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14 pages, 2655 KiB

Open AccessArticle

Transcutol^® P Containing SLNs for Improving 8-Methoxypsoralen Skin Delivery

by Giulia Pitzanti, Antonella Rosa, Mariella Nieddu, Donatella Valenti, Rosa Pireddu, Francesco Lai, Maria Cristina Cardia, Anna Maria Fadda and Chiara Sinico

Pharmaceutics 2020, 12(10), 973; https://doi.org/10.3390/pharmaceutics12100973 - 15 Oct 2020

Cited by 16 | Viewed by 3868

Abstract

Topical psoralens plus ultraviolet A radiation (PUVA) therapy consists in the topical application of 8-methoxypsoralen (8-MOP) followed by the skin irradiation with ultraviolet A radiation. The employment of classical 8-MOP vehicles in topical PUVA therapy is associated with poor skin deposition and weak [...] Read more.

Topical psoralens plus ultraviolet A radiation (PUVA) therapy consists in the topical application of 8-methoxypsoralen (8-MOP) followed by the skin irradiation with ultraviolet A radiation. The employment of classical 8-MOP vehicles in topical PUVA therapy is associated with poor skin deposition and weak skin permeability of psoralens, thus requiring frequent drug administration. The aim of the present work was to formulate solid lipid nanoparticles (SLNs) able to increase the skin permeation of 8-MOP. For this purpose, the penetration enhancer Transcutol^® P (TRC) was added to the SLN formulation. SLNs were characterized with respect to size, polydispersity index, zeta potential, entrapment efficiency, morphology, stability, and biocompatibility. Finally, 8-MOP skin diffusion and distribution within the skin layers was investigated using Franz cells and newborn pig skin. Freshly prepared nanoparticles showed spherical shape, mean diameters ranging between 120 and 133 nm, a fairly narrow size distribution, highly negative ζ potential values, and high entrapment efficiency. Empty and loaded formulations were almost stable over 30 days. In vitro penetration and permeation studies demonstrated a greater 8-MOP accumulation in each skin layer after SLN TRC 2% and TRC 4% application than that after SLN TRC 0% application. Finally, the results of experiments on 3T3 fibroblasts showed that the incorporation of TRC into SLNs could enhance the cellular uptake of nanoparticles, but it did not increase their cytotoxicity. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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17 pages, 4260 KiB

Open AccessArticle

Development of Liposomal Vesicles for Osimertinib Delivery to EGFR Mutation—Positive Lung Cancer Cells

by Paulina Skupin-Mrugalska and Tamara Minko

Pharmaceutics 2020, 12(10), 939; https://doi.org/10.3390/pharmaceutics12100939 - 30 Sep 2020

Cited by 15 | Viewed by 4164

Abstract

Osimertinib (OSI, AZD9291), is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. OSI has been approved as a first-line treatment of EGFR-mutant lung cancer and for metastatic [...] Read more.

Osimertinib (OSI, AZD9291), is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. OSI has been approved as a first-line treatment of EGFR-mutant lung cancer and for metastatic EGFR T790M-mutant non-small cell lung cancer. Liposome-based delivery of OSI can provide a new formulation of the drug that can be administered via alternative delivery routes (intravenous, inhalation). In this manuscript, we report for the first time development and characterization of liposomal OSI formulations with diameters of ca. 115 nm. Vesicles were composed of phosphatidylcholines with various saturation and carbon chain lengths, cholesterol and pegylated phosphoethanolamine. Liposomes were loaded with OSI passively, resulting in a drug being dissolved in the phospholipid matrix or actively via remote-loading leading to the formation of OSI precipitate in the liposomal core. Remotely loaded liposomes were characterized by nearly 100% entrapment efficacy and represent a depot of OSI. Passively-loaded vesicles released OSI following the Peppas-Sahlin model, in a mechanism combining drug diffusion and liposome relaxation. OSI-loaded liposomes composed of l-α-phosphatidylcholine (egg-PC) demonstrated a higher toxicity in non-small lung cancer cells with EGFR T790M resistance mutation (H-1975) when compared with free OSI. Developed OSI formulations did not show antiproliferative activity in vitro in healthy lung epithelial cells (MRC-5) without the EGFR mutation. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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18 pages, 1997 KiB

Open AccessArticle

Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application

by Elena Lantero, Carlos Raúl Aláez-Versón, Pilar Romero, Teresa Sierra and Xavier Fernàndez-Busquets

Pharmaceutics 2020, 12(9), 825; https://doi.org/10.3390/pharmaceutics12090825 - 29 Aug 2020

Cited by 8 | Viewed by 2914

Abstract

Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the [...] Read more.

Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determined, in in vitro Plasmodium falciparum cultures, the antimalarial activity of heparin-derived structures of different origins and sizes, to obtain formulations having a good balance of in vitro safety (neither cytotoxic nor hemolytic), low anticoagulant activity (≤23 IU/mL according to activated partial thromboplastin time assays), and not too low antimalarial activity (IC50 at least around 100 µg/mL). This led to the selection of five chemically modified heparins according to the parameters explored, i.e., chain length, sulfation degree and position, and glycol-split, and whose in vivo toxicity indicated their safety for mice up to an intravenous dose of 320 mg/kg. The in vivo antimalarial activity of the selected formulations was poor as a consequence of their short blood half-life. The covalent crosslinking of heparin onto the surface of polyethylene glycol-containing liposomes did not affect its antimalarial activity in vitro and provided higher initial plasma concentrations, although it did not increase mean circulation time. Finding a suitable nanocarrier to impart long blood residence times to the modified heparins described here will be the next step toward new heparin-based antimalarial strategies. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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22 pages, 4979 KiB

Open AccessArticle

Enhancing Oral Bioavailability of Apigenin Using a Bioactive Self-Nanoemulsifying Drug Delivery System (Bio-SNEDDS): In Vitro, In Vivo and Stability Evaluations

by Mohsin Kazi, Abdullah Alhajri, Sultan M. Alshehri, Ehab M. Elzayat, Osaid T. Al Meanazel, Faiyaz Shakeel, Omar Noman, Mohammad A. Altamimi and Fars K. Alanazi

Pharmaceutics 2020, 12(8), 749; https://doi.org/10.3390/pharmaceutics12080749 - 10 Aug 2020

Cited by 50 | Viewed by 5081

Abstract

Apigenin (APG) is a very well-known flavonoid for its anti-inflammatory and anticancer properties. The purpose of this study is to improve the solubility and bioavailability of APG using a stable bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS). APG was incorporated in an oil phase [...] Read more.

Apigenin (APG) is a very well-known flavonoid for its anti-inflammatory and anticancer properties. The purpose of this study is to improve the solubility and bioavailability of APG using a stable bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS). APG was incorporated in an oil phase comprising coconut oil fatty acid, Imwitor 988, Transcutol P, and HCO30 to form a Bio-SNEDDS. This preparation was characterized for morphology, particle size, and transmission electron microscopy (TEM). The APG performance was investigated in terms of loading, precipitation, release and stability tests from the optimal Bio-SNEDDS. An antimicrobial test was performed to investigate the activity of the Bio-SNEDDS against the selected strains. Bioavailability of the Bio-SNEDDS was evaluated using Wister rats against the commercial oral product and the pure drug. The results demonstrated the formation of an efficient nanosized (57 nm) Bio-SNEDDS with a drug loading of 12.50 mg/gm which is around 500-fold higher than free APG. TEM analysis revealed the formation of spherical and homogeneous nanodroplets of less than 60 nm. The dissolution rate was faster than the commercial product and was able to maintain 90% APG in gastro intestinal solution for more than 4 h. A stability study demonstrated that the Bio-SNEDDS is stable at a harsh condition. The in vivo pharmacokinetics parameters of the Bio-SNEDDS formulation in comparison to the pure drug showed a significant increase in maximum concentration (C_max) and area under the curve (AUC _(0–t)) of 105.05% and 91.32%, respectively. Moreover, the antimicrobial study revealed moderate inhibition in the bacterial growth rate. The APG-Bio-SNEDDS could serve as potential carrier aimed at improving the clinical application of APG. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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18 pages, 4801 KiB

Open AccessArticle

In Vitro Study of Extracellular Vesicles Migration in Cartilage-Derived Osteoarthritis Samples Using Real-Time Quantitative Multimodal Nonlinear Optics Imaging

by Leonardo Mortati, Laura de Girolamo, Carlotta Perucca Orfei, Marco Viganò, Marco Brayda-Bruno, Enrico Ragni and Alessandra Colombini

Pharmaceutics 2020, 12(8), 734; https://doi.org/10.3390/pharmaceutics12080734 - 05 Aug 2020

Cited by 14 | Viewed by 2718

Abstract

Mesenchymal stromal cells (MSCs)-derived extracellular vesicles (EVs) are promising therapeutic nano-carriers for the treatment of osteoarthritis (OA). The assessment of their uptake in tissues is mandatory but, to date, available technology does not allow to track and quantify incorporation in real-time. To fill [...] Read more.

Mesenchymal stromal cells (MSCs)-derived extracellular vesicles (EVs) are promising therapeutic nano-carriers for the treatment of osteoarthritis (OA). The assessment of their uptake in tissues is mandatory but, to date, available technology does not allow to track and quantify incorporation in real-time. To fill this knowledge gap, the present study was intended to develop an innovative technology to determine kinetics of fluorescent MSC-EV uptake by means of time-lapse quantitative microscopy techniques. Adipose-derived mesenchymal stromal cells (ASCs)-EVs were fluorescently labeled and tracked during their uptake into chondrocytes micromasses or cartilage explants, both derived from OA patients. Immunofluorescence and time-lapse coherent anti-Stokes Raman scattering, second harmonic generation and two-photon excited fluorescence were used to follow and quantify incorporation. EVs penetration appeared quickly after few minutes and reached 30–40 μm depth after 5 h in both explants and micromasses. In explants, uptake was slightly faster, with EVs signal overlapping both extracellular matrix and chondrocytes, whereas in micromasses a more homogenous diffusion was observed. The finding of this study demonstrates that this innovative technology is a powerful tool to monitor EVs migration in tissues characterized by a complex extracellular network, and to obtain data resembling in vivo conditions. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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19 pages, 3828 KiB

Open AccessArticle

Enhanced Corneal Penetration of a Poorly Permeable Drug Using Bioadhesive Multiple Microemulsion Technology

by Mohamed Moustafa Ibrahim, Doaa Nabih Maria, XiangDi Wang, Raven N. Simpson, T.J. Hollingsworth and Monica M. Jablonski

Pharmaceutics 2020, 12(8), 704; https://doi.org/10.3390/pharmaceutics12080704 - 26 Jul 2020

Cited by 18 | Viewed by 2676

Abstract

Corneal penetration is a key rate limiting step in the bioavailability of topical ophthalmic formulations that incorporate poorly permeable drugs. Recent advances have greatly aided the ocular delivery of such drugs using colloidal drug delivery systems. Ribavirin, a poorly permeable BCS class-III drug, [...] Read more.

Corneal penetration is a key rate limiting step in the bioavailability of topical ophthalmic formulations that incorporate poorly permeable drugs. Recent advances have greatly aided the ocular delivery of such drugs using colloidal drug delivery systems. Ribavirin, a poorly permeable BCS class-III drug, was incorporated in bioadhesive multiple W/O/W microemulsion (ME) to improve its corneal permeability. The drug-loaded ME was evaluated regarding its physical stability, droplet size, PDI, zeta potential, ultrastructure, viscosity, bioadhesion, in vitro release, transcorneal permeability, cytotoxicity, safety and ocular tolerance. Our ME possessed excellent physical stability, as it successfully passed several cycles of centrifugation and freeze–thaw tests. The formulation has a transparent appearance due to its tiny droplet size (10 nm). TEM confirmed ME droplet size and revealed its multilayered structure. In spite of the high aqueous solubility and the low permeability of ribavirin, this unique formulation was capable of sustaining its release for up to 24 h and improving its corneal permeability by 3-fold. The in vitro safety of our ME was proved by its high percentage cell viability, while its in vivo safety was confirmed by the absence of any sign of toxicity or irritation after either a single dose or 14 days of daily dosing. Our ME could serve as a vehicle for enhanced ocular delivery of drugs with different physicochemical properties, including those with low permeability. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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16 pages, 3002 KiB

Open AccessArticle

Formulation and Optimization of Avanafil Biodegradable Polymeric Nanoparticles: A Single-Dose Clinical Pharmacokinetic Evaluation

by Hibah M. Aldawsari, Usama A. Fahmy, Fathy Abd-Allah and Osama A. A. Ahmed

Pharmaceutics 2020, 12(6), 596; https://doi.org/10.3390/pharmaceutics12060596 - 26 Jun 2020

Cited by 6 | Viewed by 2826

Abstract

Avanafil (AVA) is a second-generation phosphodiesterase-5 (PDE5) inhibitor. AVA shows high selectivity to penile tissues and fast absorption, but has a bioavailability of about 36%. The aim was to formulate and optimize AVA-biodegradable nanoparticles (NPs) to enhance AVA bioavailability. To assess the impact [...] Read more.

Avanafil (AVA) is a second-generation phosphodiesterase-5 (PDE5) inhibitor. AVA shows high selectivity to penile tissues and fast absorption, but has a bioavailability of about 36%. The aim was to formulate and optimize AVA-biodegradable nanoparticles (NPs) to enhance AVA bioavailability. To assess the impact of variables, the Box–Behnken design was utilized to investigate and optimize the formulation process variables: the AVA:poly (lactic-co-glycolic acid) (PLGA) ratio (w/w, X1); sonication time (min, X2); and polyvinyl alcohol (PVA) concentration (%, X3). Particle size (nm, Y1) and EE% (%, Y2) were the responses. The optimized NPs were characterized for surface morphology and permeation. Furthermore, a single-oral dose (50 mg AVA) pharmacokinetic investigation on healthy volunteers was carried out. Statistical analysis revealed that all the investigated factors exhibited a significant effect on the particle size. Furthermore, the entrapment efficiency (Y2) was significantly affected by both the AVA:PLGA ratio (X1) and PVA concentration (X3). Pharmacokinetic data showed a significant increase in the area under the curve (1.68 folds) and plasma maximum concentration (1.3-fold) for the AVA NPs when compared with raw AVA. The optimization and formulation of AVA as biodegradable NPs prepared using solvent evaporation (SE) proves a successful way to enhance AVA bioavailability. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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28 pages, 7066 KiB

Open AccessArticle

Liposome-Embedding Silicon Microparticle for Oxaliplatin Delivery in Tumor Chemotherapy

by Armando Cevenini, Christian Celia, Stefania Orrù, Daniela Sarnataro, Maddalena Raia, Valentina Mollo, Marcello Locatelli, Esther Imperlini, Nicoletta Peluso, Rosa Peltrini, Enrica De Rosa, Alessandro Parodi, Luigi Del Vecchio, Luisa Di Marzio, Massimo Fresta, Paolo Antonio Netti, Haifa Shen, Xuewu Liu, Ennio Tasciotti and Francesco Salvatore

Pharmaceutics 2020, 12(6), 559; https://doi.org/10.3390/pharmaceutics12060559 - 17 Jun 2020

Cited by 23 | Viewed by 4006

Abstract

Mesoporous silicon microparticles (MSMPs) can incorporate drug-carrying nanoparticles (NPs) into their pores. An NP-loaded MSMP is a multistage vector (MSV) that forms a Matryoshka-like structure that protects the therapeutic cargo from degradation and prevents its dilution in the circulation during delivery to tumor [...] Read more.

Mesoporous silicon microparticles (MSMPs) can incorporate drug-carrying nanoparticles (NPs) into their pores. An NP-loaded MSMP is a multistage vector (MSV) that forms a Matryoshka-like structure that protects the therapeutic cargo from degradation and prevents its dilution in the circulation during delivery to tumor cells. We developed an MSV constituted by 1 µm discoidal MSMPs embedded with PEGylated liposomes containing oxaliplatin (oxa) which is a therapeutic agent for colorectal cancer (CRC). To obtain extra-small liposomes able to fit the 60 nm pores of MSMP, we tested several liposomal formulations, and identified two optimal compositions, with a prevalence of the rigid lipid 1,2-distearoyl-sn-glycero-3-phosphocholine and of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. To improve the MSV assembly, we optimized the liposome-loading inside the MSMP and achieved a five-fold increase of the payload using an innovative lyophilization approach. This procedure also increased the load and limited dimensional changes of the liposomes released from the MSV in vitro. Lastly, we found that the cytotoxic efficacy of oxa-loaded liposomes and-oxa-liposome-MSV in CRC cell culture was similar to that of free oxa. This study increases knowledge about extra-small liposomes and their loading into porous materials and provides useful hints about alternative strategies for designing drug-encapsulating NPs. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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12 pages, 2136 KiB

Open AccessArticle

A Doxorubicin-Glucuronide Prodrug Released from Nanogels Activated by High-Intensity Focused Ultrasound Liberated β-Glucuronidase

by Helena C. Besse, Yinan Chen, Hans W. Scheeren, Josbert M. Metselaar, Twan Lammers, Chrit T. W. Moonen, Wim E. Hennink and Roel Deckers

Pharmaceutics 2020, 12(6), 536; https://doi.org/10.3390/pharmaceutics12060536 - 10 Jun 2020

Cited by 6 | Viewed by 2720

Abstract

The poor pharmacokinetics and selectivity of low-molecular-weight anticancer drugs contribute to the relatively low effectiveness of chemotherapy treatments. To improve the pharmacokinetics and selectivity of these treatments, the combination of a doxorubicin-glucuronide prodrug (DOX-propGA3) nanogel formulation and the liberation of endogenous β-glucuronidase from [...] Read more.

The poor pharmacokinetics and selectivity of low-molecular-weight anticancer drugs contribute to the relatively low effectiveness of chemotherapy treatments. To improve the pharmacokinetics and selectivity of these treatments, the combination of a doxorubicin-glucuronide prodrug (DOX-propGA3) nanogel formulation and the liberation of endogenous β-glucuronidase from cells exposed to high-intensity focused ultrasound (HIFU) were investigated in vitro. First, a DOX-propGA3-polymer was synthesized. Subsequently, DOX-propGA3-nanogels were formed from this polymer dissolved in water using inverse mini-emulsion photopolymerization. In the presence of bovine β-glucuronidase, the DOX-propGA3 in the nanogels was quantitatively converted into the chemotherapeutic drug doxorubicin. Exposure of cells to HIFU efficiently induced liberation of endogenous β-glucuronidase, which in turn converted the prodrug released from the DOX-propGA3-nanogels into doxorubicin. β-glucuronidase liberated from cells exposed to HIFU increased the cytotoxicity of DOX-propGA3-nanogels to a similar extend as bovine β-glucuronidase, whereas in the absence of either bovine β-glucuronidase or β-glucuronidase liberated from cells exposed to HIFU, the DOX-propGA3-nanogels hardly showed cytotoxicity. Overall, DOX-propGA3-nanogels systems might help to further improve the outcome of HIFU-related anticancer therapy. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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15 pages, 2595 KiB

Open AccessArticle

Preserving the Integrity of Liposomes Prepared by Ethanol Injection upon Freeze-Drying: Insights from Combined Molecular Dynamics Simulations and Experimental Data

by Silvia Franzè, Francesca Selmin, Paolo Rocco, Giuseppe Colombo, Antonella Casiraghi and Francesco Cilurzo

Pharmaceutics 2020, 12(6), 530; https://doi.org/10.3390/pharmaceutics12060530 - 09 Jun 2020

Cited by 14 | Viewed by 3368

Abstract

The freeze-drying of complex formulations, such as liposomes, is challenging, particularly if dispersions contain residual organic solvents. This work aimed to investigate the effects of possible protectants, namely sucrose, trehalose and/or poly(vinyl pyrrolidone) (PVP), on the main features of the dried product using [...] Read more.

The freeze-drying of complex formulations, such as liposomes, is challenging, particularly if dispersions contain residual organic solvents. This work aimed to investigate the effects of possible protectants, namely sucrose, trehalose and/or poly(vinyl pyrrolidone) (PVP), on the main features of the dried product using a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based liposomal dispersion prepared by ethanol injection and containing ethanol up to 6%, as a model. The interactions among vesicles and protectants were preliminary screened by Molecular Dynamics (MD) simulations, which have been proved useful in rationalizing the selection of protectant(s). The freeze-drying protocol was based on calorimetric results. Overall data suggested a stronger cryo-protectant effect of trehalose, compared with sucrose, due to stronger interactions with the DPPC bilayer and the formation of highly ordered clusters around the lipids. The effect further improved in the presence of PVP. Differently from the other tested protectants, the selected trehalose/PVP combination allows to preserve liposome size, even in the presence of 6% ethanol, as demonstrated by Nanoparticle Tracking Analysis (NTA). Nevertheless, it should be also underlined that cakes blew out at an ethanol concentration higher than 1% v/v, probably due to the poor cohesion within the cake and solvent vapour pressure upon sublimation. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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17 pages, 6557 KiB

Open AccessArticle

Oral Administration of Artemisone for the Treatment of Schistosomiasis: Formulation Challenges and In Vivo Efficacy

by Johanna Zech, Daniel Gold, Nadeen Salaymeh, Netanel Cohen Sasson, Ithai Rabinowitch, Jacob Golenser and Karsten Mäder

Pharmaceutics 2020, 12(6), 509; https://doi.org/10.3390/pharmaceutics12060509 - 03 Jun 2020

Cited by 12 | Viewed by 3477

Abstract

Artemisone is an innovative artemisinin derivative with applications in the treatment of malaria, schistosomiasis and other diseases. However, its low aqueous solubility and tendency to degrade after solubilisation limits the translation of this drug into clinical practice. We developed a self-microemulsifying drug delivery [...] Read more.

Artemisone is an innovative artemisinin derivative with applications in the treatment of malaria, schistosomiasis and other diseases. However, its low aqueous solubility and tendency to degrade after solubilisation limits the translation of this drug into clinical practice. We developed a self-microemulsifying drug delivery system (SMEDDS), which is easy to produce (simple mixing) with a high drug load. In addition to known pharmaceutical excipients (Capmul MCM, Kolliphor HS15, propylene glycol), we identified Polysorb ID 46 as a beneficial new additional excipient. The physicochemical properties were characterized by dynamic light scattering, conductivity measurements, rheology and electron microscopy. High storage stability, even at 30 °C, was achieved. The orally administrated artemisone SMEDDS formulation was highly active in vivo in S. mansoni infected mice. Thorough elimination of the adult worms, their eggs and prevention of the deleterious granuloma formation in the livers of infected mice was observed even at a relatively low dose of the drug. The new formulation has a high potential to accelerate the clinical use of artemisone in schistosomiasis and malaria. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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24 pages, 2699 KiB

Open AccessArticle

Neuroprotective Effect of Ropinirole Lipid Nanoparticles Enriched Hydrogel for Parkinson’s Disease: In Vitro, Ex Vivo, Pharmacokinetic and Pharmacodynamic Evaluation

by Narendar Dudhipala and Thirupathi Gorre

Pharmaceutics 2020, 12(5), 448; https://doi.org/10.3390/pharmaceutics12050448 - 13 May 2020

Cited by 67 | Viewed by 5077

Abstract

Parkinson’s disease (rp) is a progressive neurodegenerative disorder. Ropinirole (RP) is a newer generation dopamine agonist used for the treatment of PD. It is prescribed as oral dosage form. However, limited oral bioavailability and frequent dosing limits the RP usage. The objective of [...] Read more.

Parkinson’s disease (rp) is a progressive neurodegenerative disorder. Ropinirole (RP) is a newer generation dopamine agonist used for the treatment of PD. It is prescribed as oral dosage form. However, limited oral bioavailability and frequent dosing limits the RP usage. The objective of the current investigation was to develop, optimize, evaluate pharmacokinetic (PK) and pharmacodynamic (PCD) activity of RP loaded solid lipid nanoparticles (RP-SLNs) and nanostructured lipid carriers (RP-NLCs) and containing hydrogel (RP-SLN-C and RP-NLC-C) formulations for improved oral and topical delivery. RP loaded lipid nanoparticles were optimized and converted to hydrogel using carbopol 934 as the gelling polymer. PK and PCD studies in haloperidol-induced PD were conducted in male Wistar rats. In vitro and ex vivo permeation studies showed sustained release profile and enhanced permeation compared with control formulations. Differential scanning calorimeter and X-ray diffraction studies revealed amorphous transformation; scanning electron microscope showed the spherical shape of RP in lipid nanoparticles. PK studies showed 2.1 and 2.7-folds enhancement from RP-SLN and RP-NLC from oral administration, 3.0 and 3.3-folds enhancement from RP-SLN-C and RP-NLC-C topical administration, compared with control formulations, respectively. RP-SLN-C and RP-NLC-C showed 1.4 and 1.2-folds topical bioavailability enhancement compared with RP-SLN and RP-NLC oral administration, respectively. PCD studies showed enhanced dopamine, glutathione, catalase levels and reduced lipid peroxidation levels, compared with the haloperidol-induced PD model. Overall, the results demonstrated that lipid nanoparticles and corresponding hydrogel formulations can be considered as an alternative delivery approach for the improved oral and topical delivery of RP for the effective treatment of PD. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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23 pages, 8251 KiB

Open AccessArticle

Oral Treatment of Spontaneously Hypertensive Rats with Captopril-Surface Functionalized Furosemide-Loaded Multi-Wall Lipid-Core Nanocapsules

by Cecilia B. Michalowski, Marcelo D. Arbo, Louise Altknecht, Andréia N. Anciuti, Angélica S. G. Abreu, Luciana M. R. Alencar, Adriana R. Pohlmann, Solange C. Garcia and Sílvia S. Guterres

Pharmaceutics 2020, 12(1), 80; https://doi.org/10.3390/pharmaceutics12010080 - 18 Jan 2020

Cited by 12 | Viewed by 3703

Abstract

Multi-wall lipid-core nanocapsule (MLNC) functionalized with captopril and nanoencapsulating furosemide within the core was developed as a liquid formulation for oral administration. The nanocapsules had mean particle size below 200 nm, showing unimodal and narrow size distributions with moderate dispersity (laser diffraction and [...] Read more.

Multi-wall lipid-core nanocapsule (MLNC) functionalized with captopril and nanoencapsulating furosemide within the core was developed as a liquid formulation for oral administration. The nanocapsules had mean particle size below 200 nm, showing unimodal and narrow size distributions with moderate dispersity (laser diffraction and dynamic light scattering). Zeta potential was inverted from −14.3 mV [LNC-Fur(0,5)] to +18.3 mV after chitosan coating. Transmission electron microscopy and atomic force microscopy showed spherical structures corroborating the nanometric diameter of the nanocapsules. Regarding the systolic pressure, on the first day, the formulations showed antihypertensive effect and a longer effect than the respective drug solutions. When both drugs were associated, the anti-hypertensive effect was prolonged. On the fifth day, a time effect reduction was observed for all treatments, except for the nanocapsule formulation containing both drugs [Capt(0.5)-Zn(25)-MLNC-Fur(0.45)]. For diastolic pressure, only Capt(0.5)-Zn(25)-MLNC-Fur(0.45) presented a significant difference (p < 0.05) on the first day. On the fifth day, both Capt(0.5)-MLNC-Fur(0.45) and Capt(0.5)-Zn(25)-MLNC-Fur(0.45) had an effect lasting up to 24 h. The analysis of early kidney damage marker showed a potential protection in renal function by Capt(0.5)-Zn(25)-MLNC-Fur(0.45). In conclusion, the formulation Capt(0.5)-Zn(25)-MLNC-Fur(0.45) proved to be suitable for hypertension treatment envisaging an important innovation. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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16 pages, 4188 KiB

Open AccessArticle

Niosomal Formulation of a Lipoyl-Carnosine Derivative Targeting TRPA1 Channels in Brain

by Francesca Maestrelli, Elisa Landucci, Enrico De Luca, Giulia Nerli, Maria Camilla Bergonzi, Vieri Piazzini, Domenico E. Pellegrini-Giampietro, Francesca Gullo, Andrea Becchetti, Francesco Tadini-Buoninsegni, Oscar Francesconi and Cristina Nativi

Pharmaceutics 2019, 11(12), 669; https://doi.org/10.3390/pharmaceutics11120669 - 10 Dec 2019

Cited by 8 | Viewed by 3551

Abstract

The transient receptor potential akyrin type-1 (TRPA1) is a non-selective cation channel playing a pivotal role in pain sensation and neurogenic inflammation. TRPA1 channels expressed in the central nervous system (CNS) have a critical role in the modulation of cortical spreading depression (CSD), [...] Read more.

The transient receptor potential akyrin type-1 (TRPA1) is a non-selective cation channel playing a pivotal role in pain sensation and neurogenic inflammation. TRPA1 channels expressed in the central nervous system (CNS) have a critical role in the modulation of cortical spreading depression (CSD), which is a key pathophysiological basis of migraine pain. ADM_09 is a recently developed lipoic acid-based TRPA1 antagonist that is able to revert oxaliplatin-induced neuropathic pain and inflammatory trigeminal allodynia. In this context, aiming at developing drugs that are able to target TRPA1 channels in the CNS and promote an antioxidant effect, permeability across the blood–brain barrier (BBB) represents a central issue. Niosomes are nanovesicles that can be functionalized with specific ligands selectively recognized by transporters expressed on the BBB. In this work, the activity of ADM_09 on neocortex cultures was studied, and an efficient formulation to cross the BBB was developed with the aim of increasing the concentration of ADM_09 into the brain and selectively delivering it to the CNS rapidly after parenteral administration. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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Review

Jump to: Research

27 pages, 1100 KiB

Open AccessReview

Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems

by Shi Su and Peter M. Kang

Pharmaceutics 2020, 12(9), 837; https://doi.org/10.3390/pharmaceutics12090837 - 01 Sep 2020

Cited by 96 | Viewed by 4630

Abstract

Nanotechnologies have attracted increasing attention in their application in medicine, especially in the development of new drug delivery systems. With the help of nano-sized carriers, drugs can reach specific diseased areas, prolonging therapeutic efficacy while decreasing undesired side-effects. In addition, recent nanotechnological advances, [...] Read more.

Nanotechnologies have attracted increasing attention in their application in medicine, especially in the development of new drug delivery systems. With the help of nano-sized carriers, drugs can reach specific diseased areas, prolonging therapeutic efficacy while decreasing undesired side-effects. In addition, recent nanotechnological advances, such as surface stabilization and stimuli-responsive functionalization have also significantly improved the targeting capacity and therapeutic efficacy of the nanocarrier assisted drug delivery system. In this review, we evaluate recent advances in the development of different nanocarriers and their applications in therapeutics delivery. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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33 pages, 2414 KiB

Open AccessReview

Current Trends in ATRA Delivery for Cancer Therapy

by Maria Valeria Giuli, Patrizia Nadia Hanieh, Eugenia Giuliani, Federica Rinaldi, Carlotta Marianecci, Isabella Screpanti, Saula Checquolo and Maria Carafa

Pharmaceutics 2020, 12(8), 707; https://doi.org/10.3390/pharmaceutics12080707 - 28 Jul 2020

Cited by 36 | Viewed by 5231

Abstract

All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights [...] Read more.

All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights the anti-tumor activity of this compound. Notably, oral administration of ATRA is the first choice treatment in Acute Promyelocytic Leukemia (APL) in adults and NeuroBlastoma (NB) in children. Regrettably, the promising results obtained for these diseases have not been translated yet into the clinics for solid tumors. This is mainly due to ATRA-resistance developed by cancer cells and to ineffective delivery and targeting. This up-to-date review deals with recent studies on different ATRA-loaded Drug Delivery Systems (DDSs) development and application on several tumor models. Moreover, patents, pre-clinical, and clinical studies are also reviewed. To sum up, the main aim of this in-depth review is to provide a detailed overview of the several attempts which have been made in the recent years to ameliorate ATRA delivery and targeting in cancer. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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21 pages, 1019 KiB

Open AccessReview

Nanotechnology in Modern Photodynamic Therapy of Cancer: A Review of Cellular Resistance Patterns Affecting the Therapeutic Response

by Elvin Peter Chizenga and Heidi Abrahamse

Pharmaceutics 2020, 12(7), 632; https://doi.org/10.3390/pharmaceutics12070632 - 06 Jul 2020

Cited by 40 | Viewed by 3633

Abstract

Photodynamic therapy (PDT) has emerged as a potential therapeutic option for most localized cancers. Its high measure of specificity and minimal risk of side effects compared to other therapies has put PDT on the forefront of cancer research in the current era. The [...] Read more.

Photodynamic therapy (PDT) has emerged as a potential therapeutic option for most localized cancers. Its high measure of specificity and minimal risk of side effects compared to other therapies has put PDT on the forefront of cancer research in the current era. The primary cause of treatment failure and high mortality rates is the occurrence of cancer resistance to therapy. Hence, PDT is designed to be selective and tumor-specific. However, because of complex biological characteristics and cell signaling, cancer cells have shown a propensity to acquire cellular resistance to PDT by modulating the photosensitization process or its products. Fortunately, nanotechnology has provided many answers in biomedical and clinical applications, and modern PDT now employs the use of nanomaterials to enhance its efficacy and mitigate the effects of acquired resistance. This review, therefore, sought to scrutinize the mechanisms of cellular resistance that affect the therapeutic response with an emphasis on the use of nanomaterials as a way of overriding cancer cell resistance. The resistance mechanisms that have been reported are complex and photosensitizer (PS)-specific. We conclude that altering the structure of PSs using nanotechnology is an ideal paradigm for enhancing PDT efficacy in the presence of cellular resistance. Full article

(This article belongs to the Special Issue Nanocarriers and Nanomedicine for Drug Delivery)

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