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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 65148

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Dr. Dimitris Tsiourvas

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Institute of Nanoscience and Nanotechnology, National Centre for Scientific Research “Demokritos”, P.O. Box 60037, 15310 Aghia Paraskevi, Greece
Interests: functional liposomes; functional dendritic polymers; nano-sized drug delivery systems; drug targeting; triggered drug release
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Dear Colleagues,

Since the introduction of the “magic bullet” concept by Paul Ehrlich in 1900, medicinal research has focused on developing pharmaceuticals that have the property of being directed towards specific targets of the body so as to increase therapeutic outcome and/or reduce side effects. From the early days, it was realized that the route of administration can yield different therapeutic results, initiating research on drug delivery. Drug delivery systems have therefore been introduced as a means to control drug biodistribution and reduce non-specific localization. The concept of drug carriers that can encapsulate a bioactive compound, increasing its solubility and its physicochemical stability, evade the attack of the immune system, finally find the target and release their payload in a controlled fashion, had limited success in the past but was largely reinvigorated with the advent of nanotechnology. Nano-sized drug delivery systems have been widely studied during the last three decades, engaging scientists of very different backgrounds, from chemists and material scientists to biologists and medical doctors. The renewed optimism in the field brought about by the introduction of nanoscience and nanotechnology in medicine, gave rise to the pursuit of additional goals such as triggered release, enhanced cell membrane permeation and, even, subcellular targeting. To date, more than fifty nanotherapeutics/nanoformulations have been approved, primarily based on liposomes, polymeric micelles or PEGylated peptides/proteins, and even more are currently under clinical investigation. One may argue that, despite great research efforts, relatively few systems are currently on the market, but this will change due to ongoing research, exploring new ways to evade the immune system, and identifying and targeting new cell receptors related to diseases. Further advances are anticipated by the use of appropriate mathematical modeling and computer science, including artificial neural networks, that are emerging to facilitate further understanding of the complex processes related to drug delivery.

In this Special Issue of Pharmaceuticals, both research, mini-review and review articles advancing our knowledge on nano-sized drug delivery systems are invited. Topics include, but are not limited to, theoretical and experimental research on the synthesis and development of nanocarriers or nanoformulations, their physicochemical and biological characterization, nanoparticle interaction with the immune system, computational modeling of nanoparticle drug delivery, in vitro and in vivo studies, preclinical and clinical studies, as well as safety issues regarding their production, handling and disposal.

Dr. Dimitris Tsiourvas
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

nano-sized systems
drug encapsulation
drug targeting
biodistribution
controlled release
triggered release

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Published Papers (9 papers)

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Research

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23 pages, 4781 KiB

Open AccessArticle

Micellisation Mechanism and Behaviour of Soluplus^{^{^®}}–Furosemide Micelles: Preformulation Studies of an Oral Nanocarrier-Based System

by Julia F. Alopaeus, Ellen Hagesæther and Ingunn Tho

Pharmaceuticals 2019, 12(1), 15; https://doi.org/10.3390/ph12010015 - 19 Jan 2019

Cited by 62 | Viewed by 6565

Abstract

In this study, self-assembling Soluplus^{^®} micelles were examined for inherent properties. Through calorimetric analysis, the critical micelle concentration (CMC) could be determined at 25 and 37 °C, and the influence of three media (Milli-Q water, phosphate-buffered saline (PBS) with a pH of 7.4 and 0.1 M HCl) on the lower critical solution temperature (LCST) was detected. Furthermore, the solubilisation of a poorly soluble drug, furosemide, into the Soluplus^{^®} micelles was studied. The concentration-dependent properties of the micellar system were assessed through an examination of the micellar size, polydispersity, morphology, viscosity and solubilising properties, which were all found to be affected by the concentration, but temperature, pH and the composition of the test medium were also found to have an effect. Homogeneity in the estimated micellar size and morphology was shown for monophasic micelle dispersions in lower concentrations and with a shift towards more complex structures or aggregates in higher concentrations. The micelles were further investigated in terms of drug release and biocompatibility with mucus-producing HT29-MTX cells, where no biocompatibility issues were found. In this research, the implications for oral drug delivery are discussed and valuable preformulation information is provided on the micellar properties of a Soluplus^{^®} drug system in a liquid or semi-solid form. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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11 pages, 1368 KiB

Open AccessArticle

Decrease of Antimicrobial Resistance through Polyelectrolyte-Coated Nanoliposomes Loaded with β-Lactam Drug

by Lina M. Arévalo, Cristhian J. Yarce, José Oñate-Garzón and Constain H. Salamanca

Pharmaceuticals 2019, 12(1), 1; https://doi.org/10.3390/ph12010001 - 23 Dec 2018

Cited by 17 | Viewed by 4721

Abstract

Currently, one of the greatest health challenges worldwide is the resistance to antibiotic drugs, which has led to the pursuit of new alternatives for the recovery of biological activity, where the use of different types of nano-systems has shown an interesting potential. In this study, we evaluated the antibiotic activity of a model drug (ampicillin) encapsulated within coated-nanoliposomes on strains of Staphylococcus aureus with different antibiotic-resistance degrees. Hence, liposomes were elaborated by the ethanol injection method and were coated with a cationic polymer (Eudragit E-100) through the layer-by-layer process. Liposome characterization, such as size, polydispersity, zeta potential, and encapsulation efficiency were determined using dynamic light scattering and ultrafiltration/centrifugation techniques. Although biological activity was evaluated using three ATCC strains of S. aureus corresponding to ATCC 25923 (sensitive), ATCC 29213 (resistant) and ATCC 43300 (very resistant). The results showed changes in size (from ~150 to 220 nm), polydispersity (from 0.20 to 0.45) and zeta potential (from −37 to +45 mV) for the coating process. In contrast, encapsulation efficiency of approximately 70% and an increase in antibiotic activity of 4 and 18 times more on those S. aureus-resistant strains have been observed. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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14 pages, 3963 KiB

Open AccessArticle

Differential Scanning Calorimetry Analyses of Idebenone-Loaded Solid Lipid Nanoparticles Interactions with a Model of Bio-Membrane: A Comparison with In Vitro Skin Permeation Data

by Lucia Montenegro, Francesco Castelli and Maria Grazia Sarpietro

Pharmaceuticals 2018, 11(4), 138; https://doi.org/10.3390/ph11040138 - 16 Dec 2018

Cited by 23 | Viewed by 4870

Abstract

Differential scanning calorimetry (DSC) has emerged as a helpful technique both to characterize drug delivery systems and to study their interactions with bio-membranes. In this work, we compared idebenone (IDE)-loaded solid lipid nanoparticle (SLN) interactions with bio-membranes assessed by DSC with previous in vitro skin penetration data to evaluate the feasibility of predicting IDE skin penetration using DSC analyses. In vitro interactions experiments were performed using multi-lamellar liposomes as a model of bio-membrane. Enthalpy changes (ΔH) and transition temperature (Tm) were assessed during nine repeated DSC scans to evaluate IDE-loaded SLN–bio-membrane interactions over time. Analyzing ΔH and Tm values for each scan, we observed that the difference of ΔH and Tm values between the first and the last scan seemed to be related to SLN ability to locate IDE in the epidermis and in the stratum corneum, respectively. Therefore, the results of this study suggest the possibility of qualitatively predicting in vitro IDE skin penetration from IDE-loaded SLN utilizing the calorimetric parameters obtained from interaction experiments between the carriers under investigation and a model of bio-membrane. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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16 pages, 4409 KiB

Open AccessArticle

Smart Bandage Based on Molecularly Imprinted Polymers (MIPs) for Diclofenac Controlled Release

by Ortensia Ilaria Parisi, Mariarosa Ruffo, Luca Scrivano, Rocco Malivindi, Antonio Vassallo and Francesco Puoci

Pharmaceuticals 2018, 11(4), 92; https://doi.org/10.3390/ph11040092 - 22 Sep 2018

Cited by 19 | Viewed by 5536

Abstract

The aim of the present study was the development of a “smart bandage” for the topical administration of diclofenac, in the treatment of localized painful and inflammatory conditions, incorporating Molecularly Imprinted Polymers (MIPs) for the controlled release of this anti-inflammatory drug. For this purpose, MIP spherical particles were synthesized by precipitation polymerization, loaded with the therapeutic agent and incorporated into the bandage surface. Batch adsorption binding studies were performed to investigate the adsorption isotherms and kinetics and the selective recognition abilities of the synthesized MIP. In vitro diffusion studies were also carried out using Franz cells and the obtained results were reported as percentage of the diffused dose, cumulative amount of diffused drug, steady-state drug flux and permeability coefficient. Moreover, the biocompatibility of the developed device was evaluated using the EPISKIN™ model. The Scatchard analysis indicated that the prepared MIP is characterized by the presence of specific binding sites for diclofenac, which are not present in the corresponding non-imprinted polymer, and the obtained results confirmed both the ability of the prepared bandage to prolong the drug release and the absence of skin irritation reactions. Therefore, these results support the potential application of the developed “smart bandage” as topical device for diclofenac sustained release. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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13 pages, 4092 KiB

Open AccessArticle

A Novel PAA Derivative with Enhanced Drug Efficacy in Pancreatic Cancer Cell Lines

by Ali Alsuraifi, Paul Kong Thoo Lin, Anthony Curtis, Dimitrios A. Lamprou and Clare Hoskins

Pharmaceuticals 2018, 11(4), 91; https://doi.org/10.3390/ph11040091 - 22 Sep 2018

Cited by 3 | Viewed by 4802

Abstract

Nanoparticles have been shown to be effective drug carriers in cancer therapy. Pancreatic cancer forms dense tumours which are often resistant to drug molecules. In order to overcome such multidrug resistance, new drug entities, novel delivery systems and combination therapy strategies are being explored. In this paper, we report the design and synthesis of a poly(allylamine)-based amphiphile modified with hydrophobic naphthalimido pendant groups. Bisnaphthalimide compounds have been shown to possess anticancer activity. The potential of this polymer to encapsulate, solubilize and enhance drug (5-fluorouricil and bis-(naphthalimidopropyl)-diaminooctane) cytotoxicity in BxPC-3 cells was evaluated. Our studies showed that the insoluble drugs could be formulated up to 4.3 mg mL⁻¹ and 2.4 mg mL⁻¹ inside the amphiphiles, respectively. Additionally, the novel poly(allylamine)-naphthalimide carrier resulted in an amplification of cytotoxic effect with drug treatment after 24 h, and was capable of reduction of 50% cell population at concentrations as low as 3 μg mL⁻¹. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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13 pages, 3579 KiB

Open AccessArticle

Low Molecular Weight Chitosan-Coated PLGA Nanoparticles for Pulmonary Delivery of Tobramycin for Cystic Fibrosis

by Nusaiba K. Al-Nemrawi, Nid’’A H. Alshraiedeh, Aref L. Zayed and Bashar M. Altaani

Pharmaceuticals 2018, 11(1), 28; https://doi.org/10.3390/ph11010028 - 8 Mar 2018

Cited by 69 | Viewed by 9745

Abstract

(1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to LMWC were prepared: control (0:0.50), F₀ (1:0.25), F₀.₅ (1:0.5), and F₁ (1:1). (3) Results: The results showed that the size of the particles increased from 220.7 nm to 575.77 nm as the concentration of LMWC used in the formulation increased. The surface charge was also affected by the amount of LMWC, where uncoated-PLGA nanoparticles had negative charges (−2.8 mV), while coated-PLGA NPs had positive charges (+33.47 to +50.13 mV). SEM confirmed the size and the spherical homogeneous morphology of the NPs. Coating the NPs with LMWC enhanced the mucoadhesive properties of the NPs and sustained the tobramycin release over two days. Finally, all NPs had antimicrobial activity that increased as the amount of LMWC increased. (4) Conclusion: In conclusion, the formulation of mucoadhesive, controlled-release, tobramycin-LMWC-PLGA nanoparticles for the treatment of P. aeruginosa in cystic fibrosis patients is possible, and their properties could be controlled by controlling the concentration of LMWC. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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15 pages, 11550 KiB

Open AccessArticle

Application of Nanoparticle Technology to Reduce the Anti-Microbial Resistance through β-Lactam Antibiotic-Polymer Inclusion Nano-Complex

by Constain H. Salamanca, Cristhian J. Yarce, Yony Roman, Andrés F. Davalos and Gustavo R. Rivera

Pharmaceuticals 2018, 11(1), 19; https://doi.org/10.3390/ph11010019 - 10 Feb 2018

Cited by 20 | Viewed by 5521

Abstract

Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the capability of the inclusion of nano-Complex formed between the sodium salt of poly(maleic acid-alt-octadecene) and a β-lactam drug (ampicillin trihydrate) to avoid the chemical and enzymatic degradation and enhance the biological activity were evaluated. PAM-18Na was produced and characterized, as reported previously. The formation of polymeric hydrophobic aggregates in aqueous solution was determined, using pyrene as a fluorescent probe. Furthermore, the formation of polymer-drug nano-complexes was characterized by Differential Scanning Calorimetry-DSC, viscometric, ultrafiltration/centrifugation assays, zeta potential and size measurements were determined by dynamic light scattering-DLS. The PAM-18Na capacity to avoid the chemical degradation was studied through stress stability tests. The enzymatic degradation was evaluated from a pure β-lactamase, while the biological degradation was determined by different β-lactamase producing Staphylococcus aureus strains. When ampicillin was associated with PAM-18Na, the half-life time in acidic conditions increased, whereas both the enzymatic degradation and the minimum inhibitory concentration decreased to a 90 and 75%, respectively. These results suggest a promissory capability of this polymer to protect the β-lactam drugs against chemical, enzymatic and biological degradation. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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Review

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23 pages, 3018 KiB

Open AccessReview

Functional Polymer Nanocarriers for Photodynamic Therapy

by Tuanwei Li and Lifeng Yan

Pharmaceuticals 2018, 11(4), 133; https://doi.org/10.3390/ph11040133 - 30 Nov 2018

Cited by 34 | Viewed by 8169

Abstract

Photodynamic therapy (PDT) is an appealing therapeutic modality in management of some solid tumors and other diseases for its minimal invasion and non-systemic toxicity. However, the hydrophobicity and non-selectivity of the photosensitizers, inherent serious hypoxia of tumor tissues and limited penetration depth of light restrict PDT further applications in clinic. Functional polymer nanoparticles can be used as a nanocarrier for accurate PDT. Here, we elucidate the mechanism and application of PDT in cancer treatments, and then review some strategies to administer the biodistribution and activation of photosensitizers (PSs) to ameliorate or utilize the tumor hypoxic microenvironment to enhance the photodynamic therapy effect. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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24 pages, 5276 KiB

Open AccessReview

Lipid Nanoparticles and Their Hydrogel Composites for Drug Delivery: A Review

by Claire Desfrançois, Rachel Auzély and Isabelle Texier

Pharmaceuticals 2018, 11(4), 118; https://doi.org/10.3390/ph11040118 - 1 Nov 2018

Cited by 78 | Viewed by 13997

Abstract

Several drug delivery systems already exist for the encapsulation and subsequent release of lipophilic drugs that are well described in the scientific literature. Among these, lipid nanoparticles (LNP) have specifically come up for dermal, transdermal, mucosal, intramuscular and ocular drug administration routes in the last twenty years. However, for some of them (especially dermal, transdermal, mucosal), the LNP aqueous dispersions display unsuitable rheological properties. They therefore need to be processed as semi-solid formulations such as LNP-hydrogel composites to turn into versatile drug delivery systems able to provide precise spatial and temporal control of active ingredient release. In the present review, recent developments in the formulation of lipid nanoparticle-hydrogel composites are highlighted, including examples of successful encapsulation and release of lipophilic drugs through the skin, the eyes and by intramuscular injections. In relation to lipid nanoparticles, a specific emphasis has been put on the LNP key properties and how they influence their inclusion in the hydrogel. Polymer matrices include synthetic polymers such as poly(acrylic acid)-based materials, environment responsive (especially thermo-sensitive) polymers, and innovative polysaccharide-based hydrogels. The composite materials constitute smart, tunable drug delivery systems with a wide range of features, suitable for dermal, transdermal, and intramuscular controlled drug release. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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