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Journal of Nanobiotechnology Mar 2022The absence of an effective treatment and vaccine in HIV-1 pandemic place preventive strategies such as safety and effective microbicide development as a central...
BACKGROUND
The absence of an effective treatment and vaccine in HIV-1 pandemic place preventive strategies such as safety and effective microbicide development as a central therapeutic approach to control HIV-1 pandemic nowadays.
RESULTS
Studies of cytotoxicity, immune population status, inflammation or tissue damage and mainly prophylactic inhibition of HIV-1 infection in vaginal human explants demonstrate the biosafety and effectivity of G2-S16 dendrimer. Human explants treated with G2-S16 dendrimer or treated and HIV-1 infected do not presented signs of irritation, inflammation, immune activation or T cell populations deregulation.
CONCLUSIONS
Herein we conclude that G2-S16 dendrimer has demonstrated sufficient efficacy, biosafety, effectivity and behavior in the closest to the real-life condition model represented by the human healthy donor vaginal tissue explants, to raise G2-S16 dendrimer as a promising candidate to clinical trials to develop an effective microbicide against HIV-1 infection.
Topics: Anti-Infective Agents; Dendrimers; Female; HIV-1; Humans; Vagina
PubMed: 35307031
DOI: 10.1186/s12951-022-01350-8 -
Molecules (Basel, Switzerland) Apr 2016Hydrogels have emerged as a versatile class of polymeric materials with a wide range of applications in biomedical sciences. The judicious choice of hydrogel precursors... (Review)
Review
Hydrogels have emerged as a versatile class of polymeric materials with a wide range of applications in biomedical sciences. The judicious choice of hydrogel precursors allows one to introduce the necessary attributes to these materials that dictate their performance towards intended applications. Traditionally, hydrogels were fabricated using either polymerization of monomers or through crosslinking of polymers. In recent years, dendrimers and dendrons have been employed as well-defined building blocks in these materials. The multivalent and multifunctional nature of dendritic constructs offers advantages in either formulation or the physical and chemical properties of the obtained hydrogels. This review highlights various approaches utilized for the fabrication of hydrogels using well-defined dendrimers, dendrons and their polymeric conjugates. Examples from recent literature are chosen to illustrate the wide variety of hydrogels that have been designed using dendrimer- and dendron-based building blocks for applications, such as sensing, drug delivery and tissue engineering.
Topics: Biocompatible Materials; Click Chemistry; Dendrimers; Hydrogels; Molecular Structure; Tissue Engineering
PubMed: 27092481
DOI: 10.3390/molecules21040497 -
Molecules (Basel, Switzerland) Nov 2022The structure of phosphorus-containing dendrimers has been studied by IR spectroscopy and optical polarization microscopy. The repeating units of dendrimer molecules are...
The structure of phosphorus-containing dendrimers has been studied by IR spectroscopy and optical polarization microscopy. The repeating units of dendrimer molecules are mesogens. This property arises from the conjugation of the aromatic ring and the hydrazone group. An analysis of the IR spectra showed that, with an increase in the generation number, the width of the stretching vibration bands ν(PN) and ν(PO) increases. Difficulties in packing molecules of higher generations cause conformational diversity. The shape of the dendrimer molecules was determined by analyzing the increments of dipole moments. Additionally, the modeling of the stacking of repeating links was performed. The spherical model of molecules does not satisfy the experimental dipole moments of the dendrimers. The flat disk model is more suitable for explaining step changes in dipole moments. The liquid-crystalline ordering of dendrimers under the action of applied pressure was found. With simultaneous heating and uniaxial compression, optical anisotropy appears in dendrimers. It is associated with the formation of liquid-crystalline order. However, a thermodynamically stable liquid-crystalline phase is not formed in this case. Dendrimers most likely have disk-shaped molecules.
Topics: Phosphorus; Dendrimers; Liquid Crystals; Molecular Conformation; Spectrophotometry, Infrared
PubMed: 36500305
DOI: 10.3390/molecules27238214 -
BioMed Research International 2021Dendrimers are nanosized, symmetrical molecules in which a small atom or group of atoms is surrounded by the symmetric branches known as dendrons. The structure of... (Review)
Review
Dendrimers are nanosized, symmetrical molecules in which a small atom or group of atoms is surrounded by the symmetric branches known as dendrons. The structure of dendrimers possesses the greatest impact on their physical and chemical properties. They grow outwards from the core-shell which further reacts with monomers having one reactive or two dormant molecules. Dendrimers' unique characteristics such as hyperbranching, well-defined spherical structure, and high compatibility with the biological systems are responsible for their wide range of applications including medical and biomedical areas. Particularly, the dendrimers' three-dimensional structure can incorporate a wide variety of drugs to form biologically active drug conjugates. In this review, we focus on the synthesis, mechanism of drug encapsulations in dendrimers, and their wide applications in drug delivery.
Topics: Dendrimers; Drug Carriers; Humans; Nanostructures
PubMed: 33644232
DOI: 10.1155/2021/8844030 -
Proceedings of the National Academy of... May 2023Nucleic acid therapeutics are becoming an important drug modality, offering the unique opportunity to address "undruggable" targets, respond rapidly to evolving...
Nucleic acid therapeutics are becoming an important drug modality, offering the unique opportunity to address "undruggable" targets, respond rapidly to evolving pathogens, and treat diseases at the gene level for precision medicine. However, nucleic acid therapeutics have poor bioavailability and are chemolabile and enzymolabile, imposing the need for delivery vectors. Dendrimers, by virtue of their well-defined structure and cooperative multivalence, represent precision delivery systems. We synthesized and studied bola-amphiphilic dendrimers for cargo-selective and on-demand delivery of DNA and small interfering RNA (siRNA), both important nucleic acid therapeutics. Remarkably, superior performances were achieved for siRNA delivery with the second-generation dendrimer, yet for DNA delivery with the third generation. We systematically studied these dendrimers with regard to cargo binding, cellular uptake, endosomal release, and in vivo delivery. Differences in size both of the dendrimers and their nucleic acid cargos impacted the cooperative multivalent interactions for cargo binding and release, leading to cargo-adaptive and selective delivery. Moreover, both dendrimers harnessed the advantages of lipid and polymer vectors, while offering nanotechnology-based tumor targeting and redox-responsive cargo release. Notably, they allowed tumor- and cancer cell-specific delivery of siRNA and DNA therapeutics for effective treatment in different cancer models, including aggressive and metastatic malignancies, outperforming the currently available vectors. This study provides avenues to engineer tailor-made vectors for nucleic acid delivery and precision medicine.
Topics: Humans; Dendrimers; Nucleic Acids; RNA, Small Interfering; DNA; Neoplasms; RNA, Double-Stranded
PubMed: 37186846
DOI: 10.1073/pnas.2220787120 -
Biomolecules Sep 2019Dendrimers are nanosized, arborescent polymers of which size and structure are perfectly controlled. This is one reason why they are widely used for biomedical purposes....
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.
Topics: Animals; Anti-Inflammatory Agents; Dendrimers; Female; Hydrazones; Mice; Rats; Safety; Tissue Distribution
PubMed: 31514434
DOI: 10.3390/biom9090475 -
Molecules (Basel, Switzerland) Nov 2018Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald... (Review)
Review
Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named 'starburst polymers'. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.
Topics: Animals; Biomedical Research; Chemistry Techniques, Synthetic; Dendrimers; Drug Carriers; Drug Delivery Systems; Gene Transfer Techniques; Humans; Nanotechnology; Structure-Activity Relationship; Tissue Distribution
PubMed: 30400134
DOI: 10.3390/molecules23112849 -
Pharmacology Research & Perspectives Aug 2021The most crucial role of granulocyte colony-stimulating factor (G-CSF) in the body is to increase the strength of immune system. In recent years, research on the use of...
The most crucial role of granulocyte colony-stimulating factor (G-CSF) in the body is to increase the strength of immune system. In recent years, research on the use of nanoparticles in pharmaceuticals has been considered, most of which have been for drug-loading purposes. In this study, a novel G-CSF conjugated dendrimer was synthesized and characterized using different techniques. In vitro cytotoxicity was assessed on A549 and L929 cells, while abnormal toxicity was studied in mice. In vitro and in vivo biological activities were assessed in NFS60 cells and rats, respectively. In addition, in vivo distribution, plasma half-life, and histopathological effect were studied in rat. The characterization tests confirmed the successful conjugation. There was no difference between G-CSF cytotoxicity before and after conjugation, and no difference with the control group. No mice showed abnormal toxicity. Although in vitro biological activity revealed both conjugated and free G-CSF promote proliferation cells, biological activity decreased significantly after conjugation about one-third of the unconjugated form. Nonetheless, in vivo biological activity of conjugated G-CSF increased by more than 2.5-fold relative to the unconjugated form, totally. Fortunately, no histopathologic adverse effect was observed in vital rat tissues. Also, in vivo distribution of the conjugate was similar to the native protein with an enhanced terminal half-life. Our data revealed that G-CSF conjugated dendrimer could be considered as a candidate to improve the in vivo biological activity of G-CSF. Moreover, multivalent capability of the dendrimer may be used for other new potentials of G-CSF in future perspectives.
Topics: Animals; Cell Line; Dendrimers; Granulocyte Colony-Stimulating Factor; Heart; Humans; Kidney; Liver; Male; Mice; Rats; Tissue Distribution
PubMed: 34269522
DOI: 10.1002/prp2.826 -
Journal of the American Chemical Society Jan 2018New antibiotics are urgently needed to address multidrug-resistant (MDR) bacteria. Herein we report that second-generation (G2) peptide dendrimers bearing a fatty acid...
New antibiotics are urgently needed to address multidrug-resistant (MDR) bacteria. Herein we report that second-generation (G2) peptide dendrimers bearing a fatty acid chain at the dendrimer core efficiently kill Gram-negative bacteria including Pseudomonas aeruginosa and Acinetobacter baumannii, two of the most problematic MDR bacteria worldwide. Our most active dendrimer TNS18 is also active against Gram-positive methicillin-resistant Staphylococcus aureus. Based on circular dichroism and molecular dynamics studies, we hypothesize that TNS18 adopts a hydrophobically collapsed conformation in water with the fatty acid chain backfolded onto the peptide dendrimer branches and that the dendrimer unfolds in contact with the membrane to expose its lipid chain and hydrophobic residues, thereby facilitating membrane disruption leading to rapid bacterial cell death. Dendrimer TNS18 shows promising in vivo activity against MDR clinical isolates of A. baumannii and Escherichia coli, suggesting that lipidated peptide dendrimers might become a new class of antibacterial agents.
Topics: Acinetobacter baumannii; Animals; Anti-Bacterial Agents; Dendrimers; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Escherichia coli; Lipids; Mice; Microbial Sensitivity Tests; Molecular Conformation; Peptides; Pseudomonas aeruginosa; Structure-Activity Relationship
PubMed: 29206041
DOI: 10.1021/jacs.7b11037 -
Theranostics 2018Mitochondrial oxidative stress is associated with many neurodegenerative diseases, such as traumatic brain injury (TBI). Targeted delivery of antioxidants to...
Mitochondrial oxidative stress is associated with many neurodegenerative diseases, such as traumatic brain injury (TBI). Targeted delivery of antioxidants to mitochondria has failed to translate into clinical success due to their nonspecific cellular localization, poor transport properties across multiple biological barriers, and associated side effects. These challenges, coupled with the complex function of the mitochondria, create the need for innovative delivery strategies. Neutral hydroxyl-terminated polyamidoamine (PAMAM) dendrimers have shown significant potential as nanocarriers in multiple brain injury models. -acetyl cysteine (NAC) is a clinically used antioxidant and anti-inflammatory agent which has shown significant potency when delivered in a targeted manner. Here we present a mitochondrial targeting hydroxyl PAMAM dendrimer-drug construct (TPP-D-NAC) with triphenyl-phosphonium (TPP) for mitochondrial targeting and NAC for targeted delivery to mitochondria in injured glia. Co-localization and mitochondrial content of mitochondria-targeted and unmodified dendrimer were assessed in microglia and macrophages via immunohistochemistry and fluorescence quantification. Therapeutic improvements of TPP-D-NAC over dendrimer-NAC conjugate (D-NAC) and free NAC were evaluated in microglia under oxidative stress challenge. neuroinflammation targeting was confirmed in a rabbit model of TBI. TPP-conjugated dendrimer co-localized significantly more with mitochondria than unmodified dendrimer without altering overall levels of cellular internalization. This targeting capability translated to significant improvements in the attenuation of oxidative stress by TPP-D-NAC compared to D-NAC and free NAC. Upon systemic administration in a rabbit TBI model, TPP-conjugated dendrimer co-localized specifically with mitochondria in activated microglia and macrophages in the white matter of the ipsilateral/injured hemisphere, confirming its BBB penetration and glial targeting capabilities. D-NAC has shown promising efficacy in many animal models of neurodegeneration, and this work provides evidence that modification for mitochondrial targeting can further enhance its therapeutic efficacy, particularly in diseases where oxidative stress-induced glial cell death plays a significant role in disease progression.
Topics: Chromatography, High Pressure Liquid; Dendrimers; Dynamic Light Scattering; Immunohistochemistry; Macrophages; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microglia; Mitochondria; Oxidative Stress
PubMed: 30555562
DOI: 10.7150/thno.29039