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Moving Forward with Dendrimers: A Themed Issue in Honor of...
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Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 62844

Special Issue Editor

Prof. Dr. Zofia Urbanczyk-Lipkowska

E-Mail Website
Guest Editor
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka Str. 44/52, 01-224 Warsaw, Poland
Interests: bioinspired peptide dendrimers, dendrimer chemistry; nanomolecular antioxidants and free radical scavengers; chiral coordination polymers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Biomolecules invites submissions for a Special Issue in honor of Professor Donald A. Tomalia on the occasion of his 80th birthday, in recognition for his remarkable contributions to discovery and development of dendrimer’s chemistry and to mark his effort for pursuing their applications.

Professor D. A. Tomalia’s career has spanned five decades and addresses some of the most fundamental questions related to synthesis, classification, characterization and applications of a new class of nanomolecules with branched structures, named by him as polyamidoamine (PAMAM) dendrimers.

Dendrimers are nanosized hyperbranched polymers synthesized using classic organic chemistry techniques, and characterized by well-defined molecular mass and structures. They can be engineered to perform specific chemical or biological functions. Due to the attractive and unique properties of these nanomolecules, which are capable of interacting with biological systems (e.g., multivalency, near-monodispersity, etc.), our knowledge of many cellular processes has been enhanced significantly. These include, among the others, supramolecular processes at water/lipid interfaces, transport of various biologically relevant molecules across cellular membranes, targeting receptors, and the opportunity to follow metabolic pathways related to processes of life.

These interesting properties seem to be of a general character and are related to the branched architecture and polyvalency. Indeed, since 1985 when Professor Tomalia published the first fundamental paper on PAMAMs, several other types of dendrimers have been designed and successfully applied in biomedical research. His vision of molecules with tree-like structures and well-defined 3D architectures has given rise to multifunctional, highly attractive smart materials such as drug and gene delivery vectors.

For this Special Issue, we invite submissions of papers on topics related to the work of Professor D. A. Tomalia, particularly focusing on the biological aspects in the wide context of these interesting molecules.

Prof. Zofia Urbanczyk-Lipkowska
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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Methodology of dendrimers synthesis and characterization
  • Structural studies (experimental and theoretical)
  • Interactions with biological systems (proteins, DNA, RNA)
  • Molecular targeting
  • Dendrimer-mediated drug delivery/gene delivery
  • Clinical aspects of dendrimers applications

Published Papers (15 papers)

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Research

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19 pages, 2226 KiB  
Article
Exploring the Interactions of Ruthenium (II) Carbosilane Metallodendrimers and Precursors with Model Cell Membranes through a Dual Spin-Label Spin-Probe Technique Using EPR
by Riccardo Carloni, Natalia Sanz del Olmo, Paula Ortega, Alberto Fattori, Rafael Gómez, Maria Francesca Ottaviani, Sandra García-Gallego, Michela Cangiotti and F. Javier de la Mata
Biomolecules 2019, 9(10), 540; https://doi.org/10.3390/biom9100540 - 27 Sep 2019
Cited by 18 | Viewed by 2729
Abstract
Dendrimers exhibit unique interactions with cell membranes, arising from their nanometric size and high surface area. To a great extent, these interactions define their biological activity and can be reported in situ by spin-labelling techniques. Schiff-base carbosilane ruthenium (II) metallodendrimers are promising antitumor [...] Read more.
Dendrimers exhibit unique interactions with cell membranes, arising from their nanometric size and high surface area. To a great extent, these interactions define their biological activity and can be reported in situ by spin-labelling techniques. Schiff-base carbosilane ruthenium (II) metallodendrimers are promising antitumor agents with a mechanism of action yet to explore. In order to study their in situ interactions with model cell membranes occurring at a molecular level, namely cetyltrimethylammonium bromide micelles (CTAB) and lecithin liposomes (LEC), electron paramagnetic resonance (EPR) was selected. Both a spin probe, 4-(N,N-dimethyl-N-dodecyl)ammonium-2,2,6,6-tetramethylpiperidine-1-oxyl bromide (CAT12), able to enter the model membranes, and a spin label, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) covalently attached at newly synthesized heterofunctional dendrimers, were used to provide complementary information on the dendrimer–membrane interactions. The computer-aided EPR analysis demonstrated a good agreement between the results obtained for the spin probe and spin label experiments. Both points of view suggested the partial insertion of the dendrimer surface groups into the surfactant aggregates, mainly CTAB micelles, and the occurrence of both polar and hydrophobic interactions, while dendrimer–LEC interactions involved more polar interactions between surface groups. We found out that subtle changes in the dendrimer structure greatly modified their interacting abilities and, subsequently, their anticancer activity. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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22 pages, 7918 KiB  
Article
Biodistribution and Biosafety of a Poly(Phosphorhydrazone) Dendrimer, an Anti-Inflammatory Drug-Candidate
by Séverine Fruchon, Elisabeth Bellard, Nicolas Beton, Cécile Goursat, Abdelouahd Oukhrib, Anne-Marie Caminade, Muriel Blanzat, Cédric-Olivier Turrin, Muriel Golzio and Rémy Poupot
Biomolecules 2019, 9(9), 475; https://doi.org/10.3390/biom9090475 - 11 Sep 2019
Cited by 13 | Viewed by 3109
Abstract
Dendrimers are nanosized, arborescent polymers of which size and structure are perfectly controlled. This is one reason why they are widely used for biomedical purposes. Previously, we showed that a phosphorus-based dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and [...] Read more.
Dendrimers are nanosized, arborescent polymers of which size and structure are perfectly controlled. This is one reason why they are widely used for biomedical purposes. Previously, we showed that a phosphorus-based dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of chronic inflammatory disorders. On the way to clinical translation, the biodistribution and the safety of this drug-candidate has to be thoroughly assessed. In this article, we present preliminary non-clinical data regarding biodistribution, hematological safety, genotoxicity, maximal tolerated doses, and early cardiac safety of the ABP dendrimer. One of the genotoxicity assays reveals a potential mutagen effect of the item at a concentration above 200 µM, i.e., up to 100 times the active dose in vitro on human immune cells. However, as the results obtained for all the other assays show that the ABP dendrimer has promising biodistribution and safety profiles, there is no red flag raised to hamper the regulatory pre-clinical development of the ABP dendrimer. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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20 pages, 5743 KiB  
Article
Synthesis and Different Effects of Biotinylated PAMAM G3 Dendrimer Substituted with Nimesulide in Human Normal Fibroblasts and Squamous Carcinoma Cells
by Łukasz Uram, Aleksandra Filipowicz-Rachwał, Maria Misiorek, Aleksandra Winiarz, Elżbieta Wałajtys-Rode and Stanisław Wołowiec
Biomolecules 2019, 9(9), 437; https://doi.org/10.3390/biom9090437 - 01 Sep 2019
Cited by 11 | Viewed by 2848
Abstract
Squamous cell carcinoma (SCC) remains a main cause of mortality in patients with neck and head cancers, with poor prognosis and increased prevalence despite of available therapies. Recent studies have identified a role of cyclooxygenases, particularly inducible isoform cyclooxygenase-2 (COX-2) and its metabolite [...] Read more.
Squamous cell carcinoma (SCC) remains a main cause of mortality in patients with neck and head cancers, with poor prognosis and increased prevalence despite of available therapies. Recent studies have identified a role of cyclooxygenases, particularly inducible isoform cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in cancer cell proliferation, and its inhibition become a target for control of cancer development, particularly in the view of recognized additive or synergic action of COX-2 inhibitors with other forms of therapy. Nimesulide (N), the selective COX-2 inhibitor, inhibits growth and proliferation of various types of cancer cells by COX-2 dependent and independent mechanisms. In the presented study, the conjugates of biotinylated third generation poly(amidoamine) dendrimer (PAMAM) with covalently linked 18 (G3B18N) and 31 (G3B31N) nimesulide residues were synthesized and characterized by NMR spectroscopy. Biological properties of conjugates were evaluated, including cytotoxicity, proliferation, and caspase 3/7 activities in relation to COX-2/PGE2 axis signaling in human normal fibroblast (BJ) and squamous cell carcinoma (SCC-15). Both conjugates exerted a selective cytotoxicity against SCC-15 as compared with BJ cells at low 1.25–10 µM concentration range and their action in cancer cells was over 250-fold stronger than nimesulide alone. Conjugates overcome apoptosis resistance and sensitized SCC-15 cells to the apoptotic death independently of COX-2/PGE2 axis. In normal human fibroblasts the same concentrations of G3B31N conjugate were less effective in inhibition of proliferation and induction of apoptosis, as measured by caspase 3/7 activity in a manner depending on increase of PGE2 production by either COX-1/COX-2. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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15 pages, 2257 KiB  
Article
Tumor Uptake of Triazine Dendrimers Decorated with Four, Sixteen, and Sixty-Four PSMA-Targeted Ligands: Passive versus Active Tumor Targeting
by Jongdoo Lim, Bing Guan, Kien Nham, Guiyang Hao, Xiankai Sun and Eric E. Simanek
Biomolecules 2019, 9(9), 421; https://doi.org/10.3390/biom9090421 - 28 Aug 2019
Cited by 15 | Viewed by 3454
Abstract
Various glutamate urea ligands have displayed high affinities to prostate specific membrane antigen (PSMA), which is highly overexpressed in prostate and other cancer sites. The multivalent versions of small PSMA-targeted molecules are known to be even more efficiently bound to the receptor. Here, [...] Read more.
Various glutamate urea ligands have displayed high affinities to prostate specific membrane antigen (PSMA), which is highly overexpressed in prostate and other cancer sites. The multivalent versions of small PSMA-targeted molecules are known to be even more efficiently bound to the receptor. Here, we employ a well-known urea-based ligand, 2-[3-(1,3-dicarboxypropyl)-ureido] pentanedioic acid (DUPA) and triazine dendrimers in order to study the effect of molecular size on multivalent targeting in prostate cancer. The synthetic route starts with the preparation of a dichlorotriazine bearing DUPA in 67% overall yield over five steps. This dichlorotriazine reacts with G1, G3, and G5 triazine dendrimers bearing a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) group for 64Cu-labeling at the core to afford poly(monochlorotriazine) intermediates. Addition of 4-aminomethylpiperidine (4-AMP) and the following deprotection produce the target compounds, G1-(DUPA)4, G3-(DUPA)16, and G5-(DUPA)64. These targets include 4/16/64 DUPA groups on the surface and a DOTA group at the core, respectively. In vitro cell assay using PC3-PIP (PSMA positive) and PC3-FLU (PSMA negative) cells reveals that G1-(DUPA)4 has the highest PC3-PIP to PC3-FLU uptake ratio (10-fold) through the PSMA-mediated specific uptake. While G5-(DUPA)64 displayed approximately 12 times higher binding affinity (IC50 23.6 nM) to PC3-PIP cells than G1-(DUPA)4 (IC50 282.3 nM) as evaluated in a competitive binding assay, the G5 dendrimer also showed high non-specific binding to PC3-FLU cells. In vivo uptake of the 64Cu-labeled dendrimers was also evaluated in severe combined inmmunodeficient (SCID) mice bearing PC3-PIP and PC3-FLU xenografts on each shoulder, respectively. Interestingly, quantitative imaging analysis of positron emission tomograph (PET) displayed the lowest tumor uptake in PC3-PIP cells for the midsize dendrimer G3-(DUPA)16 (19.4 kDa) (0.66 ± 0.15%ID/g at 1 h. p.i., 0.64 ± 0.11%ID/g at 4 h. p.i., and 0.67 ± 0.08%ID/g at 24 h. p.i.). Through the specific binding of G1-(DUPA)4 to PSMA, the smallest dendrimer (5.1 kDa) demonstrated the highest PC3-PIP to muscle and PC3-PIP to PC3-FLU uptake ratios (17.7 ± 5.5 and 6.7 ± 3.0 at 4 h p.i., respectively). In addition, the enhanced permeability and retention (EPR) effect appeared to be an overwhelming factor for tumor uptake of the largest dendrimer G5-(DUPA)64 as the uptake was at a similar level irrelevant to the PSMA expression. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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15 pages, 3943 KiB  
Article
Synthesis and Characterization of FITC Labelled Ruthenium Dendrimer as a Prospective Anticancer Drug
by Sylwia Michlewska, Małgorzata Kubczak, Marta Maroto-Díaz, Natalia Sanz del Olmo, Paula Ortega, Dzmitry Shcharbin, Rafael Gomez Ramirez, Francisco Javier de la Mata, Maksim Ionov and Maria Bryszewska
Biomolecules 2019, 9(9), 411; https://doi.org/10.3390/biom9090411 - 25 Aug 2019
Cited by 18 | Viewed by 4094
Abstract
Metallodendrimers—dendrimers with included metals—are widely investigated as biocompatible equivalents to metal nanoparticles. Applications can be expected in the fields of catalysis, as chemical sensors in molecular recognition and as anticancer drugs. Metallodendrimers can also mimic certain biomolecules, for example, haemoprotein in the case [...] Read more.
Metallodendrimers—dendrimers with included metals—are widely investigated as biocompatible equivalents to metal nanoparticles. Applications can be expected in the fields of catalysis, as chemical sensors in molecular recognition and as anticancer drugs. Metallodendrimers can also mimic certain biomolecules, for example, haemoprotein in the case of using a dendrimer with a porphyrin core. In previous papers, we showed the promising anticancer effects of carbosilane ruthenium dendrimers. The present paper is devoted to studying biocompatibility and the cytotoxic effect on normal and cancer cells of carbosilane ruthenium dendrimers labelled with fluorescent probe fluorescein isothiocyanate (FITC). The addition of fluorescent probe allowed tracking the metallodendrimer in both normal and cancer cells. It was found that carbosilane ruthenium dendrimer labelled with FITC in concentration up to 10 µmol/L was more cytotoxic for cancer cells than for normal cells. Thus, FITC labelled carbosilane ruthenium dendrimer is a good candidate for diagnostic imaging and studying anticancer effects of metallodendrimers in cancer therapy. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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11 pages, 1229 KiB  
Article
Antibacterial Effect of Carbosilane Metallodendrimers in Planktonic Cells of Gram-Positive and Gram-Negative Bacteria and Staphylococcus aureus Biofilm
by Celia Llamazares, Natalia Sanz del Olmo, Paula Ortega, Rafael Gómez, Juan Soliveri, F. Javier de la Mata, Sandra García-Gallego and José Luis Copa-Patiño
Biomolecules 2019, 9(9), 405; https://doi.org/10.3390/biom9090405 - 23 Aug 2019
Cited by 17 | Viewed by 3118
Abstract
Antibiotic resistance is currently one of the main threats to public health security. Biofilm formation is a resistance mechanism that is responsible for most human bacterial infections and requires new and effective therapeutic approaches, such as those provided by nanotechnology. In this work, [...] Read more.
Antibiotic resistance is currently one of the main threats to public health security. Biofilm formation is a resistance mechanism that is responsible for most human bacterial infections and requires new and effective therapeutic approaches, such as those provided by nanotechnology. In this work, the antibacterial effect of carbosilane metallodendrimers with different metals (copper(II) and ruthenium(II)), ligands (chloride and nitrate) and generations (generation 0, 1 and 2) has been studied using planktonic Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. Furthermore, the ability of the metallodendrimers to avoid the formation of S. aureus biofilms was also evaluated. The results showed a promising biocide activity in both types of planktonic bacteria, especially for first-generation dendrimers, which arises from the metal complexation to the dendrimer. Cu(II) metallodendrimers require lower concentration than Ru(II) counterpart to inhibit the production of S. aureus biofilms, but none produce hemolysis at the inhibitory concentrations and can be safely used as antibacterial agents. In particular, the first-generation Cu(II) metallodendrimer with nitrate ligands displayed the most promising properties to continue with further studies in both planktonic cells and biofilms. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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10 pages, 2137 KiB  
Article
Anticancer Activity of Water-Soluble Olsalazine-PAMAM-Dendrimer-Salicylic Acid-Conjugates
by Sandra Cortez-Maya, Luis Daniel Pedro-Hernández, Elena Martínez-Klimova, Teresa Ramírez-Ápan and Marcos Martínez-García
Biomolecules 2019, 9(8), 360; https://doi.org/10.3390/biom9080360 - 13 Aug 2019
Cited by 3 | Viewed by 3496
Abstract
Improving the activity and selectivity profile of anticancer agents will require designing drug carrier systems that employ soluble macromolecules. Olsalazine-PAMAM-dendrimer-salicylic acid-conjugates with dendritic arms of different lengths have shown good stability regarding the chemical link between drug and spacer. In this study, the [...] Read more.
Improving the activity and selectivity profile of anticancer agents will require designing drug carrier systems that employ soluble macromolecules. Olsalazine-PAMAM-dendrimer-salicylic acid-conjugates with dendritic arms of different lengths have shown good stability regarding the chemical link between drug and spacer. In this study, the drug release was followed in vitro by ultraviolet (UV) studies. Evaluation of the cytotoxicity of the olsalazine-PAMAM-dendrimer-salicylic acid-conjugates employing a sulforhodamine B (SRB) assay in PC-3 (human prostatic adenocarcinoma) and MCF-7 (human mammary adenocarcinoma) cell lines demonstrated that conjugate 9 was more active as an antiproliferative agent than cisplatin, and no cytotoxicity towards the African green monkey kidney fibroblast (COS-7) cell line was observed in any of the conjugates synthesized in the present work. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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15 pages, 4105 KiB  
Article
In Vitro Anticancer Properties of Copper Metallodendrimers
by Marcin Hołota, Jakub Magiera, Sylwia Michlewska, Małgorzata Kubczak, Natalia Sanz del Olmo, Sandra García-Gallego, Paula Ortega, Francisco Javier de la Mata, Maksim Ionov and Maria Bryszewska
Biomolecules 2019, 9(4), 155; https://doi.org/10.3390/biom9040155 - 18 Apr 2019
Cited by 22 | Viewed by 3751
Abstract
Newly synthesized carbosilane copper dendrimers (CCD) with chloride and nitrate surface groups seem to be good candidates to be used as gene and drug carriers in anti-cancer therapy, due to their properties such as size and surface charge. Copper attached to the nanoparticles [...] Read more.
Newly synthesized carbosilane copper dendrimers (CCD) with chloride and nitrate surface groups seem to be good candidates to be used as gene and drug carriers in anti-cancer therapy, due to their properties such as size and surface charge. Copper attached to the nanoparticles is an important element of many biological processes and recently their anti-cancer properties have been widely examined. Zeta size and potential, transmission electron microscopy (TEM), circular dichroism (CD), analysis of haemolytic activity, and fluorescence anisotropy techniques were used to characterize copper dendrimers. Additionally, their cytotoxic properties toward normal (PBMC) and cancer (1301; HL-60) cells were examined. All tested dendrimers were more cytotoxic against cancer cells in comparison with normal cells. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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21 pages, 3062 KiB  
Article
Molecular Antioxidant Properties and In Vitro Cell Toxicity of the p-Aminobenzoic Acid (PABA) Functionalized Peptide Dendrimers §
by Marta Sowinska, Maja Morawiak, Marta Bochyńska-Czyż, Andrzej W. Lipkowski, Elżbieta Ziemińska, Barbara Zabłocka and Zofia Urbanczyk-Lipkowska
Biomolecules 2019, 9(3), 89; https://doi.org/10.3390/biom9030089 - 05 Mar 2019
Cited by 30 | Viewed by 4198
Abstract
Background: Exposure to ozone level and ultraviolet (UV) radiation is one of the major concerns in the context of public health. Numerous studies confirmed that abundant free radicals initiate undesired processes, e.g. carcinogenesis, cells degeneration, etc. Therefore, the design of redox-active molecules with [...] Read more.
Background: Exposure to ozone level and ultraviolet (UV) radiation is one of the major concerns in the context of public health. Numerous studies confirmed that abundant free radicals initiate undesired processes, e.g. carcinogenesis, cells degeneration, etc. Therefore, the design of redox-active molecules with novel structures, containing radical quenchers molecules with novel structures, and understanding their chemistry and biology, might be one of the prospective solutions. Methods: We designed a group of peptide dendrimers carrying multiple copies of p-aminobenzoic acid (PABA) and evaluated their molecular antioxidant properties in 1,1′-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests. Cytotoxicity against human melanoma and fibroblast cells as well as against primary cerebral granule cells (CGC) alone and challenged by neurotoxic sodium glutamate and production of reactive oxygen species (ROS) in presence of dendrimers were measured. Results: PABA-terminated dendrimers express enhanced radical and radical cation scavenging properties in relation to PABA alone. In cellular tests, the dendrimers at 100 μM fully suppress and between 20–100 μM reduce proliferation of the human melanoma cell line. In concentration 20 μM dendrimers generate small amount of the reactive oxygen species (<25%) but even in their presence human fibroblast and mouse cerebellar granule cells remain intact Moreover, dendrimers at 0.2–20 µM concentration (except one) increased the percentage of viable fibroblasts and CGC cells treated with 100 μM glutamate. Conclusions: Designed PABA-functionalized peptide dendrimers might be a potential source of new antioxidants with cationic and neutral radicals scavenging potency and/or new compounds with marked selectivity against human melanoma cell or glutamate-stressed CGC neurons. The scavenging level of dendrimers depends strongly on the chemical structure of dendrimer and the presence of other groups that may be prompted into radical form. The present studies found different biological properties for dendrimers constructed from the same chemical fragments but the differing structure of the dendrimer tree provides once again evidence that the structure of dendrimer can have a significant impact on drug–target interactions. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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11 pages, 832 KiB  
Article
On Eccentricity-Based Topological Indices Study of a Class of Porphyrin-Cored Dendrimers
by Wei Gao, Zahid Iqbal, Muhammad Ishaq, Rabia Sarfraz, Muhammad Aamir and Adnan Aslam
Biomolecules 2018, 8(3), 71; https://doi.org/10.3390/biom8030071 - 07 Aug 2018
Cited by 44 | Viewed by 3685
Abstract
It is revealed from the previous studies that there is a strong relation between the chemical characteristic of a chemical compound and its molecular structure. Topological indices defined on the molecular structure of biomolecules can help to gain a better understanding of their [...] Read more.
It is revealed from the previous studies that there is a strong relation between the chemical characteristic of a chemical compound and its molecular structure. Topological indices defined on the molecular structure of biomolecules can help to gain a better understanding of their physical features and biological activities. Eccentricity connectivity indices are distance-based molecular structure descriptors that have been used for the mathematical modeling of biological activities of diverse nature. As the porphyrin has photofunctional properties, such as a large absorption cross-section, fluorescence emission, and photosensitizing properties, due to these properties, porphyrin dendrimers can be used as photofunctional nanodevices. In this paper, we compute the exact formulae of different versions of eccentric connectivity index and their corresponding polynomials for a class of porphyrin-cored dendrimers. The results obtained can be used in computer-aided molecular design methods applied to pharmaceutical engineering. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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Review

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56 pages, 32130 KiB  
Review
The Role of Branch Cell Symmetry and Other Critical Nanoscale Design Parameters in the Determination of Dendrimer Encapsulation Properties
by Donald A. Tomalia, Linda S. Nixon and David M. Hedstrand
Biomolecules 2020, 10(4), 642; https://doi.org/10.3390/biom10040642 - 21 Apr 2020
Cited by 43 | Viewed by 4824
Abstract
This article reviews progress over the past three decades related to the role of dendrimer-based, branch cell symmetry in the development of advanced drug delivery systems, aqueous based compatibilizers/solubilizers/excipients and nano-metal cluster catalysts. Historically, it begins with early unreported work by the Tomalia [...] Read more.
This article reviews progress over the past three decades related to the role of dendrimer-based, branch cell symmetry in the development of advanced drug delivery systems, aqueous based compatibilizers/solubilizers/excipients and nano-metal cluster catalysts. Historically, it begins with early unreported work by the Tomalia Group (i.e., The Dow Chemical Co.) revealing that all known dendrimer family types may be divided into two major symmetry categories; namely: Category I: symmetrical branch cell dendrimers (e.g., Tomalia, Vögtle, Newkome-type dendrimers) possessing interior hollowness/porosity and Category II: asymmetrical branch cell dendrimers (e.g., Denkewalter-type) possessing no interior void space. These two branch cell symmetry features were shown to be pivotal in directing internal packing modes; thereby, differentiating key dendrimer properties such as densities, refractive indices and interior porosities. Furthermore, this discovery provided an explanation for unimolecular micelle encapsulation (UME) behavior observed exclusively for Category I, but not for Category II. This account surveys early experiments confirming the inextricable influence of dendrimer branch cell symmetry on interior packing properties, first examples of Category (I) based UME behavior, nuclear magnetic resonance (NMR) protocols for systematic encapsulation characterization, application of these principles to the solubilization of active approved drugs, engineering dendrimer critical nanoscale design parameters (CNDPs) for optimized properties and concluding with high optimism for the anticipated role of dendrimer-based solubilization principles in emerging new life science, drug delivery and nanomedical applications. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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29 pages, 2598 KiB  
Review
Dendrimer-Based Drug Delivery Systems for Brain Targeting
by Yuefei Zhu, Chunying Liu and Zhiqing Pang
Biomolecules 2019, 9(12), 790; https://doi.org/10.3390/biom9120790 - 27 Nov 2019
Cited by 115 | Viewed by 7706
Abstract
Human neuroscience has made remarkable progress in understanding basic aspects of functional organization; it is a renowned fact that the blood–brain barrier (BBB) impedes the permeation and access of most drugs to central nervous system (CNS) and that many neurological diseases remain undertreated. [...] Read more.
Human neuroscience has made remarkable progress in understanding basic aspects of functional organization; it is a renowned fact that the blood–brain barrier (BBB) impedes the permeation and access of most drugs to central nervous system (CNS) and that many neurological diseases remain undertreated. Therefore, a number of nanocarriers have been designed over the past few decades to deliver drugs to the brain. Among these nanomaterials, dendrimers have procured an enormous attention from scholars because of their nanoscale uniform size, ease of multi-functionalization, and available internal cavities. As hyper-branched 3D macromolecules, dendrimers can be maneuvered to transport diverse therapeutic agents, incorporating small molecules, peptides, and genes; diminishing their cytotoxicity; and improving their efficacy. Herein, the present review will give exhaustive details of extensive researches in the field of dendrimer-based vehicles to deliver drugs through the BBB in a secure and effectual manner. It is also a souvenir in commemorating Donald A. Tomalia on his 80th birthday. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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30 pages, 11258 KiB  
Review
Unchain My Blood: Lessons Learned from Self-Assembled Dendrimers as Nanoscale Heparin Binders
by Domenico Marson, Erik Laurini, Suzana Aulic, Maurizio Fermeglia and Sabrina Pricl
Biomolecules 2019, 9(8), 385; https://doi.org/10.3390/biom9080385 - 20 Aug 2019
Cited by 5 | Viewed by 2689
Abstract
This review work reports a collection of coupled experimental/computational results taken from our own experience in the field of self-assembled dendrimers for heparin binding. These studies present and discuss both the potentiality played by this hybrid methodology to the design, synthesis, and development [...] Read more.
This review work reports a collection of coupled experimental/computational results taken from our own experience in the field of self-assembled dendrimers for heparin binding. These studies present and discuss both the potentiality played by this hybrid methodology to the design, synthesis, and development of possible protamine replacers for heparin anticoagulant activity reversal in biomedical applications, and the obstacles this field has still to overcome before these molecules can be translated into nanomedicines available in clinical settings. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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23 pages, 2463 KiB  
Review
Cytotoxicity of Dendrimers
by Anna Janaszewska, Joanna Lazniewska, Przemysław Trzepiński, Monika Marcinkowska and Barbara Klajnert-Maculewicz
Biomolecules 2019, 9(8), 330; https://doi.org/10.3390/biom9080330 - 01 Aug 2019
Cited by 228 | Viewed by 8101
Abstract
Drug delivery systems are molecular platforms in which an active compound is packed into or loaded on a biocompatible nanoparticle. Such a solution improves the activity of the applied drug or decreases its side effects. Dendrimers are promising molecular platforms for drug delivery [...] Read more.
Drug delivery systems are molecular platforms in which an active compound is packed into or loaded on a biocompatible nanoparticle. Such a solution improves the activity of the applied drug or decreases its side effects. Dendrimers are promising molecular platforms for drug delivery due to their unique properties. These macromolecules are known for their defined size, shape, and molecular weight, as well as their monodispersity, the presence of the void space, tailorable structure, internalization by cells, selectivity toward cells and intracellular components, protection of guest molecules, and controllable release of the cargo. Dendrimers were tested as carriers of various molecules and, simultaneously, their toxicity was examined using different cell lines. It was discovered that, in general, dendrimer cytotoxicity depended on the generation, the number of surface groups, and the nature of terminal moieties (anionic, neutral, or cationic). Higher cytotoxicity occurred for higher-generation dendrimers and for dendrimers with positive charges on the surface. In order to decrease the cytotoxicity of dendrimers, scientists started to introduce different chemical modifications on the periphery of the nanomolecule. Dendrimers grafted with polyethylene glycol (PEG), acetyl groups, carbohydrates, and other moieties did not affect cell viability, or did so only slightly, while still maintaining other advantageous properties. Dendrimers clearly have great potential for wide utilization as drug and gene carriers. Moreover, some dendrimers have biological properties per se, being anti-fungal, anti-bacterial, or toxic to cancer cells without affecting normal cells. Therefore, intrinsic cytotoxicity is a comprehensive problem and should be considered individually depending on the potential destination of the nanoparticle. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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6 pages, 1995 KiB  
Essay
Bach Goes to Town
by Jørn Bolstad Christensen
Biomolecules 2018, 8(3), 75; https://doi.org/10.3390/biom8030075 - 20 Aug 2018
Viewed by 3970
Abstract
Donald A. Tomalia is one of the pioneers in the field of dendrimers, who is still active at the age of 80 years-old. The present contribution is a journey through his scientific contributions from the early beginning until his discovery of the poly(amidoamine), [...] Read more.
Donald A. Tomalia is one of the pioneers in the field of dendrimers, who is still active at the age of 80 years-old. The present contribution is a journey through his scientific contributions from the early beginning until his discovery of the poly(amidoamine), (PAMAM)-dendrimers. Full article
(This article belongs to the Special Issue Moving Forward with Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 80th Birthday)
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