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Dendrimers and more specifically neutral, cationic or anionic phosphorus dendrimers are known for their large panel of applications in nano sciences, biology, polymer science, catalysis or for the formation of nanomaterials. Their activity strongly depends on their internal structure and on the nature of their end groups. We report novel multistep synthesis in high yield of original stable and not sensitive to hydrolysis of a variety of neutral or anionic phosphorus dendrimers thus opening new possibilities to use them for various applications including therapeutic applications such as, for instance, cancers, inflammations, tuberculosis as well osteoclasto-genesis domain. [ABSTRACT FROM AUTHOR]

Objectives: Incidental diagnosis of vertebral fractures (VFs) may represent a key point in the assessment of bone health status. Our purpose was to retrospectively evaluate localisation sequences (MR-loc) of breast MRI as a potential tool to detect osteoporotic VFs.Methods: MR-loc sagittal images of 856 breast MRIs were reviewed by three expert musculoskeletal radiologists with a semiquantitative approach to detecting VFs. Anamnesis and data of patients were investigated. Official breast MRI and previous imaging reports were checked to understand if VFs or other relevant bone findings were known in patients' clinical history.Results: A total of 780/856 female patients (91.1 %) undergoing MRI for oncological reasons and 76/856 (8.9 %) with non-oncological aims were recruited into the study (54.7 ± 12.2 years old, 21-89 years); 57/856 MR-loc images (6.7 %) were considered inadequate for diagnostic purposes and were excluded from the analysis. MR-loc detected VFs in 71/799 patients (8.9 %). VFs were neither reported nor previously known in the clinical history of 63/71 patients (88.7 %; P < 0.001). No mention of VFs was found in any breast MR reports. In four patients MR-loc identified vertebral metastases.Conclusions: A systematic evaluation of MR-loc may offer additional clinical information to prevent unrecognised VFs. MR-loc may screen for VFs in other imaging settings.Key Points: Vertebral fractures are usually a hallmark of osteoporosis. Localisation sequences before breast MR examinations can identify vertebral fractures. MR localisers should be inspected for vertebral fractures in other clinical settings. [ABSTRACT FROM AUTHOR]

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Dendrimers are a wide range of nanoparticles with desirable properties that can be used in many areas of medicine. However, little is known about their potential use in wound healing. This study examined the properties of phosphorus dendrimers that were built on a cyclotriphosphazene core and pyrrolidinium (DPP) or piperidinium (DPH) terminated groups, to be used as potential factors that support wound healing ( in vitro ). Therefore, the degree of toxicity of the tested compounds for human erythrocytes and the human fibroblast cell line (BJ) was determined, and it was found that at low concentrations, the tested compounds are compatible with blood. The influence of phosphorus dendrimers on plasma proteins (human serum albumin (HSA) and fibrinogen) was examined, with a lack of conformational changes in the structure of these proteins, suggesting that their physiological function was not disturbed. The effects on plasma coagulation cascade and fibrinolysis were also assessed, and it was found that phosphorus dendrimers in low concentrations are blood compatible and interfere neither with coagulation processes nor in clot breakdown. Skin injuries, especially chronic wounds, are also susceptible to infection; therefore, the antimicrobial potential of dendrimers was tested, and it was found that these dendrimers had antibacterial activity against both Gram-negative and Gram-positive bacteria. The highest activity of the tested compounds was found for higher applied concentrations.

Reprogramming imbalanced synovial macrophages and shaping an immune microenvironment conducive to bone and cartilage growth is crucial for efficient tackling of osteoarthritis (OA). Herein, we present a co-delivery nanosystem based on generation 2 (G2) hydroxyl-terminated bioactive phosphorus dendrimers (G2-OH 24 ) that were loaded with both catalase (CAT) and quercetin (Que). The created G2-OH 24 /CAT@Que complexes exhibit a uniformly distributed spherical morphology with a size of 138.8 nm, possess robust stability, and induce macrophage reprogramming toward anti-inflammatory M2 phenotype polarization and antioxidation through cooperative CAT-catalyzed oxygen generation, Que-mediated mitochondrial homeostasis restoration, and inherent immunomodulatory activity of dendrimer. Such macrophage reprogramming leads to chondrocyte apoptosis inhibition and osteogenic differentiation of bone mesenchymal stem cells. Administration of G2-OH 24 /CAT@Que to an OA mouse model results in attenuation of pathological features such as cartilage degeneration, bone erosion, and synovitis through oxidative stress alleviation and inflammatory factor downregulation in inflamed joints. Excitingly, the G2-OH 24 /CAT@Que also polarized macrophages in adherent effusion monocytes (AEMs) extracted from joint cavity effusions of OA patients to M2 phenotype and downregulated reactive oxygen species levels in AEMs. This study suggests a promising nanomedicine formulation of phosphorus dendrimer-based co-delivery system to effectively tackle OA through the benefits of full-active ingredients of dendrimer, drug, and protein., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The development of new multi-target combination treatment strategies to tackle ischemic stroke (IS) remains to be challenging. Herein, a proof-of-concept demonstration of an advanced nanomedicine formulation composed of macrophage membrane (MM)-camouflaged phosphorous dendrimer (termed as AK137)/fibronectin (FN) nanocomplexes (NCs) loaded with antioxidant edaravone (EDV) to modulate both microglia and neurons for effective IS therapy is showcased. The created MM@AK137-FN/EDV (M@A-F/E) NCs with a mean size of 260 nm possess good colloidal stability, sustained EDV release kinetics, and desired cytocompatibility. By virtue of MM decoration, the M@A-F/E NCs can cross blood-brain barrier, act on microglia to exert the anti-inflammatory (AK137 and FN) and antioxidative (FN and EDV) effects in vitro for oxidative stress alleviation, microglia M2 polarization, and reduction of pro-inflammatory cytokine secretion, and act on neuron cells to be anti-apoptotic. In a transient middle cerebral artery occlusion rat model, the developed M@A-F/E NCs can exert enhanced antioxidant/anti-inflammatory/anti-apoptotic therapeutic effects to comprehensively regulate the brain microenvironment and promote vascular regeneration to collaboratively restore the blood flow after ischemia-reperfusion. The designed MM-coated NCs composed of all-active ingredients of phosphorous dendrimers, FN, and EDV that can fully regulate the brain inflammatory microenvironment may expand their application scope in other neurodegenerative diseases., (© 2024 Wiley‐VCH GmbH.)

Effective treatment of Parkinson's disease (PD), a prevalent central neurodegenerative disorder particularly affecting the elderly population, still remains a huge challenge. We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers (termed as AK123) complexed with fibronectin (FN) with anti-inflammatory and antioxidative activities. The created optimized AK123/FN nanocomplexes (NCs) with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting. We show that the AK123/FN NCs are able to consume excessive reactive oxygen species, promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors. With the abundant dendrimer surface hydroxyl terminal groups, the developed NCs are able to cross blood-brain barrier (BBB) to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects, thus reducing the aggregation of α-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels in vivo . The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive per se phosphorus dendrimers and FN, which is expected to be extended for the treatment of different neurodegenerative diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α 4 and β 1 integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Mycobacterium tuberculosis (Mtb), causative agent of tuberculosis (TB) and non-tubercular mycobacterial (NTM) pathogens such as Mycobacterium abscessus are one of the most critical concerns worldwide due to increased drug-resistance resulting in increased morbidity and mortality. Therefore, focusing on developing novel therapeutics to minimize the treatment period and reducing the burden of drug-resistant Mtb and NTM infections are an urgent and pressing need. In our previous study, we identified anti-mycobacterial activity of orally bioavailable, non-cytotoxic, polycationic phosphorus dendrimer 2G0 against Mtb. In this study, we report ability of 2G0 to potentiate activity of multiple classes of antibiotics against drug-resistant mycobacterial strains. The observed synergy was confirmed using time-kill kinetics and revealed significantly potent activity of the combinations as compared to individual drugs alone. More importantly, no re-growth was observed in any tested combination. The identified combinations were further confirmed in intra-cellular killing assay as well as murine model of NTM infection, where 2G0 potentiated the activity of all tested antibiotics significantly better than individual drugs. Taken together, this nanoparticle with intrinsic antimycobacterial properties has the potential to represents an alternate drug candidate and/or a novel delivery agent for antibiotics of choice for enhancing the treatment of drug-resistant mycobacterial pathogens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The application of nanotechnology in biological and medical fields have resulted in the creation of new devices, supramolecular systems, structures, complexes, and composites. Dendrimers are relatively new nanotechnological polymers with unique features; they are globular in shape, with a topological structure formed by monomeric subunit branches diverging to the sides from the central nucleus. This review analyzes the main features of dendrimers and their applications in biology and medicine regarding cancer treatment. Dendrimers have applications that include drug and gene carriers, antioxidant agents, imaging agents, and adjuvants, but importantly, dendrimers can create complex nanosized constructions that combine features such as drug/gene carriers and imaging agents. Dendrimer-based nanosystems include different metals that enhance oxidative stress, polyethylene glycol to provide biosafety, an imaging agent (a fluorescent, radioactive, magnetic resonance imaging probe), a drug or/and nucleic acid that provides a single or dual action on cells or tissues. One of major benefit of dendrimers is their easy release from the body (in contrast to metal nanoparticles, fullerenes, and carbon nanotubes), allowing the creation of biosafe constructions. Some dendrimers are already clinically approved and are being used as drugs, but many nanocomplexes are currently being studied for clinical practice. In summary, dendrimers are very useful tool in the creation of complex nanoconstructions for personalized nanomedicine. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2024 Wiley Periodicals LLC.)

The development of nonviral dendritic polymers with a simple molecular backbone and great gene delivery efficiency to effectively tackle cancer remains a great challenge. Phosphorus dendrimers or dendrons are promising vectors due to their structural uniformity, rigid molecular backbones, and tunable surface functionalities. Here, we report the development of a new low-generation unsymmetrical cationic phosphorus dendrimer bearing 5 pyrrolidinium groups and one amino group as a nonviral gene delivery vector. The created AB 5 -type dendrimers with simple molecular backbone can compress microRNA-30d (miR-30d) to form polyplexes with desired hydrodynamic sizes and surface potentials and can effectively transfect miR-30d to cancer cells to suppress the glycolysis-associated SLC2A1 and HK1 expression, thus significantly inhibiting the migration and invasion of a murine breast cancer cell line in vitro and the corresponding subcutaneous tumor mouse model in vivo . Such unsymmetrical low-generation phosphorus dendrimers may be extended to deliver other genetic materials to tackle other diseases.

Nanocarrier-based cytoplasmic protein delivery offers opportunities to develop protein therapeutics; however, many delivery systems are positively charged, causing severe toxic effects. For enhanced therapeutics, it is also of great importance to design nanocarriers with intrinsic bioactivity that can be integrated with protein drugs due to the limited bioactivity of proteins alone for disease treatment. We report here a protein delivery system based on anionic phosphite-terminated phosphorus dendrimers with intrinsic anti-inflammatory activity. A phosphorus dendrimer termed AK-137 with optimized anti-inflammatory activity was selected to complex proteins through various physical interactions. Model proteins such as bovine serum albumin, ribonuclease A, ovalbumin, and fibronectin (FN) can be transfected into cells to exert their respective functions, including cancer cell apoptosis, dendritic cell maturation, or macrophage immunomodulation. Particularly, the constructed AK-137@FN nanocomplexes display powerful therapeutic effects in acute lung injury and acute gout arthritis models by integrating the anti-inflammatory activity of both the carrier and protein. The developed anionic phosphite-terminated phosphorus dendrimers may be employed as a universal carrier for protein delivery and particularly utilized to deliver proteins and fight different inflammatory diseases with enhanced therapeutic efficacy.

β-Phenylalanine derivatives (β-PAD) represent a structural family of therapeutic interest, either as components of drugs or as starting materials for access to key compounds. As scaffolds for medicinal chemistry work, β-PAD offer the advantage of great diversity and modularity, a chiral pseudopeptidic character that opens up the capacity to be recognized by natural systems, and greater stability than natural α-amino acids. Nevertheless, their synthesis remains a challenge in drug discovery and numerous methods have been devoted to their preparation. This review is an update of the access routes to β-PAD and their various therapeutic applications.