through a Box–Behnken design, with the same CQAs being evaluated for the first optimization. For the second part of the optimization studies, were selected two rivastigmine-loaded NLC formulations: one produced by ultrasound technique and the other by the high-pressure homogenization (HPH) method. Afterwards, the pH and osmolarity of these formulations were adjusted to the physiological nasal mucosa values and in vitro drug release studies were performed. The results of the first part of the optimization showed that the most adequate ratios of lipids and surfactants were 7.49:1.94 and 4.5:0.5 (%, w/w), respectively. From the second part of the optimization, the results for the particle size, PDI, ZP, and EE of the rivastigmine-loaded NLC formulations produced by ultrasound technique and HPH method were, respectively, 114.0 ± 1.9 nm and 109.0 ± 0.9 nm; 0.221 ± 0.003 and 0.196 ± 0.007; −30.6 ± 0.3 mV and −30.5 ± 0.3 mV; 97.0 ± 0.5% and 97.2 ± 0.3%. Herein, the HPH was selected as the most suitable production method, although the ultrasound technique has also shown effectiveness. In addition, no significant changes in CQAs were observed after 90 days of storage of the formulations at different temperatures. In vitro studies showed that the release of rivastigmine followed a non-Fickian mechanism, with an initial fast drug release followed by a prolonged release over 48 h. This study has optimized a rivastigmine-loaded NLC formulation produced by the HPH method for nose-to-brain delivery of rivastigmine. The next step is for in vitro and in vivo experiments to demonstrate preclinical efficacy and safety. QbD was demonstrated to be a useful approach for the optimization of NLC formulations for which specific physicochemical requisites can be identified. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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Liposomes to Augment Dialysis in Preclinical Models: A Structured Review

by Kevin Hart, Martyn Harvey, Mingtan Tang, Zimei Wu and Grant Cave

Pharmaceutics 2021, 13(3), 395; https://doi.org/10.3390/pharmaceutics13030395 - 16 Mar 2021

Cited by 8 | Viewed by 2911

Abstract

In recent years, a number of groups have been investigating the use of “empty” liposomes with no drug loaded as scavengers both for exogenous intoxicants and endogenous toxic molecules. Preclinical trials have demonstrated that repurposing liposomes to sequester such compounds may prove clinically [...] Read more.

In recent years, a number of groups have been investigating the use of “empty” liposomes with no drug loaded as scavengers both for exogenous intoxicants and endogenous toxic molecules. Preclinical trials have demonstrated that repurposing liposomes to sequester such compounds may prove clinically useful. The use of such “empty” liposomes in the dialysate during dialysis avoids recognition by complement surveillance, allowing high doses of liposomes to be used. The “reach” of dialysis may also be increased to molecules that are not traditionally dialysable. We aim to review the current literature in this area with the aims of increasing awareness and informing further research. A structured literature search identified thirteen papers which met the inclusion criteria. Augmenting the extraction of ammonia in hepatic failure with pH-gradient liposomes with acidic centres in peritoneal dialysis is the most studied area, with work progressing toward phase one trials. Liposomes used to augment the removal of exogenous intoxicants and protein-bound uraemic and hepatic toxins that accumulate in these organ failures and liposome-supported enzymatic dialysis have also been studied. It is conceivable that liposomes will be repurposed from the role of pharmaceutical vectors to gain further indications as clinically useful nanomedical antidotes/treatments within the next decade. Full article

(This article belongs to the Special Issue Preclinical Evaluation of Lipid-Based Nanosystems)

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