Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday for His Outstanding Achievements in Advancing the Field of Dendrimers

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

Deadline for manuscript submissions: 30 April 2024 | Viewed by 16928

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Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka Str. 44/52, 01-224 Warsaw, Poland
Interests: dendrimers: synthesis and applications; antimicrobial peptides; crystallochemistry; MOF-materials
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Special Issue Information

Dear Colleagues,

“Pharmaceutics” is highly pleased to host a themed issue honoring Dr. Donald A. Tomalia for his outstanding achievements in advancing the field of dendrimers on the occasion of his 85th birthday.

Donald A. Tomalia was born in Owosso, Michigan, where he earned his bachelor’s degree in chemistry at the University of Michigan. Soon after graduation, he went to work at Dow. This company supported his doctoral studies in physical organic chemistry at Michigan State University. The initial studies of D. Tomalia concerned cationic polymerization, which were recognized by international industrial awards for creative research in 1978 and 1986. As Dow permitted scientists to explore their own pet projects on Friday afternoons, he proposed building polymers with an ordered, predictable branching structure. His colleagues greeted him with skepticism, but he persisted, and he and some colleagues produced polymers with a central core and tendrils that branched outward, one from another, in a precise, predictable manner. D. Tomalia called them dendrimers in 1985, after dendros, the Greek word for trees and meros for parts. He received another industrial award for creative research in 1991 for such discovery. He played a key role in establishing the place of dendrimers in polymer chemistry, and provided continued inspiration to many in expanding the scope and potential of these well-defined molecular architectures. D. Tomalia holds more than 100 dendrimer-related U.S. patents. He co-founded Dendritech, a dendrimer production company in Midland, Michigan, in 1992, he founded Dendritic NanoTechnologies in Mount Pleasant, Michigan, in a joint venture with StarPharma in Melbourne, Australia, in 2002, a nanotechnology company called NanoSynthons LLC in 2010, and he is CEO and director of the National Dendrimer and Nanotechnology Center located at the NanoSynthons site in Mount Pleasant. 

Tomalia was inducted in 2011 into the Thomas Reuters Hall of Citation Laureates in Chemistry, a listing of the 40 most highly cited international scientists in the field of chemistry. He has received many awards for discovering dendritic polymers, including the Leonardo da Vinci award (1996) and Society of Polymer Science Japan award (2003). He worked at Michigan Molecular Institute from 1990-1999 in the capacity as Professor and Director. Then, he served as Adjunct Professor in the Department of Chemistry at the University of Pennsylvania. He co-authored more than 270 articles and several books on dendrimers.

Pharmaceutics invites scientists to submit original contributions to “Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of his 85th Birthday”, and join us in collectively congratulating him for his outstanding accomplishments.

Prof. Dr. Zofia Urbanczyk-Lipkowska
Prof. Dr. Anne-Marie Caminade
Guest Editors

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Keywords

  • dendrimers
  • synthesis
  • theranostic
  • cancer
  • biosensors
  • dendrons
  • disease treatments

Published Papers (10 papers)

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Research

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19 pages, 3133 KiB  
Article
Molecular Ballet: Investigating the Complex Interaction between Self-Assembling Dendrimers and Human Serum Albumin via Computational and Experimental Methods
by Gabriele Cavalieri, Domenico Marson, Nicoletta Giurgevich, Rachele Valeri, Fulvia Felluga, Erik Laurini and Sabrina Pricl
Pharmaceutics 2024, 16(4), 533; https://doi.org/10.3390/pharmaceutics16040533 - 12 Apr 2024
Viewed by 370
Abstract
Dendrimers, intricate macromolecules with highly branched nanostructures, offer unique attributes including precise control over size, shape, and functionality, making them promising candidates for a wide range of biomedical applications. The exploration of their interaction with biological environments, particularly human serum albumin (HSA), holds [...] Read more.
Dendrimers, intricate macromolecules with highly branched nanostructures, offer unique attributes including precise control over size, shape, and functionality, making them promising candidates for a wide range of biomedical applications. The exploration of their interaction with biological environments, particularly human serum albumin (HSA), holds significant importance for biomedical utilization. In this study, the interaction between HSA and a recently developed self-assembling amphiphilic dendrimer (AD) was investigated using various experimental techniques. Fluorescence spectroscopy and isothermal titration calorimetry revealed moderate interactions between the protein and the AD nanomicelles (NMs), primarily attributed to favorable enthalpic contributions arising from electrostatic interactions and hydrogen bonding. Structural analysis indicated minimal changes in HSA upon complexation with the AD NMs, which was further supported by computational simulations demonstrating stable interactions at the atomistic level. These findings provide valuable insights into the binding mechanisms and thermodynamic parameters governing HSA/AD NM interactions, thereby contributing to the understanding of their potential biomedical applications. Full article
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15 pages, 4354 KiB  
Article
Fine-Tuning the Amphiphilic Properties of Carbosilane Dendritic Networks towards High-Swelling Thermogels
by Silvia Muñoz-Sánchez, Andrea Barrios-Gumiel, Francisco Javier de la Mata and Sandra García-Gallego
Pharmaceutics 2024, 16(4), 495; https://doi.org/10.3390/pharmaceutics16040495 - 03 Apr 2024
Viewed by 426
Abstract
Dendritic hydrogels based on carbosilane crosslinkers are promising drug delivery systems, as their amphiphilic nature improves the compatibility with poorly water-soluble drugs. In this work, we explored the impact of the complementary polymer on the amphiphilic properties of the dendritic network. Different polymers [...] Read more.
Dendritic hydrogels based on carbosilane crosslinkers are promising drug delivery systems, as their amphiphilic nature improves the compatibility with poorly water-soluble drugs. In this work, we explored the impact of the complementary polymer on the amphiphilic properties of the dendritic network. Different polymers were selected as precursors, from the highly lipophilic propylene glycol (PPG) to the hydrophilic polyethylene glycol (PEG), including amphiphilic Pluronics L31, L35 and L61. The dithiol polymers reacted with carbosilane crosslinkers through UV-initiated thiol–ene coupling (TEC), and the resultant materials were classified as non-swelling networks (for PPG, PLUL31 and PLUL61) and high-swelling hydrogels (for PEG and PLUL35). The hydrogels exhibited thermo-responsive properties, shrinking at higher temperatures, and exhibited an intriguing drug release pattern due to internal nanostructuring. Furthermore, we fine-tuned the dendritic crosslinker, including hydroxyl and azide pendant groups in the focal point, generating functional networks that can be modified through degradable (ester) and non-degradable (triazol) bonds. Overall, this work highlighted the crucial role of the amphiphilic balance in the design of dendritic hydrogels with thermo-responsive behavior and confirmed their potential as functional networks for biomedical applications. Full article
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19 pages, 3289 KiB  
Article
Carbosilane Dendritic Amphiphiles from Cholesterol or Vitamin E for Micelle Formation
by Gabriel Mencia, Sergio Algar, Tania Lozano-Cruz, Mª Ángeles Muñoz-Fernández, Elizabeth R. Gillies, Jesús Cano, Mercedes Valiente and Rafael Gómez
Pharmaceutics 2024, 16(4), 451; https://doi.org/10.3390/pharmaceutics16040451 - 25 Mar 2024
Viewed by 535
Abstract
Cationic dendritic amphiphiles were prepared through the linkage of interesting hydrophobic molecules such as cholesterol or vitamin E to the focal point of carbosilane dendrons. These new dendritic systems self-assembled in saline, producing micellar aggregates with hydrodynamic diameters ranging from 6.5 to 9.2 [...] Read more.
Cationic dendritic amphiphiles were prepared through the linkage of interesting hydrophobic molecules such as cholesterol or vitamin E to the focal point of carbosilane dendrons. These new dendritic systems self-assembled in saline, producing micellar aggregates with hydrodynamic diameters ranging from 6.5 to 9.2 nm, and critical micelle concentrations of approximately 5 and 10 μM for second- and third-generation systems, respectively. The assemblies were able to encapsulate drugs of different charges (anionic, neutral, and cationic). Surprisingly, a 92% encapsulation efficiency for diclofenac was achieved in micelles prepared from second-generation dendrons. Toxicity measurements on peripheral blood mononuclear cells indicated different behavior depending on the generation, corresponding to the micellar regime. In contrast to the third-generation system, the second-generation system was non-toxic up to 20 μM, opening a window for its use in a micellar regimen, thereby operating as a drug delivery system for different biomedical applications. Full article
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19 pages, 9429 KiB  
Article
Dendritic Glycerol-Cholesterol Amphiphiles as Drug Delivery Systems: A Comparison between Monomeric and Polymeric Structures
by Jocelyn Fernanda Romero, Svenja Herziger, Mariam Cherri, Mathias Dimde, Katharina Achazi, Ehsan Mohammadifar and Rainer Haag
Pharmaceutics 2023, 15(10), 2452; https://doi.org/10.3390/pharmaceutics15102452 - 12 Oct 2023
Viewed by 1073
Abstract
The application of micelles as drug delivery systems has gained a great deal of attention as a means to overcome the current several drawbacks present in conventional cancer treatments. In this work, we highlight the comparison of polymeric and monomeric amphiphilic systems with [...] Read more.
The application of micelles as drug delivery systems has gained a great deal of attention as a means to overcome the current several drawbacks present in conventional cancer treatments. In this work, we highlight the comparison of polymeric and monomeric amphiphilic systems with a similar hydrophilic–lipophilic balance (HLB) in terms of their biocompatibility, aggregation behavior in aqueous solution, and potential in solubilizing hydrophobic compounds. The polymeric system consists of non-ionic polymeric amphiphiles synthesized via sequential RAFT polymerization of polyglycerol first-generation [G1] dendron methacrylate and cholesterol methacrylate to obtain poly(G1-polyglycerol dendron methacrylate)-block-poly(cholesterol methacrylate) (pG1MA-b-pCMA). The monomeric system is a polyglycerol second-generation [G2] dendron end-capped to a cholesterol unit. Both amphiphiles form spherical micellar aggregations in aqueous solution, with differences in size and the morphology in which hydrophobic molecules can be encapsulated. The polymeric and monomeric micelles showed a low critical micelle concentration (CMC) of 0.2 and 17 μg/mL, respectively. The results of our cytotoxicity assays showed that the polymeric system has significantly higher cell viability compared to that of the monomeric amphiphiles. The polymeric micelles were implemented as drug delivery systems by encapsulation of the hydrophobic small molecule doxorubicin, achieving a loading capacity of 4%. In summary, the results of this study reveal that using cholesterol as a building block for polymer synthesis is a promising method of preparation for efficient drug delivery systems while improving the cell viability of monomeric cholesterol. Full article
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19 pages, 3214 KiB  
Article
Systemic Dendrimer-Peptide Therapies for Wet Age-Related Macular Degeneration
by Tony Wu, Chang Liu and Rangaramanujam M. Kannan
Pharmaceutics 2023, 15(10), 2428; https://doi.org/10.3390/pharmaceutics15102428 - 05 Oct 2023
Viewed by 973
Abstract
Wet age-related macular degeneration (AMD) is an end-stage event in a complex pathogenesis of macular degeneration, involving the abnormal growth of blood vessels at the retinal pigment epithelium driven by vascular endothelial growth factor (VEGF). Current therapies seek to interrupt VEGF signaling to [...] Read more.
Wet age-related macular degeneration (AMD) is an end-stage event in a complex pathogenesis of macular degeneration, involving the abnormal growth of blood vessels at the retinal pigment epithelium driven by vascular endothelial growth factor (VEGF). Current therapies seek to interrupt VEGF signaling to halt the progress of neovascularization, but a significant patient population is not responsive. New treatment modalities such as integrin-binding peptides (risuteganib/Luminate/ALG-1001) are being explored to address this clinical need but these treatments necessitate the use of intravitreal injections (IVT), which carries risks of complications and restricts its availability in less-developed countries. Successful systemic delivery of peptide-based therapeutics must overcome obstacles such as degradation by proteinases in circulation and off-target binding. In this work, we present a novel dendrimer-integrin-binding peptide (D-ALG) synthesized with a noncleavable, “clickable” linker. In vitro, D-ALG protected the peptide payload from enzymatic degradation for up to 1.5 h (~90% of the compound remained intact) in a high concentration of proteinase (2 mg/mL) whereas ~90% of free ALG-1001 was degraded in the same period. Further, dendrimer conjugation preserved the antiangiogenic activity of ALG-1001 in vitro with significant reductions in endothelial vessel network formation compared to untreated controls. In vivo, direct intravitreal injections of ALG-1001 and D-ALG produced reductions in the CNV lesion area but in systemically dosed animals, only D-ALG produced significant reductions of CNV lesion area at 14 days. Imaging data suggested that the difference in efficacy may be due to more D-ALG remaining in the target area than ALG-1001 after administration. The results presented here offer a clinically relevant route for peptide therapeutics by addressing the major obstacles that these therapies face in delivery. Full article
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14 pages, 2419 KiB  
Article
Targeted Doxorubicin-Loaded Dendronized Gold Nanoparticles
by Lance T. Dockery and Marie-Christine Daniel
Pharmaceutics 2023, 15(8), 2103; https://doi.org/10.3390/pharmaceutics15082103 - 09 Aug 2023
Cited by 1 | Viewed by 1184
Abstract
Dendronized nanoparticles, also called nanoparticle-cored dendrimers, combine the advantages of nanoparticles and dendrimers. These very stable and polyvalent nanoparticles can be used for diverse applications. One such application is drug delivery, because the dendrons can enhance the density of the payload. In this [...] Read more.
Dendronized nanoparticles, also called nanoparticle-cored dendrimers, combine the advantages of nanoparticles and dendrimers. These very stable and polyvalent nanoparticles can be used for diverse applications. One such application is drug delivery, because the dendrons can enhance the density of the payload. In this report, we describe the design of multifunctional gold nanoparticles (AuNPs) coated with poly(propylene imine) (PPI) dendrons that contain both prostate cancer active targeting and chemotherapeutic drugs. The PPI dendron is a good candidate for the design of drug delivery vehicles because of its ability to induce a proton sponge effect that will enhance lysosomal escape and intracellular therapeutic delivery. The chemotherapeutic drug used is doxorubicin (DOX), and it was linked to the dendron through a hydrazone acid-sensitive bond. Subsequent acidification of the AuNP system to a pH of 4–5 resulted in the release of 140 DOX drugs per nanoparticles. In addition, the PPI dendron was conjugated via “click” chemistry to an EphA2-targeting antibody fragment that has been shown to target prostate cancer cells. In vitro cell viability assays revealed an IC50 of 0.9 nM for the targeted DOX-bearing AuNPs after 48 h incubation with PC3 cells. These results are very promising upon optimization of the system. Full article
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50 pages, 19450 KiB  
Article
Screening Libraries to Discover Molecular Design Principles for the Targeted Delivery of mRNA with One-Component Ionizable Amphiphilic Janus Dendrimers Derived from Plant Phenolic Acids
by Juncheng Lu, Elena N. Atochina-Vasserman, Devendra S. Maurya, Muhammad Irhash Shalihin, Dapeng Zhang, Srijay S. Chenna, Jasper Adamson, Matthew Liu, Habib Ur Rehman Shah, Honey Shah, Qi Xiao, Bryn Queeley, Nathan A. Ona, Erin K. Reagan, Houping Ni, Dipankar Sahoo, Mihai Peterca, Drew Weissman and Virgil Percec
Pharmaceutics 2023, 15(6), 1572; https://doi.org/10.3390/pharmaceutics15061572 - 23 May 2023
Cited by 6 | Viewed by 6605
Abstract
Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral [...] Read more.
Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral delivery vector used by BioNTech/Pfizer and Moderna to access COVID-19 mRNA vaccines. LNPs exhibit a statistical distribution of their four components when delivering mRNA. Here, we report a methodology that involves screening libraries to discover the molecular design principles required to realize organ-targeted mRNA delivery and mediate activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer (IAJD) derived from plant phenolic acids. IAJDs co-assemble with mRNA into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions, via the simple injection of their ethanol solution in a buffer. The precise location of the functional groups in one-component IAJDs demonstrated that the targeted organs, including the liver, spleen, lymph nodes, and lung, are selected based on the hydrophilic region, while activity is associated with the hydrophobic domain of IAJDs. These principles, and a mechanistic hypothesis to explain activity, simplify the synthesis of IAJDs, the assembly of DNPs, handling, and storage of vaccines, and reduce price, despite employing renewable plant starting materials. Using simple molecular design principles will lead to increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics. Full article
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Review

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22 pages, 2106 KiB  
Review
In Vivo Applications of Dendrimers: A Step toward the Future of Nanoparticle-Mediated Therapeutics
by Krzysztof Sztandera, José Luis Rodríguez-García and Valentín Ceña
Pharmaceutics 2024, 16(4), 439; https://doi.org/10.3390/pharmaceutics16040439 - 22 Mar 2024
Viewed by 835
Abstract
Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure [...] Read more.
Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure and the synthetic procedures used for dendrimer synthesis, as well as the cellular uptake mechanisms used by these nanoparticles to gain access to the cell. In addition, the manuscript reviews the reported in vivo applications of dendrimers as drug carriers for drugs used in the treatment of cancer, neurodegenerative diseases, infections, and ocular diseases. The dendrimer-based formulations that have reached different phases of clinical trials, including safety and pharmacokinetic studies, or as delivery agents for therapeutic compounds are also presented. The continuous development of nanotechnology which makes it possible to produce increasingly sophisticated and complex dendrimers indicates that this fascinating family of nanoparticles has a wide potential in the pharmaceutical industry, especially for applications in drug delivery systems, and that the number of dendrimer-based compounds entering clinical trials will markedly increase during the coming years. Full article
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29 pages, 15123 KiB  
Review
Dendritic Structures Functionalized with Boron Clusters, in Particular Carboranes, and Their Biological Properties
by Anne-Marie Caminade, Max Milewski and Evamarie Hey-Hawkins
Pharmaceutics 2023, 15(8), 2117; https://doi.org/10.3390/pharmaceutics15082117 - 10 Aug 2023
Cited by 1 | Viewed by 1141
Abstract
The presence of a large number of boron atoms in boron clusters make them attractive tools for the treatment of cancer using boron neutron capture therapy (BNCT). Since the quantity of boron atoms present in the target cell directly affects the effectiveness of [...] Read more.
The presence of a large number of boron atoms in boron clusters make them attractive tools for the treatment of cancer using boron neutron capture therapy (BNCT). Since the quantity of boron atoms present in the target cell directly affects the effectiveness of BNCT, the idea of gathering a high number of boron atoms in a single entity has emerged many years ago. In this perspective, using hyper-branched macromolecules such as dendrimers appears as an interesting solution. In this review, we will first present the synthesis of diverse dendritic entities (dendrimers, dendrons, and Janus dendrimers) that incorporate boron clusters, in particular carboranes, anywhere in their structure. Four parts of this review present the synthesis of dendrimers having boron clusters on the surface, or inside their structure, of dendrons and of Janus dendrimers, bearing boron clusters. Practically all these boronated dendritic structures were synthesized with the objective to study their biological properties, but in fact only a few of them have been tested against cancerous cells, and even a smaller number was tested in BNCT experiments. The biological experiments are discussed in the fifth part of this review. A good efficiency is generally observed with the boronated dendrimers, even in animal models, with an increase in their mean survival time (MST). Full article
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40 pages, 8503 KiB  
Review
Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects
by Catia Ornelas and Didier Astruc
Pharmaceutics 2023, 15(8), 2044; https://doi.org/10.3390/pharmaceutics15082044 - 29 Jul 2023
Cited by 9 | Viewed by 2713
Abstract
Ferrocene has been the most used organometallic moiety introduced in organic and bioinorganic drugs to cure cancers and various other diseases. Following several pioneering studies, two real breakthroughs occurred in 1996 and 1997. In 1996, Jaouen et al. reported ferrocifens, ferrocene analogs of [...] Read more.
Ferrocene has been the most used organometallic moiety introduced in organic and bioinorganic drugs to cure cancers and various other diseases. Following several pioneering studies, two real breakthroughs occurred in 1996 and 1997. In 1996, Jaouen et al. reported ferrocifens, ferrocene analogs of tamoxifen, the chemotherapeutic for hormone-dependent breast cancer. Several ferrocifens are now in preclinical evaluation. Independently, in 1997, ferroquine, an analog of the antimalarial drug chloroquine upon the introduction of a ferrocenyl substituent in the carbon chain, was reported by the Biot-Brocard group and found to be active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Ferroquine, in combination with artefenomel, completed phase IIb clinical evaluation in 2019. More than 1000 studies have been published on ferrocenyl-containing pharmacophores against infectious diseases, including parasitic, bacterial, fungal, and viral infections, but the relationship between structure and biological activity has been scarcely demonstrated, unlike for ferrocifens and ferroquines. In a majority of ferrocene-containing drugs, however, the production of reactive oxygen species (ROS), in particular the OH. radical, produced by Fenton catalysis, plays a key role and is scrutinized in this mini-review, together with the supramolecular approach utilizing drug delivery nanosystems, such as micelles, metal–organic frameworks (MOFs), polymers, and dendrimers. Full article
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