Polymer-Based Matrices for Drug Delivery: In Vitro, In Vivo and In Silico Approaches

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

Deadline for manuscript submissions: closed (25 August 2022) | Viewed by 24656

Special Issue Editors

Institute of Nanotechnology, National Research Council (CNR‐NANOTEC), 73100 Lecce, Italy
Interests: nanotechnology; biomedical engineering; materials science; electrospinning; electrowriting; 3D printing; microparticles; computational mathematics
Special Issues, Collections and Topics in MDPI journals
Center for Advanced Biomaterials for Health Care, Istituto Italiano di Tecnologia (IIT@CRIB), 80125 Naples, Italy
Interests: materials science; drug delivery; micro/nano encapsulation; biomolecule characterization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, a great deal of effort has been focused on drug delivery systems within the biomedical field. In this scenario, polymer-based systems (for example, microparticles, nanoparticles or microneedles) are recognized as very popular carriers and are specifically designed to deliver the encapsulated active molecules to a specific targeting site, achieving improved therapeutic effects and reduced adverse effects. The reason behind this great diffusion is several attractive features, such as the use of non-laborious techniques, low production costs, simplicity in industrial scale-up, and possibilities of different ways of administration (trans-epidermal, oral, ocular, parental, inhalation).

Together with the empirical approach, theoretical and mathematical models represent a fundamental tool to optimally design new pharmaceutical systems, study drug formulations and evaluate in vitro and in vivo releases. In this regard, the shape and dimension of the system designed to achieve a specific drug release profile as well as the amount and type of the active agent, adjuvants and polymer can be predicted, in order to obtain a fine control on the drug release kinetics and to provide a personalized therapy. Moreover, in silico models can help to more deeply understand the physical and chemical mechanisms of drug release, also reducing the number of experiments.

The aim of this Special Issue is to underline and collect research progresses and outputs in nano- and microencapsulation techniques related to the drug delivery field, including both in vivo and in vitro studies. Articles that describe in silico models to predict physicochemical properties and release profiles are also welcome.

Dr. Valentina Onesto
Dr. Concetta Di Natale
Guest Editors

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Keywords

  • microparticles
  • nanoparticles
  • microneedles
  • in vitro
  • in silico
  • mathematical models
  • drug encapsulation

Published Papers (8 papers)

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Research

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21 pages, 4780 KiB  
Article
Structure, Properties, and Release Kinetics of the Polymer/Insect Repellent System Poly (l-Lactic Acid)/Ethyl Butylacetylaminopropionate (PLLA/IR3535)
by Fanfan Du, Rafael Erdmann, Albrecht Petzold, Andre Wutzler, Andreas Leuteritz, Michael Nase and René Androsch
Pharmaceutics 2022, 14(11), 2381; https://doi.org/10.3390/pharmaceutics14112381 - 04 Nov 2022
Cited by 1 | Viewed by 1501
Abstract
The insect repellent ethyl butylacetylaminopropionate (IR3535) was used as a functional additive for poly (l-lactic acid) (PLLA) to modify its structure and mechanical properties and achieve insect repellency. PLLA/IR3535 mixtures at various compositions were prepared via melt extrusion. In the analyzed [...] Read more.
The insect repellent ethyl butylacetylaminopropionate (IR3535) was used as a functional additive for poly (l-lactic acid) (PLLA) to modify its structure and mechanical properties and achieve insect repellency. PLLA/IR3535 mixtures at various compositions were prepared via melt extrusion. In the analyzed composition range of 0 to 23 m% IR3535, PLLA and IR3535 were miscible at the length scale represented by the glass transition temperature. Addition of IR3535 resulted in a significant decrease in the glass transition temperature of PLLA, as well as in the elastic modulus, indicating its efficiency as a plasticizer. All mixtures were amorphous after extrusion, though PLLA/IR3535 extrudates with an IR3535 content between 18 and 23 m% crystallized during long-term storage at ambient temperature, due to their low glass transition temperature. Quantification of the release of IR3535 into the environment by thermogravimetric analysis at different temperatures between 50 and 100 °C allowed the estimation of the evaporation rate at lower temperatures, suggesting an extremely low release rate with a time constant of the order of magnitude of 1–2 years at body temperature. Full article
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18 pages, 3431 KiB  
Article
Deep Eutectic Solvent Formulations and Alginate-Based Hydrogels as a New Partnership for the Transdermal Administration of Anti-Inflammatory Drugs
by Sónia N. Pedro, Maria S. M. Mendes, Bruno M. Neves, Isabel Filipa Almeida, Paulo Costa, Inês Correia-Sá, Carla Vilela, Mara G. Freire, Armando J. D. Silvestre and Carmen S. R. Freire
Pharmaceutics 2022, 14(4), 827; https://doi.org/10.3390/pharmaceutics14040827 - 10 Apr 2022
Cited by 13 | Viewed by 3543
Abstract
The transdermal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is a valuable and safer alternative to their oral intake. However, most of these drugs display low water solubility, which makes their incorporation into hydrophilic biopolymeric drug-delivery systems difficult. To overcome this drawback, aqueous solutions [...] Read more.
The transdermal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is a valuable and safer alternative to their oral intake. However, most of these drugs display low water solubility, which makes their incorporation into hydrophilic biopolymeric drug-delivery systems difficult. To overcome this drawback, aqueous solutions of bio-based deep eutectic solvents (DES) were investigated to enhance the solubility of ibuprofen, a widely used NSAID, leading to an increase in its solubility of up to 7917-fold when compared to its water solubility. These DES solutions were shown to be non-toxic to macrophages with cell viabilities of 97.4% (at ibuprofen concentrations of 0.25 mM), while preserving the anti-inflammatory action of the drug. Their incorporation into alginate-based hydrogels resulted in materials with a regular structure and higher flexibility. These hydrogels present a sustained release of the drug, which is able, when containing the DES aqueous solution comprising ibuprofen, to deliver 93.5% of the drug after 8 h in PBS. Furthermore, these hydrogels were able to improve the drug permeation across human skin by 8.5-fold in comparison with the hydrogel counterpart containing only ibuprofen. This work highlights the possibility to remarkably improve the transdermal administration of NSAIDs by combining new drug formulations based on DES and biopolymeric drug delivery systems. Full article
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16 pages, 2695 KiB  
Article
The Interactions and Release Kinetics of Sodium Hyaluronate Implemented in Nonionic and Anionic Polymeric Hydrogels, Studied by Immunoenzymatic ELISA Test
by Dorota Wójcik-Pastuszka, Aleksandra Skrzypczyk and Witold Musiał
Pharmaceutics 2022, 14(1), 58; https://doi.org/10.3390/pharmaceutics14010058 - 27 Dec 2021
Cited by 4 | Viewed by 2524
Abstract
Hyaluronan is a natural polymer that was introduced to wound therapy. Formulations based on synthetic polymers such as methylcellulose (MC) and polyacrylic acid (PA) containing hyaluronan (HA) were proposed for the development of prospective wound-healing preparations. The formulations of different carrier concentrations containing [...] Read more.
Hyaluronan is a natural polymer that was introduced to wound therapy. Formulations based on synthetic polymers such as methylcellulose (MC) and polyacrylic acid (PA) containing hyaluronan (HA) were proposed for the development of prospective wound-healing preparations. The formulations of different carrier concentrations containing a fixed amount of HA were prepared, and their viscosity was measured. The HA release was evaluated by employing the apparatus paddle over a disc. The hydrogels were introduced to the donor chamber, and HA was released to the pH = 7.4 buffer. The amount of HA released was obtained using the ELISA test. The release was analyzed on the basis of different kinetic models: zero-, first-, and second-order kinetics, as well as Higuchi and Korsmeyer–Peppas equations. The release rate constants and the half release time were calculated from these equations. According to the value of the coefficient of the determination, the best model describing the observed process was selected. The comparison between the dissolution profiles was carried out by calculating the difference factor f1 and the similarity factor f2. The interaction between the hydrogel components was investigated by Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) measurements. The study revealed that the zero-order equation best described the release of HA from the formulations studied. The FTIR research and the DSC study showed the intermolecular interaction between HA chains in MC-based compositions, as well as between HA and the synthetic polymer in the PA-based formulations. The study revealed that the formulation with a higher concentration of synthetic polymer may prolong the release of HA. The obtained results indicated that the proposed hydrogels have potential for wound healing and may accelerate skin regeneration. Full article
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19 pages, 5672 KiB  
Article
Development, Characterization, Optimization, and In Vivo Evaluation of Methacrylic Acid–Ethyl Acrylate Copolymer Nanoparticles Loaded with Glibenclamide in Diabetic Rats for Oral Administration
by Omar Rodrigo Guadarrama-Escobar, Ivonne Sánchez-Vázquez, Pablo Serrano-Castañeda, German Alberto Chamorro-Cevallos, Isabel Marlen Rodríguez-Cruz, Adalí Yisell Sánchez-Padrón, Ericka Anguiano-Almazán, Ma. Concepción Peña-Juárez, Abraham Méndez-Albores, Clara Luisa Domínguez-Delgado, Crisóforo Mercado-Márquez, Betsabé Rodríguez-Pérez and José Juan Escobar-Chávez
Pharmaceutics 2021, 13(12), 2023; https://doi.org/10.3390/pharmaceutics13122023 - 27 Nov 2021
Cited by 5 | Viewed by 2648
Abstract
The methacrylic acid–ethyl acrylate copolymer nanoparticles were prepared using the solvent displacement method. The independent variables were the drug/polymer ratio, surfactant concentration, Polioxyl 40 hydrogenated castor oil, the added water volume, time, and stirring speed, while size, PDI, zeta potential, and encapsulation efficiency [...] Read more.
The methacrylic acid–ethyl acrylate copolymer nanoparticles were prepared using the solvent displacement method. The independent variables were the drug/polymer ratio, surfactant concentration, Polioxyl 40 hydrogenated castor oil, the added water volume, time, and stirring speed, while size, PDI, zeta potential, and encapsulation efficiency were the response variables analyzed. A design of screening experiments was carried out to subsequently perform the optimization of the nanoparticle preparation process. The optimal formulation was characterized through the dependent variables size, PDI, zeta potential, encapsulation efficiency and drug release profiles. In vivo tests were performed in Wistar rats previously induced with diabetes by administration of streptozotocin. Once hyperglycemia was determined in rats, a suspension of nanoparticles loaded with glibenclamide was administered to them while the other group was administered with tablets of glibenclamide. The optimal nanoparticle formulation obtained a size of 18.98 +/− 9.14 nm with a PDI of 0.37085 +/− 0.014 and a zeta potential of −13.7125 +/− 1.82 mV; the encapsulation efficiency was of 44.5%. The in vivo model demonstrated a significant effect (p < 0.05) between the group administered with nanoparticles loaded with glibenclamide and the group administered with tablets compared to the group of untreated individuals. Full article
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15 pages, 4072 KiB  
Article
Supramolecular Surface Functionalization of Iron Oxide Nanoparticles with α-Cyclodextrin-Based Cationic Star Polymer for Magnetically-Enhanced Gene Delivery
by Hanyi Li, Erwin Peng, Feng Zhao, Jun Li and Junmin Xue
Pharmaceutics 2021, 13(11), 1884; https://doi.org/10.3390/pharmaceutics13111884 - 06 Nov 2021
Cited by 8 | Viewed by 2020
Abstract
Supramolecular polymers formed through host–guest complexation have inspired many interesting developments of functional materials for biological and biomedical applications. Here, we report a novel design of a non-viral gene delivery system composed of a cationic star polymer forming supramolecular complexes with the surface [...] Read more.
Supramolecular polymers formed through host–guest complexation have inspired many interesting developments of functional materials for biological and biomedical applications. Here, we report a novel design of a non-viral gene delivery system composed of a cationic star polymer forming supramolecular complexes with the surface oleyl groups of superparamagnetic iron oxide nanoparticles (SPIONs), for magnetically enhanced delivery of DNA into mammalian cells. The cationic star polymer was synthesized by grafting multiple oligoethylenimine (OEI) chains onto an α-cyclodextrin (α-CD) core. The SPIONs were synthesized from iron(III) acetylacetonate and stabilized by hydrophobic oleic acid and oleylamine in hexane, which were characterized in terms of their size, structure, morphology, and magnetic properties. The synthesized magnetic particles were found to be superparamagnetic, making them a suitable ferrofluid for biological applications. In order to change the hydrophobic surface of the SPIONs to a hydrophilic surface with functionalities for plasmid DNA (pDNA) binding and gene delivery, a non-traditional but simple supramolecular surface modification process was used. The α-CD-OEI cationic star polymer was dissolved in water and then mixed with the SPIONs stabilized in hexane. The SPIONs were “pulled” into the water phase through the formation of supramolecular host–guest inclusion complexes between the α-CD unit and the oleyl surface of the SPIONs, while the surface of the SPIONs was changed to OEI cationic polymers. The α-CD-OEI-SPION complex could effectively bind and condense pDNA to form α-CD-OEI-SPION/pDNA polyplex nanoparticles at the size of ca. 200 nm suitable for delivery of genes into cells through endocytosis. The cytotoxicity of the α-CD-OEI-SPION complex was also found to be lower than high-molecular-weight polyethylenimine, which was widely studied previously as a standard non-viral gene vector. When gene transfection was carried out in the presence of an external magnetic field, the α-CD-OEI-SPION/pDNA polyplex nanoparticles greatly increased the gene transfection efficiency by nearly tenfold. Therefore, the study has demonstrated a facile two-in-one method to make the SPIONs water-soluble as well as functionalized for enhanced magnetofection. Full article
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Review

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19 pages, 3007 KiB  
Review
Enhancing the Stability of Bacteriophages Using Physical, Chemical, and Nano-Based Approaches: A Review
by Mateusz Wdowiak, Jan Paczesny and Sada Raza
Pharmaceutics 2022, 14(9), 1936; https://doi.org/10.3390/pharmaceutics14091936 - 13 Sep 2022
Cited by 9 | Viewed by 2847
Abstract
Phages are efficient in diagnosing, treating, and preventing various diseases, and as sensing elements in biosensors. Phage display alone has gained attention over the past decade, especially in pharmaceuticals. Bacteriophages have also found importance in research aiming to fight viruses and in the [...] Read more.
Phages are efficient in diagnosing, treating, and preventing various diseases, and as sensing elements in biosensors. Phage display alone has gained attention over the past decade, especially in pharmaceuticals. Bacteriophages have also found importance in research aiming to fight viruses and in the consequent formulation of antiviral agents and vaccines. All these applications require control over the stability of virions. Phages are considered resistant to various harsh conditions. However, stability-determining parameters are usually the only additional factors in phage-related applications. Phages face instability and activity loss when preserved for extended periods. Sudden environmental changes, including exposure to UV light, temperature, pH, and salt concentration, also lead to a phage titer fall. This review describes various formulations that impart stability to phage stocks, mainly focusing on polymer-based stabilization, encapsulation, lyophilization, and nano-assisted solutions. Full article
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39 pages, 11656 KiB  
Review
Recent Fabrication Methods to Produce Polymer-Based Drug Delivery Matrices (Experimental and In Silico Approaches)
by Anna Procopio, Elena Lagreca, Rezvan Jamaledin, Sara La Manna, Brunella Corrado, Concetta Di Natale and Valentina Onesto
Pharmaceutics 2022, 14(4), 872; https://doi.org/10.3390/pharmaceutics14040872 - 15 Apr 2022
Cited by 16 | Viewed by 2945
Abstract
The study of novel drug delivery systems represents one of the frontiers of the biomedical research area. Multi-disciplinary scientific approaches combining traditional or engineered technologies are used to provide major advances in improving drug bioavailability, rate of release, cell/tissue specificity and therapeutic index. [...] Read more.
The study of novel drug delivery systems represents one of the frontiers of the biomedical research area. Multi-disciplinary scientific approaches combining traditional or engineered technologies are used to provide major advances in improving drug bioavailability, rate of release, cell/tissue specificity and therapeutic index. Biodegradable and bio-absorbable polymers are usually the building blocks of these systems, and their copolymers are employed to create delivery components. For example, poly (lactic acid) or poly (glycolic acid) are often used as bricks for the production drug-based delivery systems as polymeric microparticles (MPs) or micron-scale needles. To avoid time-consuming empirical approaches for the optimization of these formulations, in silico-supported models have been developed. These methods can predict and tune the release of different drugs starting from designed combinations. Starting from these considerations, this review has the aim of investigating recent approaches to the production of polymeric carriers and the combination of in silico and experimental methods as promising platforms in the biomedical field. Full article
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22 pages, 4683 KiB  
Review
Single and Multiple Stimuli-Responsive Polymer Particles for Controlled Drug Delivery
by Aida López Ruiz, Ann Ramirez and Kathleen McEnnis
Pharmaceutics 2022, 14(2), 421; https://doi.org/10.3390/pharmaceutics14020421 - 15 Feb 2022
Cited by 22 | Viewed by 5180
Abstract
Polymers that can change their properties in response to an external or internal stimulus have become an interesting platform for drug delivery systems. Polymeric nanoparticles can be used to decrease the toxicity of drugs, improve the circulation of hydrophobic drugs, and increase a [...] Read more.
Polymers that can change their properties in response to an external or internal stimulus have become an interesting platform for drug delivery systems. Polymeric nanoparticles can be used to decrease the toxicity of drugs, improve the circulation of hydrophobic drugs, and increase a drug’s efficacy. Furthermore, polymers that are sensitive to specific stimuli can be used to achieve controlled release of drugs into specific areas of the body. This review discusses the different stimuli that can be used for controlled drug delivery based on internal and external stimuli. Internal stimuli have been defined as events that evoke changes in different characteristics, inside the body, such as changes in pH, redox potential, and temperature. External stimuli have been defined as the use of an external source such as light and ultrasound to implement such changes. Special attention has been paid to the particular chemical structures that need to be incorporated into polymers to achieve the desired stimuli response. A current trend in this field is the incorporation of several stimuli in a single polymer to achieve higher specificity. Therefore, to access the most recent advances in stimuli-responsive polymers, the focus of this review is to combine several stimuli. The combination of different stimuli is discussed along with the chemical structures that can produce it. Full article
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