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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (22 October 2021) | Viewed by 42802

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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, Attiki, Greece
Interests: functional liposomes; functional dendritic polymers; nano-sized drug delivery systems; drug targeting; triggered drug release
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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. In the past, 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 and, finally, find the target and release their payload in a controlled fashion has had limited success, but was largely reinvigorated recently 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, has given 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, 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, interaction of nanoparticles 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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (10 papers)

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Research

15 pages, 6552 KiB

Open AccessArticle

Polyhydroxybutyrate-Based Nanocomposites for Bone Tissue Engineering

by Anand Mohan, Madhuri Girdhar, Raj Kumar, Harshil S. Chaturvedi, Agrataben Vadhel, Pratima R. Solanki, Anil Kumar, Deepak Kumar and Narsimha Mamidi

Pharmaceuticals 2021, 14(11), 1163; https://doi.org/10.3390/ph14111163 - 15 Nov 2021

Cited by 34 | Viewed by 3618

Abstract

Bone-related diseases have been increasing worldwide, and several nanocomposites have been used to treat them. Among several nanocomposites, polyhydroxybutyrate (PHB)-based nanocomposites are widely used in drug delivery and tissue engineering due to their excellent biocompatibility and biodegradability. However, PHB use in bone tissue engineering is limited due to its inadequate physicochemical and mechanical properties. In the present work, we synthesized PHB-based nanocomposites using a nanoblend and nano-clay with modified montmorillonite (MMT) as a filler. MMT was modified using trimethyl stearyl ammonium (TMSA). Nanoblend and nano-clay were fabricated using the solvent-casting technique. Inspection of the composite structure revealed that the basal spacing of the polymeric matrix material was significantly altered depending on the loading percentage of organically modified montmorillonite (OMMT) nano-clay. The PHB/OMMT nanocomposite displayed enhanced thermal stability and upper working temperature upon heating as compared to the pristine polymer. The dispersed (OMMT) nano-clay assisted in the formation of pores on the surface of the polymer. The pore size was proportional to the weight percentage of OMMT. Further morphological analysis of these blends was carried out through FESEM. The obtained nanocomposites exhibited augmented properties over neat PHB and could have an abundance of applications in the industry and medicinal sectors. In particular, improved porosity, non-immunogenic nature, and strong biocompatibility suggest their effective application in bone tissue engineering. Thus, PHB/OMMT nanocomposites are a promising candidate for 3D organ printing, lab-on-a-chip scaffold engineering, and bone tissue engineering. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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20 pages, 3336 KiB

Open AccessArticle

Luteolin-Loaded Elastic Liposomes for Transdermal Delivery to Control Breast Cancer: In Vitro and Ex Vivo Evaluations

by Mohammad A. Altamimi, Afzal Hussain, Mohammad AlRajhi, Sultan Alshehri, Syed Sarim Imam and Wajhul Qamar

Pharmaceuticals 2021, 14(11), 1143; https://doi.org/10.3390/ph14111143 - 11 Nov 2021

Cited by 22 | Viewed by 5008

Abstract

The study aimed to prepare and optimize luteolin (LUT)-loaded transdermal elastic liposomes (LEL1-LEL12), followed by in vitro and ex vivo evaluations of their ability to control breast cancer. Various surfactants (Span 60, Span 80, and Brij 35), and phosphatidyl choline (PC) as a lipid, were used to tailor various formulation as dictated by “Design Expert^® software (DOE). These were characterized for size, polydispersity index (PDI), and zeta potential. The optimized formulation (OLEL1) was selected for comparative investigations (in vitro and ex vivo) against lipo (conventional liposomes) and drug suspension (DS). Moreover, the in vitro anticancer activity of OLEL1 was compared against a control using MCF-7 cell lines. Preliminary selection of the suitable PC: surfactant ratio for formulations F1–F9 showed relative advantages of Span 80. DOE suggested two block factorial designs with four center points to identify the design space and significant factors. OLEL1 was the most robust with high functional desirability (0.95), minimum size (202 nm), relatively high drug release, increased drug entrapment (92%), and improved permeation rate (~3270 µg/cm²) as compared with liposomes (~1536 µg/cm²) over 24 h. OLEL1 exhibited a 6.2- to 2.9-fold increase in permeation rate as compared with DS (drug solution). The permeation flux values of OLEL1, and lipo were found to be 136.3, 64 and 24.3 µg/h/cm², respectively. The drug disposition values were 670 µg, 473 µg and 148 µg, for OLEL1, lipo and DS, respectively. Thus, ex vivo parameters were significantly better for OLEL1 compared with lipo and DS which is attributed to the flexibility and deformability of the optimized formulation. Furthermore, OLEL1 was evaluated for anticancer activity and showed maximized inhibition as compared with DS. Thus, elastic liposomes may be a promising approach for improved transdermal delivery of luteolin, as well as enhancing its therapeutic efficacy in controlling breast cancer. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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25 pages, 5534 KiB

Open AccessArticle

Engineering Mitochondriotropic Carbon Dots for Targeting Cancer Cells

by Archontia Kaminari, Eleni Nikoli, Alexandros Athanasopoulos, Elias Sakellis, Zili Sideratou and Dimitris Tsiourvas

Pharmaceuticals 2021, 14(9), 932; https://doi.org/10.3390/ph14090932 - 16 Sep 2021

Cited by 11 | Viewed by 2986

Abstract

Aiming to understand and enhance the capacity of carbon dots (CDs) to transport through cell membranes and target subcellular organelles—in particular, mitochondria—a series of nitrogen-doped CDs were prepared by the one-step microwave-assisted pyrolysis of citric acid and ethylenediamine. Following optimization of the reaction conditions for maximum fluorescence, functionalization at various degrees with alkylated triphenylphosphonium functional groups of two different alkyl chain lengths afforded a series of functionalized CDs that exhibited either lysosome or mitochondria subcellular localization. Further functionalization with rhodamine B enabled enhanced fluorescence imaging capabilities in the visible spectrum and allowed the use of low quantities of CDs in relevant experiments. It was thus possible, by the appropriate selection of the alkyl chain length and degree of functionalization, to attain successful mitochondrial targeting, while preserving non-toxicity and biocompatibility. In vitro cell experiments performed on normal as well as cancer cell lines proved their non-cytotoxic character and imaging potential, even at very low concentrations, by fluorescence microscopy. Precise targeting of mitochondria is feasible with carefully designed CDs that, furthermore, are specifically internalized in cells and cell mitochondria of high transmembrane potential and thus exhibit selective uptake in malignant cells compared to normal cells. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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14 pages, 2693 KiB

Open AccessArticle

Hydrotalcite–Niclosamide Nanohybrid as Oral Formulation towards SARS-CoV-2 Viral Infections

by Goeun Choi, Huiyan Piao, N. Sanoj Rejinold, Seungjin Yu, Ki-yeok Kim, Geun-woo Jin and Jin-Ho Choy

Pharmaceuticals 2021, 14(5), 486; https://doi.org/10.3390/ph14050486 - 19 May 2021

Cited by 13 | Viewed by 6605

Abstract

COVID-19 has been affecting millions of individuals worldwide and, thus far, there is no accurate therapeutic strategy. This critical situation necessitates novel formulations for already existing, FDA approved, but poorly absorbable drug candidates, such as niclosamide (NIC), which is of great relevance. In this context, we have rationally designed NIC-loaded hydrotalcite composite nanohybrids, which were further coated with Tween 60 or hydroxypropyl methyl cellulose (HPMC), and characterized them in vitro. The optimized nanohybrids showed particle sizes <300 nm and were orally administrated to rats to determine whether they could retain an optimum plasma therapeutic concentration of NIC that would be effective for treating COVID-19. The pharmacokinetic (PK) results clearly indicated that hydrotalcite-based NIC formulations could be highly potential options for treating the ongoing pandemic and we are on our way to understanding the in vivo anti-viral efficacy sooner. It is worth mentioning that hydrotalcite–NIC nanohybrids maintained a therapeutic NIC level, even above the required IC₅₀ value, after just a single administration in 8–12 h. In conclusion, we were very successfully able to develop a NIC oral formulation by immobilizing with hydrotalcite nanoparticles, which were further coated with Tween 60 or HPMC, in order to enhance their emulsification in the gastrointestinal tract. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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19 pages, 8613 KiB

Open AccessArticle

Design of Topical Ocular Ciprofloxacin Nanoemulsion for the Management of Bacterial Keratitis

by Ahmed Adel Ali Youssef, Chuntian Cai, Narendar Dudhipala and Soumyajit Majumdar

Pharmaceuticals 2021, 14(3), 210; https://doi.org/10.3390/ph14030210 - 03 Mar 2021

Cited by 42 | Viewed by 4444

Abstract

Bacterial keratitis (BK) is a critical ocular infection that can lead to serious visual disability. Ciprofloxacin (CIP), moxifloxacin (MOX), and levofloxacin (LFX) have been accepted as monotherapies by the US Food and Drug Administration for BK treatment. CIP is available commercially at 0.3% w/v concentration as an ophthalmic solution and as an ointment for ocular delivery. Because of solubility issues at physiological pH, CIP precipitation can occur at the corneal surface post instillation of the solution dosage form. Consequently, the ocular bioavailability of CIP is reduced. The ointment dosage form is associated with side effects such as blurred vision, itching, redness, eye discomfort, and eye dryness. This study aimed to design a CIP loaded nanoemulsion (NE; CIP-NE) to facilitate drug penetration into the corneal layers for improved therapeutic outcomes as well as to overcome the drawbacks of the current commercial ophthalmic formulations. CIP-NE formulations were prepared by hot homogenization and ultrasonication, using oleic acid (CIP-O-NE) and Labrafac^® Lipophile WL 1349 (CIP-L-NE) as the oily phase, and Tween^® 80 and Poloxamer 188 as surfactants. Optimized CIP-NE was further evaluated with respect to in vitro release, ex vivo transcorneal permeation, and moist heat sterilization process, using commercial CIP ophthalmic solution as a control. Optimized CIP-O-NE formulation showed a globule size, polydispersity index, and zeta potential of 121.6 ± 1.5 nm, 0.13 ± 0.01, and −35.1 ± 2.1 mV, respectively, with 100.1 ± 2.0% drug content and was spherical in shape. In vitro release and ex vivo transcorneal permeation studies exhibited sustained release and a 2.1-fold permeation enhancement, respectively, compared with commercial CIP ophthalmic solution. Autoclaved CIP-O-NE formulation was found to be stable for one month (last time-point tested) at refrigerated and room temperature. Therefore, CIP-NE formulation could serve as an effective delivery system for CIP and could improve treatment outcomes in BK. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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18 pages, 2859 KiB

Open AccessArticle

In Vitro Characterization of Inhalable Cationic Hybrid Nanoparticles as Potential Vaccine Carriers

by Iman M. Alfagih, Kan Kaneko, Nitesh K. Kunda, Fars Alanazi, Sarah R. Dennison, Hesham M. Tawfeek and Imran Y. Saleem

Pharmaceuticals 2021, 14(2), 164; https://doi.org/10.3390/ph14020164 - 18 Feb 2021

Cited by 8 | Viewed by 3067

Abstract

In this study, PGA-co-PDL nanoparticles (NPs) encapsulating model antigen, bovine serum albumin (BSA), were prepared via double emulsion solvent evaporation. In addition, chitosan hydrochloride (CHL) was incorporated into the external phase of the emulsion solvent method, which resulted in surface adsorption onto the NPs to form hybrid cationic CHL NPs. The BSA encapsulated CHL NPs were encompassed into nanocomposite microcarriers (NCMPs) composed of l-leucine to produce CHL NPs/NCMPs via spray drying. The CHL NPs/NCMPs were investigated for in vitro aerosolization, release study, cell viability and uptake, and stability of protein structure. Hybrid cationic CHL NPs (CHL: 10 mg/mL) of particle size (480.2 ± 32.2 nm), charge (+14.2 ± 0.72 mV), and BSA loading (7.28 ± 1.3 µg/mg) were produced. The adsorption pattern was determined to follow the Freundlich model. Aerosolization of CHL NPs/NCMPs indicated fine particle fraction (FPF: 46.79 ± 11.21%) and mass median aerodynamic diameter (MMAD: 1.49 ± 0.29 µm). The BSA α-helical structure was maintained, after release from the CHL NPs/NCMPs, as indicated by circular dichroism. Furthermore, dendritic cells (DCs) and A549 cells showed good viability (≥70% at 2.5 mg/mL after 4–24 h exposure, respectively). Confocal microscopy and flow cytometry data showed hybrid cationic CHL NPs were successfully taken up by DCs within 1 h of incubation. The upregulation of CD40, CD86, and MHC-II cell surface markers indicated that the DCs were successfully activated by the hybrid cationic CHL NPs. These results suggest that the CHL NPs/NCMPs technology platform could potentially be used for the delivery of proteins to the lungs for immunostimulatory applications such as vaccines. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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30 pages, 6905 KiB

Open AccessArticle

Formulation and Optimization of Nanospanlastics for Improving the Bioavailability of Green Tea Epigallocatechin Gallate

by Eman A. Mazyed, Doaa A. Helal, Mahmoud M. Elkhoudary, Ahmed G. Abd Elhameed and Mohamed Yasser

Pharmaceuticals 2021, 14(1), 68; https://doi.org/10.3390/ph14010068 - 15 Jan 2021

Cited by 38 | Viewed by 3592

Abstract

The present study aimed to investigate the potential of nanospanlastics for boosting the bioavailability of epigallocatechin gallate (EGCG). EGCG has valuable effects like anti-inflammation, anti-oxidation, and anti-tumorigenesis. Unfortunately, it has a low oral bioavailability due to its limited permeation and poor stability. To overcome these pitfalls, EGCG was fabricated as a nanospanlastic. Nanospanlastics are flexible nanovesicles that are composed of surfactants and edge activators (EAs). EAs improve the deformability of spanlastics by acting as a destabilizing factor of their vesicular membranes. EGCG-loaded spanlastics were prepared by an ethanol injection method, according to 2³ factorial design, to explore the impact of different independent variables on entrapment efficiency (EE%), % drug released after 12 h (Q_12h), and particle size (PS). In vitro characterization, ex vivo intestinal permeation test, and pharmacokinetic study of the optimized formula were performed. A newly developed RP-HPLC technique was adopted for the estimation of EGCG. The optimized formula (F4) demonstrated more prolonged drug release and a significant improvement in the EE%, permeability, deformability and stability than the corresponding niosomes. The pharmacokinetic study investigated that F4 had a more sustained drug release and a higher bioavailability than the conventional niosomes and free drugs. Nanospanlastics could be a promising approach for improving the bioavailability of EGCG. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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25 pages, 4969 KiB

Open AccessFeature PaperArticle

Apremilast Microemulsion as Topical Therapy for Local Inflammation: Design, Characterization and Efficacy Evaluation

by Paulo Sarango-Granda, Marcelle Silva-Abreu, Ana Cristina Calpena, Lyda Halbaut, María-José Fábrega, María J. Rodríguez-Lagunas, Natalia Díaz-Garrido, Josefa Badia and Lupe Carolina Espinoza

Pharmaceuticals 2020, 13(12), 484; https://doi.org/10.3390/ph13120484 - 21 Dec 2020

Cited by 16 | Viewed by 6288

Abstract

Apremilast (APR) is a selective phosphodiesterase 4 inhibitor administered orally in the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis. The low solubility and permeability of this drug hinder its dermal administration. The purpose of this study was to design and characterize an apremilast-loaded microemulsion (APR-ME) as topical therapy for local skin inflammation. Its composition was determined using pseudo-ternary diagrams. Physical, chemical and biopharmaceutical characterization were performed. Stability of this formulation was studied for 90 days. Tolerability of APR-ME was evaluated in healthy volunteers while its anti-inflammatory potential was studied using in vitro and in vivo models. A homogeneous formulation with Newtonian behavior and droplets of nanometric size and spherical shape was obtained. APR-ME released the incorporated drug following a first-order kinetic and facilitated drug retention into the skin, ensuring a local effect. Anti-inflammatory potential was observed for its ability to decrease the production of IL-6 and IL-8 in the in vitro model. This effect was confirmed in the in vivo model histologically by reduction in infiltration of inflammatory cells and immunologically by decrease of inflammatory cytokines IL-8, IL-17A and TNFα. Consequently, these results suggest that this formulation could be used as an attractive topical treatment for skin inflammation. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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9 pages, 1021 KiB

Open AccessArticle

Gel-Based Nanocarrier for Intravesical Chemotherapy Delivery: In Vitro and In Vivo Study

by Ting-Yu Chen, Ming-Jun Tsai, I-Ling Lin, Li-Ching Chang and Pao-Chu Wu

Pharmaceuticals 2020, 13(11), 329; https://doi.org/10.3390/ph13110329 - 22 Oct 2020

Cited by 2 | Viewed by 1794

Abstract

Intravesical administration of chemotherapeutic agents can enhance drug accumulation in tumors and reduce systemic side effects. Nanocarriers were developed for intravesical administration and exploit the permeation enhancement effect. In vitro permeation evaluation, the drug transdermal amount and accumulation amounts in the tissue of gemcitabine-loaded nanocarriers through biological membrane significantly increased about 14.8~33.0-fold and 1.5~14.1-fold respectively, when compared to a control group of 1% gemcitabine saline solution. In in vivo intravesical administration, the drug accumulation amount in bladder tissue of nanocarrier of 75.2 ± 5.4 μg was revealed as being comparably higher than that of the control group of 44.8 ± 6.4 μg. In confocal laser scanning microscopy imagery, the penetration depth of fluorescent dyes-rhodamine was increased from 80 μm up to 120 μm when a nanocarrier was used. This result implies that the nanocarrier is a promising drug delivery agent for intravesical administration. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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18 pages, 5928 KiB

Open AccessArticle

Combination Therapy with Doxorubicin-Loaded Reduced Albumin Nanoparticles and Focused Ultrasound in Mouse Breast Cancer Xenografts

by Daehyun Kim, Seung Soo Lee, Woo Young Yoo, Hyungwon Moon, Aesin Cho, So Yeon Park, Yoon-Seok Kim, Hyun Ryoung Kim and Hak Jong Lee

Pharmaceuticals 2020, 13(9), 235; https://doi.org/10.3390/ph13090235 - 07 Sep 2020

Cited by 11 | Viewed by 3467

Abstract

Because chemotherapeutic drugs are often associated with serious side effects, the central topic in modern drug delivery is maximizing the localization of drugs at the target while minimizing non-specific drug interactions at unwanted regions. To address this issue, biocompatible nanoparticles have been developed to enhance the drug half-life while minimizing the associated toxicity. Nevertheless, relying solely on the enhanced half-life and enhanced permeability and retention (EPR) effects has been ineffective, and designing stimulus-sensitive nanoparticles to introduce the precise control of drug release has been desired. In this paper, we introduce a pH-sensitive, reduced albumin nanoparticle in combination with focused ultrasound treatment. Not only did these nanoparticles have superior therapeutic efficacy and toxicity profiles when compared to the free drugs in xenograft mouse models, but we were also able to show that the albumin nanoparticles reported in this paper were more suitable than other types of non-reduced albumin nanoparticles as vehicles for drug delivery. As such, we believe that the albumin nanoparticles presented in this paper with desirable characteristics including the induction of strong anti-tumor response, precise control, and superior safety profiles hold strong potential for preclinical and clinical anticancer therapy. Full article

(This article belongs to the Special Issue Nano Drug Carriers 2021)

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