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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 43257

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Prof. Jean-Michel Escoffre

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iBrain UMR 1253, Université de Tours, Inserm, France
Interests: microbubbles; ultrasound; sonoporation; ultrasound imaging; drug and gene delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the increasing development of therapeutic molecules and novel-targeted therapies, therapeutic progress remains modest for many prevalent and costly diseases (i.e., cancer, neurological disorders, cardiovascular diseases, etc.). The main obstacles are the non-specific delivery of drugs (related to drug formulation or physicochemical properties) and the presence of biological barriers (i.e., endothelial barriers, interstitial pressure, extracellular matrix, plasma membranes, etc.). These barriers thus limit the access of a drug to its molecular or cellular target, hence restraining their therapeutic efficacies. In addition, the majority of these therapeutic molecules induce significant side effects in healthy tissues. In this context, any targeted and active drug delivery method promoting increased drug bioavailability specifically in diseased tissues, while at the same time reducing healthy tissue side effects, remains a major challenge in pharmacotherapy.

Among all drug delivery methods, physical methods represent a promising approach for the safe and efficient delivery of therapeutic molecules in clinics. The better understanding of the action of physical forces (electric field, ultrasound, magnetic field, laser, etc.) at the tissue level has increased the interest of scientific and medical communities for the use of these physical methods alone or in combination with physically responsive particles (e.g., liposomes, bubbles, micelles) in drug delivery. These methods lead to the reversible permeabilization of vessels and/or targeted tissues, thus facilitating extravasation of drugs into permeabilized tissues and in turn enhancing their bioavailability. In addition, these physical forces can also induce the local release of drugs from nanoparticles through a mechanical and/or thermal stimulus in the target tissue. Hence, the delivery of drugs in the target tissue can be controlled spatially and temporally through focus and action on these physical forces. In comparison with other drug delivery methods, physical methods are a minimally invasive, easy to apply, and cost-effective method.

The present Special Issue in Pharmaceutics aims to gather a collection of research articles or reviews describing:

Basic mechanisms (in vitro, ex vivo, in vivo) of physically mediated drug delivery;
Proof-of-concept, preclinical, and clinical investigations;
Pharmacokinetics and biodistribution aspects upon physically mediated drug delivery;
Efficacy and safety aspects upon physically mediated drug delivery.

Below is an inclusive, but not exhaustive, list of various technologies that this Special Issue will cover: electric field; ultrasound; photoporation; magnetic field; hydrodynamic injection; biolistic; laser beam drug delivery; jet injection and plasma.

Prof. Jean-Michel Escoffre
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.

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Keywords

physical methods
drug delivery
physically responsive particles
efficacy
safety

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Published Papers (10 papers)

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Research

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18 pages, 7090 KiB

Open AccessArticle

Silk Fibroin Microneedle Patches for the Treatment of Insomnia

by Zhenzhen Qi, Jiaxin Cao, Xiaosheng Tao, Xinyi Wu, Subhas C. Kundu and Shenzhou Lu

Pharmaceutics 2021, 13(12), 2198; https://doi.org/10.3390/pharmaceutics13122198 - 20 Dec 2021

Cited by 25 | Viewed by 5594

Abstract

As a patient-friendly technology, drug-loaded microneedles can deliver drugs through the skin into the body. This system has broad application prospects and is receiving wide attention. Based on the knowledge acquired in this work, we successfully developed a melatonin-loaded microneedle prepared from proline/melatonin/silk fibroin. The engineered microneedles’ morphological, physical, and chemical properties were characterized to investigate their structural transformation mechanism and transdermal drug-delivery capabilities. The results indicated that the crystal structure of silk fibroin in drug-loaded microneedles was mainly Silk I crystal structure, with a low dissolution rate and suitable swelling property. Melatonin-loaded microneedles showed high mechanical properties, and the breaking strength of a single needle was 1.2 N, which could easily be penetrated the skin. The drug release results in vitro revealed that the effective drug concentration was obtained quickly during the early delivery. The successful drug concentration was maintained through continuous release at the later stage. For in vivo experimentation, the Sprague Dawley (SD) rat model of insomnia was constructed. The outcome exhibited that the melatonin-loaded microneedle released the drug into the body through the skin and maintained a high blood concentration (over 5 ng/mL) for 4–6 h. The maximum blood concentration was above 10 ng/mL, and the peak time was 0.31 h. This system indicates that it achieved the purpose of mimicking physiological release and treating insomnia. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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13 pages, 2521 KiB

Open AccessArticle

Transdermal Delivery of Macromolecules Using Two-in-One Nanocomposite Device for Skin Electroporation

by Juliette Simon, Bastien Jouanmiqueou, Marie-Pierre Rols, Emmanuel Flahaut and Muriel Golzio

Pharmaceutics 2021, 13(11), 1805; https://doi.org/10.3390/pharmaceutics13111805 - 28 Oct 2021

Cited by 12 | Viewed by 3384

Abstract

Delivery of hydrophilic molecules through the skin using electroporation is a promising alternative approach to intradermal injection. Recently, we developed a two-in-one electrode/reservoir material composed of carbon nanotubes and agarose hydrogel. In this work, we evaluated the potential of the device to achieve non-invasive transdermal drug delivery using skin electroporation. As it involved an electrode configuration different from the literature, critical questions were raised. First, we demonstrated the efficiency of the device to permeabilize the skin of hairless mice, as observed by propidium iodide (PI) uptake in the nuclei of the epidermis cells through macro fluorescence imaging and histology. Application of Lucifer yellow (LY) at different times after unipolar electroporation treatment demonstrated the partial reversibility of the skin permeabilization after 30 min, and as such, that barrier function properties tended to be restored. We uncovered, for the first time to our knowledge, an intrinsic asymmetry of permeation pathways generated in the stratum corneum during treatment. Electrophoresis was here the main driving force for macromolecule delivery, but it competed with passive diffusion through the generated aqueous pathways for smaller molecules. Finally, we validated 4 kDa dextran labelled with fluorescein isothiocyanate (FD4) as a model molecule to optimize the electrical parameters, needed to improve macromolecule delivery. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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22 pages, 4835 KiB

Open AccessArticle

Non-Clinical In Vitro Evaluation of Antibiotic Resistance Gene-Free Plasmids Encoding Human or Murine IL-12 Intended for First-in-Human Clinical Study

by Spela Kos, Masa Bosnjak, Tanja Jesenko, Bostjan Markelc, Urska Kamensek, Katarina Znidar, Urska Matkovic, Andrej Rencelj, Gregor Sersa, Rosana Hudej, Aneja Tuljak, Matjaz Peterka and Maja Cemazar

Pharmaceutics 2021, 13(10), 1739; https://doi.org/10.3390/pharmaceutics13101739 - 19 Oct 2021

Cited by 12 | Viewed by 3619

Abstract

Interleukin 12 (IL-12) is a key cytokine that mediates antitumor activity of immune cells. To fulfill its clinical potential, the development is focused on localized delivery systems, such as gene electrotransfer, which can provide localized delivery of IL-12 to the tumor microenvironment. Gene electrotransfer of the plasmid encoding human IL-12 is already in clinical trials in USA, demonstrating positive results in the treatment of melanoma patients. To comply with EU regulatory requirements for clinical application, which recommend the use of antibiotic resistance gene-free plasmids, we constructed and developed the production process for the clinical grade quality antibiotic resistance gene-free plasmid encoding human IL-12 (p21-hIL-12-ORT) and its ortholog encoding murine IL-12 (p21-mIL-12-ORT). To demonstrate the suitability of the p21-hIL-12-ORT or p21-mIL-12-ORT plasmid for the first-in-human clinical trial, the biological activity of the expressed transgene, its level of expression and plasmid copy number were determined in vitro in the human squamous cell carcinoma cell line FaDu and the murine colon carcinoma cell line CT26. The results of the non-clinical evaluation in vitro set the basis for further in vivo testing and evaluation of antitumor activity of therapeutic molecules in murine models as well as provide crucial data for further clinical trials of the constructed antibiotic resistance gene-free plasmid in humans. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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10 pages, 4359 KiB

Open AccessArticle

Acoustic and Elastic Properties of a Blood Clot during Microbubble-Enhanced Sonothrombolysis: Hardening of the Clot with Inertial Cavitation

by Laurent Auboire, Damien Fouan, Jean-Marc Grégoire, Fréderic Ossant, Camille Plag, Jean-Michel Escoffre and Ayache Bouakaz

Pharmaceutics 2021, 13(10), 1566; https://doi.org/10.3390/pharmaceutics13101566 - 26 Sep 2021

Cited by 5 | Viewed by 2785

Abstract

Stroke is the second leading cause of death worldwide. Existing therapies present limitations, and other therapeutic alternatives are sought, such as sonothrombolysis with microbubbles (STL). The aim of this study was to evaluate the change induced by STL with or without recombinant tissue-type plasminogen activator (rtPA) on the acoustic and elastic properties of the blood clot by measuring its sound speed (SoS) and shear wave speed (SWS) with high frequency ultrasound and ultrafast imaging, respectively. An in-vitro setup was used and human blood clots were submitted to a combination of microbubbles and rtPA. The results demonstrate that STL induces a raise of SoS in the blood clot, specifically when combined with rtPA (p < 0.05). Moreover, the combination of rtPA and STL induces a hardening of the clot in comparison to rtPA alone (p < 0.05). This is the first assessment of acoustoelastic properties of blood clots during STL. The combination of rtPA and STL induce SoS and hardening of the clot, which is known to impair the penetration of thrombolytic drugs and their efficacy. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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12 pages, 666 KiB

Open AccessArticle

Bleomycin Concentration in Patients’ Plasma and Tumors after Electrochemotherapy. A Study from InspECT Group

by Ales Groselj, Masa Bosnjak, Mojca Krzan, Tina Kosjek, Kriszta Bottyán, Helena Plesnik, Crt Jamsek, Maja Cemazar, Erika Kis and Gregor Sersa

Pharmaceutics 2021, 13(9), 1324; https://doi.org/10.3390/pharmaceutics13091324 - 24 Aug 2021

Cited by 7 | Viewed by 3258

Abstract

The plasma concentration profile of bleomycin in the distribution phase of patients younger than 65 years is needed to determine the suitable time interval for efficient application of electric pulses during electrochemotherapy. Additionally, bleomycin concentrations in the treated tumors for effective tumor response are not known. In this study, the pharmacokinetic profile of bleomycin in the distribution phase in 12 patients younger than 65 years was determined. In 17 patients, the intratumoral bleomycin concentration was determined before the application of electric pulses. In younger patients, the pharmacokinetics of intravenously injected bleomycin demonstrated a faster plasma clearance rate than that in patients older than 65 years. This outcome might indicate that the lowering of the standard bleomycin dose of 15,000 IU/m² with intravenous bleomycin injection for electrochemotherapy is not recommended in younger patients. Based on the plasma concentration data gathered, a time interval for electrochemotherapy of 5–15 min after bleomycin injection was determined. The median bleomycin concentration in tumors 8 min after bleomycin injection, at the time of electroporation, was 170 ng/g. Based on collected data, the reduction of the bleomycin dose is not recommended in younger patients; however, a shortened time interval for application of electric pulses in electrochemotherapy to 5–15 min after intravenous bleomycin injection should be considered. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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18 pages, 4355 KiB

Open AccessArticle

A Setup for Microscopic Studies of Ultrasounds Effects on Microliters Scale Samples: Analytical, Numerical and Experimental Characterization

by Florian N. Gailliègue, Mindaugas Tamošiūnas, Franck M. André and Lluis M. Mir

Pharmaceutics 2021, 13(6), 847; https://doi.org/10.3390/pharmaceutics13060847 - 8 Jun 2021

Cited by 1 | Viewed by 2429

Abstract

Sonoporation is the process of cell membrane permeabilization, due to exposure to ultrasounds. There is a lack of consensus concerning the mechanisms of sonoporation: Understanding the mechanisms of sonoporation refines the choice of the ultrasonic parameters to be applied on the cells. Cells’ classical exposure systems to ultrasounds have several drawbacks, like the immersion of the cells in large volumes of liquid, the nonhomogeneous acoustic pressure in the large sample, and thus, the necessity for magnetic stirring to somehow homogenize the exposure of the cells. This article reports the development and characterization of a novel system allowing the exposure to ultrasounds of very small volumes and their observation under the microscope. The observation under a microscope imposes the exposure of cells and Giant Unilamellar Vesicles under an oblique incidence, as well as the very unusual presence of rigid walls limiting the sonicated volume. The advantages of this new setup are not only the use of a very small volume of cells culture medium/microbubbles (MB), but the presence of flat walls near the sonicated region that results in a more homogeneous ultrasonic pressure field, and thus, the control of the focal distance and the real exposure time. The setup presented here comprises the ability to survey the geometrical and dynamical aspects of the exposure of cells and MB to ultrasounds, if an ultrafast camera is used. Indeed, the setup thus fulfills all the requirements to apply ultrasounds conveniently, for accurate mechanistic experiments under an inverted fluorescence microscope, and it could have interesting applications in photoacoustic research. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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15 pages, 4176 KiB

Open AccessArticle

Sonoporation Using Nanoparticle-Loaded Microbubbles Increases Cellular Uptake of Nanoparticles Compared to Co-Incubation of Nanoparticles and Microbubbles

by Sofie Snipstad, Sigurd Hanstad, Astrid Bjørkøy, Ýrr Mørch and Catharina de Lange Davies

Pharmaceutics 2021, 13(5), 640; https://doi.org/10.3390/pharmaceutics13050640 - 30 Apr 2021

Cited by 25 | Viewed by 3830

Abstract

Therapeutic agents can benefit from encapsulation in nanoparticles, due to improved pharmacokinetics and biodistribution, protection from degradation, increased cellular uptake and sustained release. Microbubbles in combination with ultrasound have been shown to improve the delivery of nanoparticles and drugs to tumors and across the blood-brain barrier. Here, we evaluate two different microbubbles for enhancing the delivery of polymeric nanoparticles to cells in vitro: a commercially available lipid microbubble (Sonazoid) and a microbubble with a shell composed of protein and nanoparticles. Various ultrasound parameters are applied and confocal microscopy is employed to image cellular uptake. Ultrasound enhanced cellular uptake depending on the pressure and duty cycle. The responsible mechanisms are probably sonoporation and sonoprinting, followed by uptake, and to a smaller degree enhanced endocytosis. The use of commercial Sonazoid microbubbles leads to significantly lower uptake than when using nanoparticle-loaded microbubbles, suggesting that proximity between cells, nanoparticles and microbubbles is important, and that mainly nanoparticles in the shell are taken up, rather than free nanoparticles in solution. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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Review

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20 pages, 801 KiB

Open AccessReview

An Overview of Cell Membrane Perforation and Resealing Mechanisms for Localized Drug Delivery

by Stephanie He, Davindra Singh and Brandon Helfield

Pharmaceutics 2022, 14(4), 886; https://doi.org/10.3390/pharmaceutics14040886 - 18 Apr 2022

Cited by 15 | Viewed by 4423

Abstract

Localized and reversible plasma membrane disruption is a promising technique employed for the targeted deposition of exogenous therapeutic compounds for the treatment of disease. Indeed, the plasma membrane represents a significant barrier to successful delivery, and various physical methods using light, sound, and electrical energy have been developed to generate cell membrane perforations to circumvent this issue. To restore homeostasis and preserve viability, localized cellular repair mechanisms are subsequently triggered to initiate a rapid restoration of plasma membrane integrity. Here, we summarize the known emergency membrane repair responses, detailing the salient membrane sealing proteins as well as the underlying cytoskeletal remodeling that follows the physical induction of a localized plasma membrane pore, and we present an overview of potential modulation strategies that may improve targeted drug delivery approaches. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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35 pages, 8808 KiB

Open AccessReview

Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application

by Charis Rousou, Carl C. L. Schuurmans, Arto Urtti, Enrico Mastrobattista, Gert Storm, Chrit Moonen, Kai Kaarniranta and Roel Deckers

Pharmaceutics 2021, 13(11), 1782; https://doi.org/10.3390/pharmaceutics13111782 - 25 Oct 2021

Cited by 18 | Viewed by 4809

Abstract

The unique anatomy of the eye and the presence of various biological barriers make efficacious ocular drug delivery challenging, particularly in the treatment of posterior eye diseases. This review focuses on the combination of ultrasound and microbubbles (USMB) as a minimally invasive method to improve the efficacy and targeting of ocular drug delivery. An extensive overview is given of the in vitro and in vivo studies investigating the mechanical effects of ultrasound-driven microbubbles aiming to: (i) temporarily disrupt the blood–retina barrier in order to enhance the delivery of systemically administered drugs into the eye, (ii) induce intracellular uptake of anticancer drugs and macromolecules and (iii) achieve targeted delivery of genes, for the treatment of ocular malignancies and degenerative diseases. Finally, the safety and tolerability aspects of USMB, essential for the translation of USMB to the clinic, are discussed. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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30 pages, 2670 KiB

Open AccessReview

Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound

by Ambre Dauba, Anthony Delalande, Hermes A. S. Kamimura, Allegra Conti, Benoit Larrat, Nicolas Tsapis and Anthony Novell

Pharmaceutics 2020, 12(11), 1125; https://doi.org/10.3390/pharmaceutics12111125 - 21 Nov 2020

Cited by 51 | Viewed by 6246

Abstract

The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies. The new generation of sono-sensitive agents, such as liquid-core droplets, can also potentially disrupt the blood-brain barrier after their ultrasound-induced vaporization. In this review, we describe the different compositions of agents used for ultrasound-mediated blood-brain barrier opening in recent studies, and we discuss the challenges of the past five years related to the optimal formulation of agents. Full article

(This article belongs to the Special Issue Advances in Physics Methods for Drug Delivery)

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