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Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Applied Chemistry".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 35768

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Dr. Marina A. Dobrovolskaia

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Guest Editor

Nanotechnology Characterization Lab, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
Interests: immunology; toxicology; nanoparticles
Special Issues, Collections and Topics in MDPI journals

Dr. Kirill A. Afonin

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Guest Editor

Department of Chemistry, UNC Charlotte, Charlotte, NC, USA
Interests: RNA nanobiology; drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Please join us to celebrate Professor Yechezkel Barenholz’s distinguished achievements. Professor Barenholz is Professor Emeritus of the Hebrew University in Jerusalem, Israel. He joined the University faculty in 1968, received his PhD in 1971, and became Professor in 1981. He has worked and taught at leading universities worldwide throughout his career. One of the prominent achievements in Prof. Barenholz’s career is the development of a PEGylated liposomal doxorubicin formulation, known as Doxil®, that completely transformed care for cancer patients worldwide. Professor Barenholz’s research focuses on the biochemistry of lipids and membranes and biophysics laws underlying the fluidity of cellular membranes. Another focus area is the development of liposomes and lipid-based nanocarriers to overcome the shortcomings of current therapeutics by improving drug delivery. Professor Barenholz has authored more than 400 papers with an h-index of 94; he is also inventor of over 55 patents and an awardee of many prestigious national and international awards in the biomedical field. Professor Barenholz is highly regarded by his peers and students. One of the examples of his continuous contribution to the education of the next generation of scientists is the “Barenholz Prize” that supports Israeli PhD students in Applied Sciences and encourages their professional growth and innovation. Professor Barenholz has founded and is currently leading the steering committee of the Hebrew University School of Business Administration BioMed-MBA program, through which he organized an online platform that enables the Israeli BioMed ecosystem.

This themed issue invites original research papers and reviews articles describing a variety of nanotechnology platforms, including but not limited to liposomes for drug delivery, which are geared toward overcoming the world’s most critical health issues and supporting the sustainability of the environment.

Dr. Marina A. Dobrovolskaia
Assoc. Prof. Dr. Kirill A. Afonin
Guest Editors

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Published Papers (11 papers)

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Editorial

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3 pages, 182 KiB

Open AccessEditorial

Special Issue “Nanotechnology to Overcome the World’s Most Critical Health Issues: Liposomes and Beyond—A Themed Issue Dedicated to Professor Yechezkel Barenholz”

by Marina A. Dobrovolskaia and Kirill A. Afonin

Molecules 2023, 28(12), 4788; https://doi.org/10.3390/molecules28124788 - 15 Jun 2023

Viewed by 977

Abstract

This Special Issue is intended to celebrate Professor Yechezkel Barenholz’s distinguished achievements [...] Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

Research

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11 pages, 3592 KiB

Open AccessArticle

Change in Lipofectamine Carrier as a Tool to Fine-Tune Immunostimulation of Nucleic Acid Nanoparticles

by Hannah S. Newton, Yasmine Radwan, Jie Xu, Jeffrey D. Clogston, Marina A. Dobrovolskaia and Kirill A. Afonin

Molecules 2023, 28(11), 4484; https://doi.org/10.3390/molecules28114484 - 1 Jun 2023

Cited by 3 | Viewed by 1869

Abstract

Nucleic acid nanoparticles (NANPs) require a carrier to allow for their intracellular delivery to immune cells. Cytokine production, specifically type I and III interferons, allows for reliable monitoring of the carrier effect on NANP immunostimulation. Recent studies have shown that changes in the delivery platform (e.g., lipid-based carriers vs. dendrimers) can alter NANPs’ immunorecognition and downstream cytokine production in various immune cell populations. Herein, we used flow cytometry and measured cytokine induction to show how compositional variations in commercially available lipofectamine carriers impact the immunostimulatory properties of NANPs with different architectural characteristics. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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11 pages, 4017 KiB

Open AccessArticle

Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer

by In Kyung Cho, Man Kyu Shim, Wooram Um, Jong-Ho Kim and Kwangmeyung Kim

Molecules 2022, 27(8), 2529; https://doi.org/10.3390/molecules27082529 - 14 Apr 2022

Cited by 11 | Viewed by 3052

Abstract

Pancreatic cancer is a highly fatal disease that is becoming an increasingly leading cause of cancer-related deaths. In clinic, the most effective approach to treat pancreatic cancers is the combination treatment of several chemotherapeutic drugs, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), but this approach is not adequate to manage patients due to their severe toxic side effects. Herein, we proposed light-activated monomethyl auristatin E (MMAE) prodrug nanoparticles for combinational photo-chemotherapy and optimized its applications for pancreatic cancer treatment. The photosensitizer (Ce6) and chemotherapeutic drug (MMAE) were conjugated through caspase-3-specific cleavable peptide (KGDEVD). The resulting CDM efficiently promoted the reactive oxygen species (ROS) under visible light irradiation and thereby induced caspase-3 overexpression in pacreatic cancers, which subsequently released the MMAE from the system. Importantly, MMAE released from CDM further amplified the activation of CDM into MMAE by inducing extensive apoptotic cell death in tumor microenvironment for treatment of tumor cells in deep in the tumor tissues as far visible light cannot reach. In addition, CDM formed prodrug nanoparticles via intermolecular π-π stacking and hydrophobic interactions, allowing durable and reliable treatment by preventing fast leakage from the pancreatic cancers via the lymphatic vessels. The CDM directly (intratumoral) injected into pancreatic cancers in orthotopic models through an invasive approach significantly delayed the tumor progression by combinational photo-chemotherapy with less toxic side effects. This study offers a promising and alternative approach for safe and more effective pancreatic cancer treatment via prodrug nanoparticles that combine photodynamic therapy and chemotherapy. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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20 pages, 4079 KiB

Open AccessArticle

An In Vitro Assessment of Immunostimulatory Responses to Ten Model Innate Immune Response Modulating Impurities (IIRMIs) and Peptide Drug Product, Teriparatide

by Claire K. Holley, Edward Cedrone, Duncan Donohue, Barry W. Neun, Daniela Verthelyi, Eric S. Pang and Marina A. Dobrovolskaia

Molecules 2021, 26(24), 7461; https://doi.org/10.3390/molecules26247461 - 9 Dec 2021

Cited by 7 | Viewed by 3983

Abstract

Understanding, predicting, and minimizing the immunogenicity of peptide-based therapeutics are of paramount importance for ensuring the safety and efficacy of these products. The so-called anti-drug antibodies (ADA) may have various clinical consequences, including but not limited to the alteration in the product’s distribution, biological activity, and clearance profiles. The immunogenicity of biotherapeutics can be influenced by immunostimulation triggered by the presence of innate immune response modulating impurities (IIRMIs) inadvertently introduced during the manufacturing process. Herein, we evaluate the applicability of several in vitro assays (i.e., complement activation, leukocyte proliferation, and cytokine secretion) for the screening of innate immune responses induced by ten common IIRMIs (Bacillus subtilis flagellin, FSL-1, zymosan, ODN2006, poly(I:C) HMW, poly(I:C) LMW, CLO75, MDP, ODN2216, and Escherichia coli O111:B4 LPS), and a model biotherapeutic Forteo™ (teriparatide). Our study identifies cytokine secretion from healthy human donor peripheral blood mononuclear cells (PBMC) as a sensitive method for the in vitro monitoring of innate immune responses to individual IIRMIs and teriparatide (TP). We identify signature cytokines, evaluate both broad and narrow multiplex cytokine panels, and discuss how the assay logistics influence the performance of this in vitro assay. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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22 pages, 5903 KiB

Open AccessArticle

Crosslinking of CD38 Receptors Triggers Apoptosis of Malignant B Cells

by M. Tommy Gambles, Jiahui Li, Jiawei Wang, Douglas Sborov, Jiyuan Yang and Jindřich Kopeček

Molecules 2021, 26(15), 4658; https://doi.org/10.3390/molecules26154658 - 31 Jul 2021

Cited by 13 | Viewed by 4210

Abstract

Recently, we designed an inventive paradigm in nanomedicine—drug-free macromolecular therapeutics (DFMT). The ability of DFMT to induce apoptosis is based on biorecognition at cell surface, and crosslinking of receptors without the participation of low molecular weight drugs. The system is composed of two nanoconjugates: a bispecific engager, antibody or Fab’ fragment—morpholino oligonucleotide (MORF1) conjugate; the second nanoconjugate is a multivalent effector, human serum albumin (HSA) decorated with multiple copies of complementary MORF2. Here, we intend to demonstrate that DFMT is a platform that will be effective on other receptors than previously validated CD20. We appraised the impact of daratumumab (DARA)- and isatuximab (ISA)-based DFMT to crosslink CD38 receptors on CD38+ lymphoma (Raji, Daudi) and multiple myeloma cells (RPMI 8226, ANBL-6). The biological properties of DFMTs were determined by flow cytometry, confocal fluorescence microscopy, reactive oxygen species determination, lysosomal enlargement, homotypic cell adhesion, and the hybridization of nanoconjugates. The data revealed that the level of apoptosis induction correlated with CD38 expression, the nanoconjugates meet at the cell surface, mitochondrial signaling pathway is strongly involved, insertion of a flexible spacer in the structure of the macromolecular effector enhances apoptosis, and simultaneous crosslinking of CD38 and CD20 receptors increases apoptosis. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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11 pages, 4277 KiB

Open AccessArticle

Design of a Near Infrared Fluorescent Ureter Imaging Agent for Prevention of Ureter Damage during Abdominal Surgeries

by Sakkarapalayam M. Mahalingam, Karson S. Putt, Madduri Srinivasarao and Philip S. Low

Molecules 2021, 26(12), 3739; https://doi.org/10.3390/molecules26123739 - 19 Jun 2021

Cited by 7 | Viewed by 2833

Abstract

The inadvertent severing of a ureter during surgery occurs in as many as 4.5% of colorectal surgeries. To help prevent this issue, several near-infrared (NIR) dyes have been developed to assist surgeons with identifying ureter location. However, the majority of these dyes exhibit at least some issue that precludes their widespread usage such as high levels of uptake in other tissues, overlapping emission wavelengths with other NIR dyes used for other fluorescence-guided surgeries, and/or rapid excretion times through the ureters. To overcome these limitations, we have synthesized and characterized the spectral properties and biodistribution of a new series of PEGylated UreterGlow derivatives. The most promising dye, UreterGlow-11 was shown to almost exclusively excrete through the kidneys/ureters with detectable fluorescence observed for at least 12 h. Additionally, while the excitation wavelength is similar to that of other NIR dyes used for cancer resections, the emission is shifted by ~30 nm allowing for discrimination between the different fluorescence-guided surgery probes. In conclusion, these new UreterGlow dyes show promising optical and biodistribution characteristics and are good candidates for translation into the clinic. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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17 pages, 3035 KiB

Open AccessArticle

Formulation of Tioconazole and Melaleuca alternifolia Essential Oil Pickering Emulsions for Onychomycosis Topical Treatment

by Barbara Vörös-Horváth, Sourav Das, Ala’ Salem, Sándor Nagy, Andrea Böszörményi, Tamás Kőszegi, Szilárd Pál and Aleksandar Széchenyi

Molecules 2020, 25(23), 5544; https://doi.org/10.3390/molecules25235544 - 26 Nov 2020

Cited by 15 | Viewed by 3542

Abstract

Onychomycosis is a disease that affects many adults, whose treatment includes both oral and topical therapies with low cure rates. The topical therapy is less effective but causes fewer side effects. This is why the development of an effective, easy to apply formulation for topical treatment is of high importance. We have used a nanotechnological approach to formulate Pickering emulsions (PEs) with well-defined properties to achieve site-specific delivery for antifungal drug combination of tioconazole and Melaleuca alternifolia essential oil. Silica nanoparticles with tailored size and partially hydrophobic surface have been synthesized and used for the stabilization of PEs. In vitro diffusion studies have been performed to evaluate the drug delivery properties of PEs. Ethanolic solution (ES) and conventional emulsions (CE) have been used as reference drug formulations. The examination of the antifungal effect of PEs has been performed on Candida albicans and Trichophyton rubrum as main pathogens. In vitro microbiological experimental results suggest that PEs are better candidates for onychomycosis topical treatment than CE or ES of the examined drugs. The used drugs have shown a significant synergistic effect, and the combination with an effective drug delivery system can result in a promising drug form for the topical treatment of onychomycosis. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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Review

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19 pages, 2774 KiB

Open AccessReview

Dissecting Functional Biological Interactions Using Modular RNA Nanoparticles

by Kaitlin Klotz, Yasmine Radwan and Kausik Chakrabarti

Molecules 2023, 28(1), 228; https://doi.org/10.3390/molecules28010228 - 27 Dec 2022

Cited by 1 | Viewed by 2113

Abstract

Nucleic acid nanoparticles (NANPs) are an exciting and innovative technology in the context of both basic and biomedical research. Made of DNA, RNA, or their chemical analogs, NANPs are programmed for carrying out specific functions within human cells. NANPs are at the forefront of preventing, detecting, and treating disease. Their nucleic acid composition lends them biocompatibility that provides their cargo with enhanced opportunity for coordinated delivery. Of course, the NANP system of targeting specific cells and tissues is not without its disadvantages. Accumulation of NANPs outside of the target tissue and the potential for off-target effects of NANP-mediated cargo delivery present challenges to research and medical professionals and these challenges must be effectively addressed to provide safe treatment to patients. Importantly, development of NANPs with regulated biological activities and immunorecognition becomes a promising route for developing versatile nucleic acid therapeutics. In a basic research context, NANPs can assist investigators in fine-tuning the structure-function relationship of final formulations and in this review, we explore the practical applications of NANPs in laboratory and clinical settings and discuss how we can use established nucleic acid research techniques to design effective NANPs. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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23 pages, 1906 KiB

Open AccessReview

Innate Immunity Modulating Impurities and the Immunotoxicity of Nanobiotechnology-Based Drug Products

by Claire K. Holley and Marina A. Dobrovolskaia

Molecules 2021, 26(23), 7308; https://doi.org/10.3390/molecules26237308 - 1 Dec 2021

Cited by 7 | Viewed by 3664

Abstract

Innate immunity can be triggered by the presence of microbial antigens and other contaminants inadvertently introduced during the manufacture and purification of bionanopharmaceutical products. Activation of these innate immune responses, including cytokine secretion, complement, and immune cell activation, can result in unexpected and undesirable host immune responses. These innate modulators can also potentially stimulate the activation of adaptive immune responses, including the formation of anti-drug antibodies which can impact drug effectiveness. To prevent induction of these adverse responses, it is important to detect and quantify levels of these innate immunity modulating impurities (IIMIs) that may be present in drug products. However, while it is universally agreed that removal of IIMIs from drug products is crucial for patient safety and to prevent long-term immunogenicity, there is no single assay capable of directly detecting all potential IIMIs or indirectly quantifying downstream biomarkers. Additionally, there is a lack of agreement as to which of the many analytical assays currently employed should be standardized for general IIMI screening. Herein, we review the available literature to highlight cellular and molecular mechanisms underlying IIMI-mediated inflammation and its relevance to the safety and efficacy of pharmaceutical products. We further discuss methodologies used for direct and indirect IIMI identification and quantification. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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12 pages, 2267 KiB

Open AccessReview

The Recognition of and Reactions to Nucleic Acid Nanoparticles by Human Immune Cells

by Dominika Bila, Yasmine Radwan, Marina A. Dobrovolskaia, Martin Panigaj and Kirill A. Afonin

Molecules 2021, 26(14), 4231; https://doi.org/10.3390/molecules26144231 - 12 Jul 2021

Cited by 16 | Viewed by 3162

Abstract

The relatively straightforward methods of designing and assembling various functional nucleic acids into nanoparticles offer advantages for applications in diverse diagnostic and therapeutic approaches. However, due to the novelty of this approach, nucleic acid nanoparticles (NANPs) are not yet used in the clinic. The immune recognition of NANPs is among the areas of preclinical investigation aimed at enabling the translation of these novel materials into clinical settings. NANPs’ interactions with the complement system, coagulation systems, and immune cells are essential components of their preclinical safety portfolio. It has been established that NANPs’ physicochemical properties—composition, shape, and size—determine their interactions with immune cells (primarily blood plasmacytoid dendritic cells and monocytes), enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. However, unlike traditional therapeutic nucleic acids (e.g., CpG oligonucleotides), NANPs do not trigger a cytokine response unless they are delivered into the cells using a carrier. Recently, it was discovered that the type of carrier provides an additional tool for regulating both the spectrum and the magnitude of the cytokine response to NANPs. Herein, we review the current knowledge of NANPs’ interactions with various components of the immune system to emphasize the unique properties of these nanomaterials and highlight opportunities for their use in vaccines and immunotherapy. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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16 pages, 622 KiB

Open AccessReview

Nanomedicine Reformulation of Chloroquine and Hydroxychloroquine

by David M. Stevens, Rachael M. Crist and Stephan T. Stern

Molecules 2021, 26(1), 175; https://doi.org/10.3390/molecules26010175 - 31 Dec 2020

Cited by 16 | Viewed by 5064

Abstract

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Additional liabilities of these medications include pharmacokinetic profiles that require extended dosing to achieve therapeutic tissue concentrations. To improve chloroquine therapy, researchers have turned toward nanomedicine reformulation of chloroquine and hydroxychloroquine to increase exposure of target tissues relative to off-target tissues, thereby improving the therapeutic index. This review highlights these reformulation efforts to date, identifying issues in experimental designs leading to ambiguity regarding the nanoformulation improvements and lack of thorough pharmacokinetics and safety evaluation. Gaps in our current understanding of these formulations, as well as recommendations for future formulation efforts, are presented. Full article

(This article belongs to the Special Issue Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz)

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Nanotechnology to Overcome World’s Most Critical Health Issues: Liposomes and beyond—a Themed Issue Dedicated to Professor Yechezkel Barenholz

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