Editorial

2 pages, 161 KiB

Open AccessEditorial

Dendrimers for Drug Delivery: Where Do We Stand in 2023?

by Evgeny K. Apartsin

Pharmaceutics 2023, 15(12), 2740; https://doi.org/10.3390/pharmaceutics15122740 - 07 Dec 2023

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Dendrimers are highly symmetric, hyperbranched macromolecules consisting of repeating structural units [...] Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

Research

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17 pages, 3288 KiB

Open AccessEditor’s ChoiceArticle

Targeted Bioluminescent Imaging of Pancreatic Ductal Adenocarcinoma Using Nanocarrier-Complexed EGFR-Binding Affibody–Gaussia Luciferase Fusion Protein

by Jessica Hersh, Yu-Ping Yang, Evan Roberts, Daniel Bilbao, Wensi Tao, Alan Pollack, Sylvia Daunert and Sapna K. Deo

Pharmaceutics 2023, 15(7), 1976; https://doi.org/10.3390/pharmaceutics15071976 - 19 Jul 2023

Cited by 4 | Viewed by 1313

Abstract

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low [...] Read more.

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low background signals. Researchers have increasingly been looking for ways to improve bioluminescent imaging for in vivo applications, which we sought to achieve by developing a bioluminescent probe that could specifically target cells of interest. We chose pancreatic ductal adenocarcinoma (PDAC) as the disease model because it is the most common type of pancreatic cancer and has an extremely low survival rate. We targeted the epidermal growth factor receptor (EGFR), which is frequently overexpressed in pancreatic cancer cells, using an EGFR-specific affibody to selectively identify PDAC cells and delivered a Gaussia luciferase (GLuc) bioluminescent protein for imaging by engineering a fusion protein with both the affibody and the bioluminescent protein. This fusion protein was then complexed with a G5-PAMAM dendrimer nanocarrier. The dendrimer was used to improve the protein stability in vivo and increase signal strength. Our targeted bioluminescent complex had an enhanced uptake into PDAC cells in vitro and localized to PDAC tumors in vivo in pancreatic cancer xenograft mice. The bioluminescent complexes could delineate the tumor shape, identify multiple masses, and locate metastases. Through this work, an EGFR-targeted bioluminescent–dendrimer complex enabled the straightforward identification and imaging of pancreatic cancer cells in vivo in preclinical models. This argues for the targeted nanocarrier-mediated delivery of bioluminescent proteins as a way to improve in vivo bioluminescent imaging. Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

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12 pages, 2050 KiB

Open AccessArticle

T Cell-Association of Carboxy-Terminal Dendrimers with Different Bound Numbers of Phenylalanine and Their Application to Drug Delivery

by Hiroya Shiba, Tomoka Hirose, Yunshen Fu, Masataka Michigami, Ikuo Fujii, Ikuhiko Nakase, Akikazu Matsumoto and Chie Kojima

Pharmaceutics 2023, 15(3), 888; https://doi.org/10.3390/pharmaceutics15030888 - 09 Mar 2023

Cited by 2 | Viewed by 1640

Abstract

T cells play important roles in various immune reactions, and their activation is necessary for cancer immunotherapy. Previously, we showed that polyamidoamine (PAMAM) dendrimers modified with 1,2-cyclohexanedicarboxylic acid (CHex) and phenylalanine (Phe) underwent effective uptake by various immune cells, including T cells and [...] Read more.

T cells play important roles in various immune reactions, and their activation is necessary for cancer immunotherapy. Previously, we showed that polyamidoamine (PAMAM) dendrimers modified with 1,2-cyclohexanedicarboxylic acid (CHex) and phenylalanine (Phe) underwent effective uptake by various immune cells, including T cells and their subsets. In this study, we synthesized various carboxy-terminal dendrimers modified with different bound numbers of Phe and investigated the association of these dendrimers with T cells to evaluate the influence of terminal Phe density. Carboxy-terminal dendrimers conjugating Phe at more than half of the termini exhibited a higher association with T cells and other immune cells. The carboxy-terminal Phe-modified dendrimers at 75% Phe density tended to exhibit the highest association with T cells and other immune cells, which was related to their association with liposomes. A model drug, protoporphyrin IX (PpIX), was encapsulated into carboxy-terminal Phe-modified dendrimers, which were then used for drug delivery into T cells. Our results suggest the carboxy-terminal Phe-modified dendrimers are useful for delivery into T cells. Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

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16 pages, 4022 KiB

Open AccessArticle

Effect of Alkaline Conditions on Forming an Effective G4.0 PAMAM Complex with Doxorubicin

by Magdalena Szota and Barbara Jachimska

Pharmaceutics 2023, 15(3), 875; https://doi.org/10.3390/pharmaceutics15030875 - 08 Mar 2023

Cited by 1 | Viewed by 1181

Abstract

In this study, special attention was paid to the correlation between the degree of ionization of the components and the effective formation of the complex under alkaline conditions. Using UV-Vis, ¹H NMR, and CD, structural changes of the drug depending on the [...] Read more.

In this study, special attention was paid to the correlation between the degree of ionization of the components and the effective formation of the complex under alkaline conditions. Using UV-Vis, ¹H NMR, and CD, structural changes of the drug depending on the pH were monitored. In the pH range of 9.0 to 10.0, the G4.0 PAMAM dendrimer can bind 1 to 10 DOX molecules, while the efficiency increases with the concentration of the drug relative to the carrier. The binding efficiency was described by the parameters of loading content (LC = 4.80–39.20%) and encapsulation efficiency (EE = 17.21–40.16%), whose values increased twofold or even fourfold depending on the conditions. The highest efficiency was obtained for G4.0PAMAM-DOX at a molar ratio of 1:24. Nevertheless, regardless of the conditions, the DLS study indicates system aggregation. Changes in the zeta potential confirm the immobilization of an average of two drug molecules on the dendrimer’s surface. Circular dichroism spectra analysis shows a stable dendrimer-drug complex for all the systems obtained. Since the doxorubicin molecule can simultaneously act as a therapeutic and an imaging agent, the theranostic properties of the PAMAM-DOX system have been demonstrated by the high fluorescence intensity observable on fluorescence microscopy. Full article

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16 pages, 2324 KiB

Open AccessArticle

Effects of Cationic Dendrimers and Their Complexes with microRNAs on Immunocompetent Cells

by Nadezhda Knauer, Ekaterina Pashkina, Alina Aktanova, Olga Boeva, Valeria Arkhipova, Margarita Barkovskaya, Mariya Meschaninova, Andrii Karpus, Jean-Pierre Majoral, Vladimir Kozlov and Evgeny Apartsin

Pharmaceutics 2023, 15(1), 148; https://doi.org/10.3390/pharmaceutics15010148 - 31 Dec 2022

Cited by 5 | Viewed by 1373

Abstract

Short regulatory oligonucleotides are considered prospective tools for immunotherapy. However, they require an adequate carrier to deliver potential therapeutics into immune cells. Herein, we explore the potential of polycationic dendrimers as carriers for microRNAs in peripheral blood mononuclear cells of healthy donors. As [...] Read more.

Short regulatory oligonucleotides are considered prospective tools for immunotherapy. However, they require an adequate carrier to deliver potential therapeutics into immune cells. Herein, we explore the potential of polycationic dendrimers as carriers for microRNAs in peripheral blood mononuclear cells of healthy donors. As an oligonucleotide cargo, we use a synthetic mimic and an inhibitor of miR-155, an important factor in the development and functioning of immunocompetent cells. Dendrimers bind microRNAs into low-cytotoxic polyelectrolyte complexes that are efficiently uptaken by immunocompetent cells. We have shown these complexes to affect the number of T-regulatory cells, CD14⁺ and CD19⁺ cell subpopulations in non-activated mononuclear cells. The treatment affected the expression of HLA-DR on T-cells and PD-1 expression on T- and B-lymphocytes. It also affected the production of IL-4 and IL-10, but not the perforin and granzyme B production. Our findings suggest the potential of dendrimer-mediated microRNA-155 treatment for immunotherapy, though the activity of microRNA-dendrimer constructions on distinct immune cell subsets can be further improved. Full article

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18 pages, 2990 KiB

Open AccessArticle

Analyzing siRNA Concentration, Complexation and Stability in Cationic Dendriplexes by Stem-Loop Reverse Transcription-qPCR

by Maximilian Neugebauer, Clara E. Grundmann, Michael Lehnert, Felix von Stetten, Susanna M. Früh and Regine Süss

Pharmaceutics 2022, 14(7), 1348; https://doi.org/10.3390/pharmaceutics14071348 - 25 Jun 2022

Cited by 2 | Viewed by 3032

Abstract

RNA interference (RNAi) is a powerful therapeutic approach for messenger RNA (mRNA) level regulation in human cells. RNAi can be triggered by small interfering RNAs (siRNAs) which are delivered by non-viral carriers, e.g., dendriplexes. siRNA quantification inside carriers is essential in drug delivery [...] Read more.

RNA interference (RNAi) is a powerful therapeutic approach for messenger RNA (mRNA) level regulation in human cells. RNAi can be triggered by small interfering RNAs (siRNAs) which are delivered by non-viral carriers, e.g., dendriplexes. siRNA quantification inside carriers is essential in drug delivery system development. However, current siRNA measuring methods either are not very sensitive, only semi-quantitative or not specific towards intact target siRNA sequences. We present a novel reverse transcription real-time PCR (RT-qPCR)-based application for siRNA quantification in drug formulations. It enables specific and highly sensitive quantification of released, uncomplexed target siRNA and thus also indirect assessment of siRNA stability and concentration inside dendriplexes. We show that comparison with a dilution series allows for siRNA quantification, exclusively measuring intact target sequences. The limit of detection (LOD) was 4.2 pM (±0.2 pM) and the limit of quantification (LOQ) 77.8 pM (±13.4 pM) for uncomplexed siRNA. LOD and LOQ of dendriplex samples were 31.6 pM (±0 pM) and 44.4 pM (±9.0 pM), respectively. Unspecific non-target siRNA sequences did not decrease quantification accuracy when present in samples. As an example of use, we assessed siRNA complexation inside dendriplexes with varying nitrogen-to-phosphate ratios. Further, protection of siRNA inside dendriplexes from RNase A degradation was quantitatively compared to degradation of uncomplexed siRNA. This novel application for quantification of siRNA in drug delivery systems is an important tool for the development of new siRNA-based drugs and quality checks including drug stability measurements. Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

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Review

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34 pages, 5182 KiB

Open AccessEditor’s ChoiceReview

The Spicy Science of Dendrimers in the Realm of Cancer Nanomedicine: A Report from the COST Action CA17140 Nano2Clinic

by Sabrina Pricl

Pharmaceutics 2023, 15(7), 2013; https://doi.org/10.3390/pharmaceutics15072013 - 24 Jul 2023

Cited by 1 | Viewed by 1146

Abstract

COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their [...] Read more.

COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, preclinical testing of efficacy, pharmacokinetics and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation, and innovative solutions, the action aims at providing a timely instrument to rationalize and focus research efforts at the European level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and societal-burdening human pathologies. Within CA17140, dendrimers in all their forms (from covalent to self-assembling dendrons) play a vital role as powerful nanotheranostic agents in oncology; therefore, the purpose of this review work is to gather and summarize the major results in the field stemming from collaborative efforts in the framework of the European Nano2Clinic COST Action. Full article

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38 pages, 4132 KiB

Open AccessFeature PaperReview

Dendrimer-Mediated Delivery of DNA and RNA Vaccines

by Lyubov A. Kisakova, Evgeny K. Apartsin, Lily F. Nizolenko and Larisa I. Karpenko

Pharmaceutics 2023, 15(4), 1106; https://doi.org/10.3390/pharmaceutics15041106 - 30 Mar 2023

Cited by 8 | Viewed by 2622

Abstract

DNA and RNA vaccines (nucleic acid-based vaccines) are a promising platform for vaccine development. The first mRNA vaccines (Moderna and Pfizer/BioNTech) were approved in 2020, and a DNA vaccine (Zydus Cadila, India), in 2021. They display unique benefits in the current COVID-19 pandemic. [...] Read more.

DNA and RNA vaccines (nucleic acid-based vaccines) are a promising platform for vaccine development. The first mRNA vaccines (Moderna and Pfizer/BioNTech) were approved in 2020, and a DNA vaccine (Zydus Cadila, India), in 2021. They display unique benefits in the current COVID-19 pandemic. Nucleic acid-based vaccines have a number of advantages, such as safety, efficacy, and low cost. They are potentially faster to develop, cheaper to produce, and easier to store and transport. A crucial step in the technology of DNA or RNA vaccines is choosing an efficient delivery method. Nucleic acid delivery using liposomes is the most popular approach today, but this method has certain disadvantages. Therefore, studies are actively underway to develop various alternative delivery methods, among which synthetic cationic polymers such as dendrimers are very attractive. Dendrimers are three-dimensional nanostructures with a high degree of molecular homogeneity, adjustable size, multivalence, high surface functionality, and high aqueous solubility. The biosafety of some dendrimers has been evaluated in several clinical trials presented in this review. Due to these important and attractive properties, dendrimers are already being used to deliver a number of drugs and are being explored as promising carriers for nucleic acid-based vaccines. This review summarizes the literature data on the development of dendrimer-based delivery systems for DNA and mRNA vaccines. Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

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31 pages, 5661 KiB

Open AccessReview

Dendrimers in Alzheimer’s Disease: Recent Approaches in Multi-Targeting Strategies

by Cécile Arbez-Gindre, Barry R. Steele and Maria Micha-Screttas

Pharmaceutics 2023, 15(3), 898; https://doi.org/10.3390/pharmaceutics15030898 - 10 Mar 2023

Cited by 5 | Viewed by 2007

Abstract

Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes of human mortality, and one that is increasing year by year, Alzheimer’s disease (AD) has been the subject of a very great body of research and [...] Read more.

Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes of human mortality, and one that is increasing year by year, Alzheimer’s disease (AD) has been the subject of a very great body of research and is an area in which nanomedicinal approaches show great promise. Dendrimers are a class of multivalent nanomaterials which can accommodate a wide range of modifications that enable them to be used as drug delivery systems. By means of suitable design, they can incorporate multiple functionalities to enable transport across the blood–brain barrier and subsequently target the diseased areas of the brain. In addition, a number of dendrimers by themselves often display therapeutic potential for AD. In this review, the various hypotheses relating to the development of AD and the proposed therapeutic interventions involving dendrimer–base systems are outlined. Special attention is focused on more recent results and on the importance of aspects such as oxidative stress, neuroinflammation and mitochondrial dysfunction in approaches to the design of new treatments. Full article

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