Drug Delivery across Biological Barriers

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 62204

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Special Issue Editors

Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia
Interests: biopolymers; pharmaceutics; bioconjugation; bioanalysis; ligand–receptor interactions; peptides; drug delivery
Special Issues, Collections and Topics in MDPI journals
1. Institute of Macromolecular Compounds, Russian Academy of Sciences, 199004 Saint-Petersburg, Russia
2. Institute of Chemistry, Saint-Petersburg State University, Universitetsky pr. 26, 198504 St. Petersburg, Russia
Interests: amphiphilic polymers; self-assembling; nanoparticles; biodegradation; drug delivery systems; proteins; peptides; DNA/RNA
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Assuring the efficient transport of therapeutics in the body represents the crucial problem that should be taken into consideration during the construction of advanced drug delivery nanosystems. Recent advances in the development of biomaterials, including their nanoparticulated forms, have rendered a significant improvement of the currently proposed drug delivery strategies. Besides the increased bioavailability of pharmaceutical agents as a result of protecting them from degradation, targeting them directly to diseased sites, and controlling their circulation time and release rate, the problem of penetration across tissues and/or entry within cells seems to be important and needs to be solved. The design of strategies to control the transport of therapeutic compounds through such physiological barriers as mucosal, endothelial, blood–brain, cellular membrane and numerous other barriers has become an imperative and a challenging need to provide better therapy efficacy.

This Special Issue will provide readers with an overview of the current advances in this field regarding delivery systems that facilitate the transport of drug-containing nanosystems at the tissue, cell, and subcellular levels.

Prof. Tatiana B. Tennikova
Prof. Evgenia G. Korzhikova-Vlakh
Guest Editors

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Keywords

  • drug delivery
  • nanosystems
  • biological barriers
  • drug transport across the barriers

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Published Papers (10 papers)

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Research

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11 pages, 2244 KiB  
Article
Skin Irritation Testing beyond Tissue Viability: Fucoxanthin Effects on Inflammation, Homeostasis, and Metabolism
by Renata Spagolla Napoleão Tavares, Silvya Stuchi Maria-Engler, Pio Colepicolo, Hosana Maria Debonsi, Monika Schäfer-Korting, Uwe Marx, Lorena Rigo Gaspar and Christian Zoschke
Pharmaceutics 2020, 12(2), 136; https://doi.org/10.3390/pharmaceutics12020136 - 05 Feb 2020
Cited by 30 | Viewed by 3693
Abstract
UV light catalyzes the ozone formation from air pollutants, like nitrogen oxides. Since ozone reacts with cutaneous sebum lipids to peroxides and, thus, promotes inflammation, tumorigenesis, and aging, even broad-spectrum sunscreens cannot properly protect skin. Meanwhile, xanthophylls, like fucoxanthin, proved their antioxidant and [...] Read more.
UV light catalyzes the ozone formation from air pollutants, like nitrogen oxides. Since ozone reacts with cutaneous sebum lipids to peroxides and, thus, promotes inflammation, tumorigenesis, and aging, even broad-spectrum sunscreens cannot properly protect skin. Meanwhile, xanthophylls, like fucoxanthin, proved their antioxidant and cytoprotective functions, but the safety of their topical application in human cell-based models remains unknown. Aiming for a more detailed insight into the cutaneous fucoxanthin toxicity, we assessed the tissue viability according to OECD test guideline no. 439 as well as changes in inflammation (IL-1α, IL-6, IL-8), homeostasis (EGFR, HSPB1) and metabolism (NAT1). First, we proved the suitability of our 24-well-based reconstructed human skin for irritation testing. Next, we dissolved 0.5% fucoxanthin either in alkyl benzoate or in ethanol and applied both solutions onto the tissue surface. None of the solutions decreased RHS viability below 50%. In contrast, fucoxanthin ameliorated the detrimental effects of ethanol and reduced the gene expression of pro-inflammatory interleukins 6 and 8, while increasing NAT1 gene expression. In conclusion, we developed an organ-on-a-chip compatible RHS, being suitable for skin irritation testing beyond tissue viability assessment. Fucoxanthin proved to be non-irritant in RHS and already showed first skin protective effects following topical application. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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17 pages, 2537 KiB  
Article
Amphiphilic Polypeptides for VEGF siRNA Delivery into Retinal Epithelial Cells
by Olga Osipova, Vladimir Sharoyko, Natalia Zashikhina, Natalya Zakharova, Tatiana Tennikova, Arto Urtti and Evgenia Korzhikova-Vlakh
Pharmaceutics 2020, 12(1), 39; https://doi.org/10.3390/pharmaceutics12010039 - 02 Jan 2020
Cited by 22 | Viewed by 3751
Abstract
Polyethyleneimine, poly-L-lysine, chitosan and some others cationic polymers have been thoroughly studied as nucleic acid delivery systems in gene therapy. However, the drug release from these systems proceeds at a very low rate due to extremely high binding between a carrier and gene [...] Read more.
Polyethyleneimine, poly-L-lysine, chitosan and some others cationic polymers have been thoroughly studied as nucleic acid delivery systems in gene therapy. However, the drug release from these systems proceeds at a very low rate due to extremely high binding between a carrier and gene material. To reduce these interactions and to enhance drug release, we developed a set of amphiphilic polypeptides containing positively and negatively charged amino acids as well as a hydrophobic one. The copolymers obtained were characterized by size-exclusion chromatography, static light scattering, HPLC amino acid analysis and 1HNMR spectroscopy. All copolymers formed particles due to a self-assembly in aqueous media. Depending on polypeptide composition, the formation of particles with hydrodynamic diameters from 180 to 900 nm was observed. Stability of polymer particles, loading and release efficiency were carefully studied. Cellular uptake of the particles was efficient and their cytotoxicity was negligible. The application of polymer carriers, containing siRNA, to vascular endothelial growth factor (VEGF-A165) silencing of ARPE-19 cells was successful. The gene silencing was confirmed by suppression of both messenger RNA and protein expression. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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12 pages, 3789 KiB  
Article
Validation of an Ex Vivo Permeation Method for the Intestinal Permeability of Different BCS Drugs and Its Correlation with Caco-2 In Vitro Experiments
by Aroha B. Sánchez, Ana C. Calpena, Mireia Mallandrich and Beatriz Clares
Pharmaceutics 2019, 11(12), 638; https://doi.org/10.3390/pharmaceutics11120638 - 29 Nov 2019
Cited by 23 | Viewed by 5898
Abstract
The absorption study of drugs through different biological membranes constitutes an essential step in the development of new pharmaceutical dosage forms. Concerning orally administered forms, methods based on monolayer cell culture of Caco-2 (Caucasian colon adenocarcinoma) have been developed to emulate intestinal mucosa [...] Read more.
The absorption study of drugs through different biological membranes constitutes an essential step in the development of new pharmaceutical dosage forms. Concerning orally administered forms, methods based on monolayer cell culture of Caco-2 (Caucasian colon adenocarcinoma) have been developed to emulate intestinal mucosa in permeability studies. Although it is widely accepted, it has disadvantages, such as high costs or high technical complexity, and limitations related to the simplified structure of the monolayer or the class of molecules that can be permeated according to the transport mechanisms. The aim of this work was to develop a new ex vivo methodology which allows the evaluation of the intestinal apparent permeability coefficient (Papp) while using fewer resources and to assess the correlation with Caco-2. To this end, pig (Sus scrofa) duodenum segments were mounted in Franz diffusion cells and used to permeate four different drugs: ketorolac tromethamine (Kt), melatonin (Mel), hydrochlorothiazide (Htz), and furosemide (Fur). No statistically significant differences (p > 0.05) were observed corelating Papp values from Franz diffusion cells and Caco-2 cell experiments for Kt, Htz, and Fur. However, there were statistically significant differences (p < 0.05) correlating Papp values and Mel. The difference is explained by the role of Mel in the duodenal epithelial paracellular permeability reduction. Ex vivo permeation may be an equivalent method to Caco-2 for drugs that do not produce intestinal membrane phenomena that could affect absorption. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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13 pages, 3065 KiB  
Article
Encapsulation in Polymeric Nanoparticles Enhances the Enzymatic Stability and the Permeability of the GLP-1 Analog, Liraglutide, Across a Culture Model of Intestinal Permeability
by Ruba Ismail, Alexandra Bocsik, Gábor Katona, Ilona Gróf, Mária A. Deli and Ildikó Csóka
Pharmaceutics 2019, 11(11), 599; https://doi.org/10.3390/pharmaceutics11110599 - 12 Nov 2019
Cited by 23 | Viewed by 4289
Abstract
The potential of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) to overcome the intestinal barrier that limits oral liraglutide delivery was evaluated. Liraglutide-loaded PLGA NPs were prepared by the double emulsion solvent evaporation method. In vitro release kinetics and enzymatic degradation studies [...] Read more.
The potential of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) to overcome the intestinal barrier that limits oral liraglutide delivery was evaluated. Liraglutide-loaded PLGA NPs were prepared by the double emulsion solvent evaporation method. In vitro release kinetics and enzymatic degradation studies were conducted, mimicking the gastrointestinal environment. The permeability of liraglutide solution, liraglutide-loaded PLGA NPs, and liraglutide in the presence of the absorption enhancer PN159 peptide was tested on the Caco-2 cell model. Liraglutide release from PLGA NPs showed a biphasic release pattern with a burst effect of less than 15%. The PLGA nanosystem protected the encapsulated liraglutide from the conditions simulating the gastric environment. The permeability of liraglutide encapsulated in PLGA NPs was 1.5-fold higher (24 × 10−6 cm/s) across Caco-2 cells as compared to liraglutide solution. PLGA NPs were as effective at elevating liraglutide penetration as the tight junction-opening PN159 peptide. No morphological changes were seen in the intercellular junctions of Caco-2 cells after treatment with liraglutide-PLGA NPs, confirming the lack of a paracellular component in the transport mechanism. PLGA NPs, by protecting liraglutide from enzyme degradation and enhancing its permeability across intestinal epithelium, hold great potential as carriers for oral GLP-1 analog delivery. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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20 pages, 3181 KiB  
Article
Improved In Vitro Model for Intranasal Mucosal Drug Delivery: Primary Olfactory and Respiratory Epithelial Cells Compared with the Permanent Nasal Cell Line RPMI 2650
by Simone Ladel, Patrick Schlossbauer, Johannes Flamm, Harald Luksch, Boris Mizaikoff and Katharina Schindowski
Pharmaceutics 2019, 11(8), 367; https://doi.org/10.3390/pharmaceutics11080367 - 01 Aug 2019
Cited by 42 | Viewed by 7765
Abstract
Background: The epithelial layer of the nasal mucosa is the first barrier for drug permeation during intranasal drug delivery. With increasing interest for intranasal pathways, adequate in vitro models are required. Here, porcine olfactory (OEPC) and respiratory (REPC) primary cells were characterised against [...] Read more.
Background: The epithelial layer of the nasal mucosa is the first barrier for drug permeation during intranasal drug delivery. With increasing interest for intranasal pathways, adequate in vitro models are required. Here, porcine olfactory (OEPC) and respiratory (REPC) primary cells were characterised against the nasal tumour cell line RPMI 2650. Methods: Culture conditions for primary cells from porcine nasal mucosa were optimized and the cells characterised via light microscope, RT-PCR and immunofluorescence. Epithelial barrier function was analysed via transepithelial electrical resistance (TEER), and FITC-dextran was used as model substance for transepithelial permeation. Beating cilia necessary for mucociliary clearance were studied by immunoreactivity against acetylated tubulin. Results: OEPC and REPC barrier models differ in TEER, transepithelial permeation and MUC5AC levels. In contrast, RPMI 2650 displayed lower levels of MUC5AC, cilia markers and TEER, and higher FITC-dextran flux rates. Conclusion: To screen pharmaceutical formulations for intranasal delivery in vitro, translational mucosal models are needed. Here, a novel and comprehensive characterisation of OEPC and REPC against RPMI 2650 is presented. The established primary models display an appropriate model for nasal mucosa with secreted MUC5AC, beating cilia and a functional epithelial barrier, which is suitable for long-term evaluation of sustained release dosage forms. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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21 pages, 2318 KiB  
Article
Boosting Drug Discovery for Parkinson’s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles
by Miguel Pinto, Carlos Fernandes, Eva Martins, Renata Silva, Sofia Benfeito, Fernando Cagide, Ricardo F. Mendes, Filipe A. Almeida Paz, Jorge Garrido, Fernando Remião and Fernanda Borges
Pharmaceutics 2019, 11(7), 331; https://doi.org/10.3390/pharmaceutics11070331 - 12 Jul 2019
Cited by 11 | Viewed by 3981
Abstract
The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely [...] Read more.
The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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16 pages, 4138 KiB  
Article
pH-Sensitive Chitosan–Heparin Nanoparticles for Effective Delivery of Genetic Drugs into Epithelial Cells
by Iuliia Pilipenko, Viktor Korzhikov-Vlakh, Vladimir Sharoyko, Nan Zhang, Monika Schäfer-Korting, Eckart Rühl, Christian Zoschke and Tatiana Tennikova
Pharmaceutics 2019, 11(7), 317; https://doi.org/10.3390/pharmaceutics11070317 - 05 Jul 2019
Cited by 60 | Viewed by 5411
Abstract
Chitosan has been extensively studied as a genetic drug delivery platform. However, its efficiency is limited by the strength of DNA and RNA binding. Expecting a reduced binding strength of cargo with chitosan, we proposed including heparin as a competing polyanion in the [...] Read more.
Chitosan has been extensively studied as a genetic drug delivery platform. However, its efficiency is limited by the strength of DNA and RNA binding. Expecting a reduced binding strength of cargo with chitosan, we proposed including heparin as a competing polyanion in the polyplexes. We developed chitosan–heparin nanoparticles by a one-step process for the local delivery of oligonucleotides. The size of the polyplexes was dependent on the mass ratio of polycation to polyanion. The mechanism of oligonucleotide release was pH-dependent and associated with polyplex swelling and collapse of the polysaccharide network. Inclusion of heparin enhanced the oligonucleotide release from the chitosan-based polyplexes. Furthermore, heparin reduced the toxicity of polyplexes in the cultured cells. The cell uptake of chitosan–heparin polyplexes was equal to that of chitosan polyplexes, but heparin increased the transfection efficiency of the polyplexes two-fold. The application of chitosan–heparin small interfering RNA (siRNA) targeted to vascular endothelial growth factor (VEGF) silencing of ARPE-19 cells was 25% higher. Overall, chitosan–heparin polyplexes showed a significant improvement of gene release inside the cells, transfection, and gene silencing efficiency in vitro, suggesting that this fundamental strategy can further improve the transfection efficiency with application of non-viral vectors. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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Review

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34 pages, 2816 KiB  
Review
Nanomaterials Designed for Antiviral Drug Delivery Transport across Biological Barriers
by Florina-Daniela Cojocaru, Doru Botezat, Ioannis Gardikiotis, Cristina-Mariana Uritu, Gianina Dodi, Laura Trandafir, Ciprian Rezus, Elena Rezus, Bogdan-Ionel Tamba and Cosmin-Teodor Mihai
Pharmaceutics 2020, 12(2), 171; https://doi.org/10.3390/pharmaceutics12020171 - 18 Feb 2020
Cited by 140 | Viewed by 13215
Abstract
Viral infections are a major global health problem, representing a significant cause of mortality with an unfavorable continuously amplified socio-economic impact. The increased drug resistance and constant viral replication have been the trigger for important studies regarding the use of nanotechnology in antiviral [...] Read more.
Viral infections are a major global health problem, representing a significant cause of mortality with an unfavorable continuously amplified socio-economic impact. The increased drug resistance and constant viral replication have been the trigger for important studies regarding the use of nanotechnology in antiviral therapies. Nanomaterials offer unique physico-chemical properties that have linked benefits for drug delivery as ideal tools for viral treatment. Currently, different types of nanomaterials namely nanoparticles, liposomes, nanospheres, nanogels, nanosuspensions and nanoemulsions were studied either in vitro or in vivo for drug delivery of antiviral agents with prospects to be translated in clinical practice. This review highlights the drug delivery nanosystems incorporating the major antiviral classes and their transport across specific barriers at cellular and intracellular level. Important reflections on nanomedicines currently approved or undergoing investigations for the treatment of viral infections are also discussed. Finally, the authors present an overview on the requirements for the design of antiviral nanotherapeutics. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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22 pages, 3030 KiB  
Review
Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?
by Marco Cavaco, Diana Gaspar, Miguel ARB Castanho and Vera Neves
Pharmaceutics 2020, 12(1), 62; https://doi.org/10.3390/pharmaceutics12010062 - 13 Jan 2020
Cited by 29 | Viewed by 6080
Abstract
The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors [...] Read more.
The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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24 pages, 3665 KiB  
Review
Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer
by Alessandro Parodi, Magdalena Rudzińska, Andrei A. Deviatkin, Surinder M. Soond, Alexey V. Baldin and Andrey A. Zamyatnin
Pharmaceutics 2019, 11(5), 245; https://doi.org/10.3390/pharmaceutics11050245 - 24 May 2019
Cited by 266 | Viewed by 6629
Abstract
Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles to improve current treatments is represented by the impermeability of the blood vessels residing within [...] Read more.
Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles to improve current treatments is represented by the impermeability of the blood vessels residing within nervous tissue as well as of the new vascular net generating from the tumor, commonly referred to as blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively. In this review, we focused on established and emerging strategies to overcome the blood-brain barrier to increase drug delivery for brain cancer. To date, there are three broad strategies being investigated to cross the brain vascular wall and they are conceived to breach, bypass, and negotiate the access to the nervous tissue. In this paper, we summarized these approaches highlighting their working mechanism and their potential impact on the quality of life of the patients as well as their current status of development. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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