Modular Synthesis of PEG-Dendritic Block Copolymers by Thermal Azide-Alkyne Cycloaddition with Internal Alkynes and Evaluation of their Self-Assembly for Drug Delivery Applications.

Linear-dendritic block copolymers assemble in solution due to differences in the solubility or charge properties of the blocks. The monodispersity and multivalency of the dendritic block provide unparalleled control for the design of drug delivery systems when incorporating poly(ethylene glycol) (PEG) as a linear block. An accelerated synthesis of PEG-dendritic block copolymers based on the click and green chemistry pillars is described. The tandem composed of the thermal azide-alkyne cycloaddition with internal alkynes and azide substitution is revealed as a flexible, reliable, atom-economical, and user-friendly strategy for the synthesis and functionalization of biodegradable (polyester) PEG-dendritic block copolymers. The high orthogonality of the sequence has been exploited for the preparation of heterolayered copolymers with terminal alkenes and alkynes, which are amenable for subsequent functionalization by thiol-ene and thiol-yne click reactions. Copolymers with tunable solubility and charge were so obtained for the preparation of various types of nanoassemblies with promising applications in drug delivery.

Methods for Radiolabeling Nanoparticles (Part 3): Therapeutic Use.

Following previously published systematic reviews on the diagnostic use of nanoparticles (NPs), in this manuscript, we report published methods for radiolabeling nanoparticles with therapeutic alpha-emitting, beta-emitting, or Auger's electron-emitting isotopes. After analyzing 234 papers, we found that different methods were used with the same isotope and the same type of nanoparticle. The most common type of nanoparticles used are the PLGA and PAMAM nanoparticles, and the most commonly used therapeutic isotope is 177Lu. Regarding labeling methods, the direct encapsulation of the isotope resulted in the most reliable and reproducible technique. Radiolabeled nanoparticles show promising results in metastatic breast and lung cancer, although this field of research needs more clinical studies, mainly on the comparison of nanoparticles with chemotherapy.

The influence of amphiphilic carbosilane dendrons on lipid model membranes.

Amphiphilic dendrons represent a relatively novel class of molecules which may show many unique properties suitable for applications in a field of molecular biology and nanomedicine. They were frequently studied as platforms suitable for drug delivery systems as were, e.g. polymersomes or hybrid lipid-polymer nanoparticles. Recently, natural extracellular lipid vesicles (EVs), called exosomes (EXs), were shown to be a promising candidate in drug delivery applications. Formation of hybrid exosome-dendron nanovesicles could bring benefits in their simple conjugation with selective targeting moieties. Unfortunately, the complex architecture of biological membranes, EXs included, makes obstacles in elucidating the important parameters and mechanisms of interaction with the artificial amphiphilic structures. The aim of the presented work was to study the interaction of two types of amphiphilic carbosilane dendritic structures (denoted as DDN-1 and DDN-2) suitable for further modification with streptavidin (DDN-1) or using click-chemistry approach (DDN-2), with selected neutral and negatively charged lipid model membranes, partially mimicking the basic properties of natural EXs biomembranes. To meet the goal, a number of biophysical methods were used for determination of the degree and mechanisms of the interaction. The results showed that the strength of interactions of amphiphilic dendrons with liposomes was related with surface charge of liposomes. Several steps of interactions were disclosed. The initialization step was mainly coupled with amphiphilic dendrons - liposomes surface interaction resulting in destabilization of large self-assembled amphiphilic dendrons structures. Such destabilization was more significant with liposomes of higher negative charge. With increasing concentration of amphiphilic dendrons in a solution the interactions were taking place also in the hydrophobic part of bilayer. Further increase of nanoparticle concentration resulted in a gradual dendritic cluster formation in a lipid bilayer structure. Due to high affinity of amphiphilic dendrons to model lipid bilayers the conclusion can be drawn that they represent promising platforms also for decoration of exosomes or other kinds of natural lipid vehicles. Such organized hybrid dendron-lipid biomembranes may be advantageous for their subsequent post-functionalization with small molecules, large biomacromolecules or polymers suitable for targeted drug-delivery or theranostic applications.

Cationic amphiphilic dendrons with effective antibacterial performance.

Bacterial infections and antibiotic resistance have become a global healthcare crisis. Herein, we designed and synthesized a series of cationic amphiphilic dendrons with cationic dendrons and hydrophobic alkyl chains for potential antibacterial applications. Our results showed that the antimicrobial activities of the cationic amphiphilic dendrons were highly dependent upon the length of the hydrophobic alkyl chain, whereas the number of cationic charges was less important. Among these cationic amphiphilic dendrons, a prime candidate was identified, which possessed excellent antimicrobial activity against various pathogens (minimum inhibitory concentrations of 9, 3, and 3 µg mL-1 for Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus, respectively). Scanning electron microscopy and fluorescence microscopy analyses showed that it could disrupt the integrity of a pathogen's membrane, leading to cell lysis and death. In addition, in vitro bacteria-killing kinetics showed that it had rapid bactericidal efficiency. It also had excellent antimicrobial activities against MRSA in vivo and promoted wound healing. In general, the synthesized cationic amphiphilic dendrons, which exhibited rapid and broad-spectrum bactericidal activity, may have great potential in antimicrobial applications.

An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate.

Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human monocytes, which is one of the effects of GA on immune cells. Several of the largest dendrimers tested were as active as GA. Detailed profiling of the best hit showed that this dendrimer induces the differentiation of monocytes towards an M2 (anti-inflammatory) state as GA does, however with a distinct immune marker profile. Our peptide dendrimer might serve as starting point to develop a well-defined immunomodulatory analog of GA.

One-Component Multifunctional Sequence-Defined Ionizable Amphiphilic Janus Dendrimer Delivery Systems for mRNA.

Efficient viral or nonviral delivery of nucleic acids is the key step of genetic nanomedicine. Both viral and synthetic vectors have been successfully employed for genetic delivery with recent examples being DNA, adenoviral, and mRNA-based Covid-19 vaccines. Viral vectors can be target specific and very efficient but can also mediate severe immune response, cell toxicity, and mutations. Four-component lipid nanoparticles (LNPs) containing ionizable lipids, phospholipids, cholesterol for mechanical properties, and PEG-conjugated lipid for stability represent the current leading nonviral vectors for mRNA. However, the segregation of the neutral ionizable lipid as droplets in the core of the LNP, the "PEG dilemma", and the stability at only very low temperatures limit their efficiency. Here, we report the development of a one-component multifunctional ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA that exhibits high activity at a low concentration of ionizable amines organized in a sequence-defined arrangement. Six libraries containing 54 sequence-defined IAJDs were synthesized by an accelerated modular-orthogonal methodology and coassembled with mRNA into dendrimersome nanoparticles (DNPs) by a simple injection method rather than by the complex microfluidic technology often used for LNPs. Forty four (81%) showed activity in vitro and 31 (57%) in vivo. Some, exhibiting organ specificity, are stable at 5 °C and demonstrated higher transfection efficiency than positive control experiments in vitro and in vivo. Aside from practical applications, this proof of concept will help elucidate the mechanisms of packaging and release of mRNA from DNPs as a function of ionizable amine concentration, their sequence, and constitutional isomerism of IAJDs.

In vitro/vivo antitumor study of modified-chitosan/carboxymethyl chitosan "boosted" charge-reversal nanoformulation.

Major obstacles in the development of nanoformulations as efficient drug delivery systems are the rapid clearance from blood circulation and lysosomal entrapment. To overcome these problems, a polysaccharide-based core-shell type charge-switchable nanoformulation (CS-LA-DMMA/CMCS/PAMAM@DOX) is constructed to improve antitumor efficacy of DOX. By applying carboxymethyl chitosan (CMCS) as bridge polymer and negatively charged chitosan-derivative as outer shell, the stability and pH-sensitivity of this nanoformulation is promisingly enhanced. Furthermore, the positively charged PAMAM@DOX could escape from lysosomes via "proton sponge effect" and "cationic-anionic interaction with lysosome membranes". Admirable cellular uptake and high apoptosis/necrosis rate were detected in this study. In vitro assays demonstrate that the CS-LA-DMMA/CMCS/PAMAM@DOX was internalized into HepG2 cells predominantly via the clathrin-mediated endocytosis pathway. Excitingly, in vivo studies showed that high accumulation of CS-LA-DMMA/CMCS/PAMAM@DOX in tumor tissue led to enhanced tumor inhibition. Compared with free DOX, the tumor inhibition rate of nanoformulation was improved up to 226%.

Organometallic dendrimers based on Ruthenium(II) N-heterocyclic carbenes and their implication as delivery systems of anticancer small interfering RNA.

With the purpose of obtaining a new dendritic system against cancer, this paper is focused on the synthesis of spherical carbosilane metallodendrimers of different generations holding Ru(II) N-heterocyclic carbene (NHC) on the periphery from the imidazolium precursors. Both imidazolium salt dendrimers and their metallodendrimers counterparts showed promising anticancer activity, similar to cisplatin, mainly at high generations. In addition, both families of second and third generations were able to form dendriplexes with anticancer small interfering RNA (siRNA), protecting the cargo against RNAse and being able to internalize it in HEPG2 (human liver cancer) tumour cells. The characterization and effectiveness of the dendriplexes were evaluated by various analytical techniques such as zeta potential, electrophoresis and circular dichroism, the stability of the system and the protective nature of the dendrimer estimated using RNAse and the internalization of dendriplexes by confocal microscopy. The major advantage observed with the ruthenium metallodendrimers with respect to the imidazolium salts precursors was in cellular uptake, where the internalization of Mcl-1-FITC siRNA (myeloid cell leukaemia-1 fluorescein labelled siRNA) proceeded more efficiently. Therefore, we propose here that both imidazolium and Ru metallodendrimers are interesting candidates in cancer due to their double action, as anticancer per se and as carrier for anticancer siRNA, providing in this way a combined action.

Simple Osthole/Nanocarrier Pesticide Efficiently Controls Both Pests and Diseases Fulfilling the Need of Green Production of Strawberry.

The application of botanical pesticides is a good choice in organic agriculture. However, most botanical pesticides have limitations of slow action and short persistence for pest and disease management, which constrain their further application. With the objective of exploring a green pesticide for controlling strawberry pests and diseases simultaneously, a star polymer (SPc) with a low production cost was synthesized as a pesticide nanocarrier through simple reactions. The SPc complexed with osthole quickly through electrostatic interaction and hydrophobic association, which decreased the particle size of osthole down to the nanoscale (17.66 nm). With the help of SPc, more nano-sized osthole was delivered into cytoplasm through endocytosis, leading to the enhanced cytotoxicity against insect cells. As a green botanical pesticide, the control efficacy of the osthole/SPc complex was improved against main strawberry pests (green peach aphid and two-spotted spider mite) and disease (powdery mildew), which fulfilled the need of both pest and disease management in sustainable production of strawberry. Meanwhile, the introduction of SPc not only improved plant-uptake but also decreased the residue of osthole due to the higher degradation rate. Furthermore, the application of the osthole/SPc complex exhibited no influence on the strawberry fruit quality and nontarget predators. To our knowledge, it is the first success to control plant pests and diseases simultaneously for sustainable agriculture by only one pesticidal formulation based on nanoparticle-delivered botanical pesticides.

Use of Half-Generation PAMAM Dendrimers (G0.5-G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs.

The DACHPtCl2 compound (trans-(R,R)-1,2-diaminocyclohexanedichloroplatinum(II)) is a potent anticancer drug with a broad spectrum of activity and is less toxic than oxaliplatin (trans-l-diaminocyclohexane oxalate platinum II), with which it shares the active metal fragment DACHPt. Nevertheless, due to poor water solubility, its use as a chemotherapeutic drug is limited. Here, DACHPtCl2 was conjugated, in a bidentate form, with half-generation PAMAM dendrimers (G0.5-G3.5) with carboxylate end-groups, and the resulting conjugates were evaluated against various types of cancer cell lines. In this way, we aimed at increasing the solubility and availability at the target site of DACHPt while potentially reducing the adverse side effects. DNA binding assays showed a hyperchromic effect compatible with DNA helix's disruption upon the interaction of the metallodendrimers and/or the released active metallic fragments with DNA. Furthermore, the prepared DACHPt metallodendrimers presented cytotoxicity in a wide set of cancer cell lines used (the relative potency regarding oxaliplatin was in general high) and were not hemotoxic. Importantly, their selectivity for A2780 and CACO-2 cancer cells with respect to non-cancer cells was particularly high. Subsequently, the anticancer drug 5-FU was loaded in a selected metallodendrimer (the G2.5COO(DACHPt)16) to investigate a possible synergistic effect between the two drugs carried by the same dendrimer scaffold and tested for cytotoxicity in A2780cisR and CACO-2 cancer cell lines. This combination resulted in IC50 values much lower than the IC50 for 5-FU but higher than those found for the metallodendrimers without 5-FU. It seems, thus, that the metallic fragment-induced cytotoxicity dominates over the cytotoxicity of 5-FU in the set of considered cell lines.

Dendronized hyaluronic acid-docetaxel conjugate as a stimuli-responsive nano-agent for breast cancer therapy.

To achieve target delivery of anti-tumor drugs with great biocompatibility into tumor tissues, a stimuli-responsive dendronized hyaluronic acid (HA)-docetaxel conjugate (HA-DTX-Dendron, HADD) was designed and prepared. The incorporation of HA in HADD improved the delivery of DTX to tumor cells with rich CD44 receptors. Enhanced biocompatibility and therapeutic outcomes were achieved using glyodendrons-modified HA and tumor microenvironment-responsive linkers in HADD. The glycodendron was connected with HA via GSH-responsive disulfide bonds, and the drug DTX was linked to the carrier via a cathepsin B-responsive tetrapeptide GFLG. This design resulted in self-assembly nanostructures for facilitating uptake of HADD by tumor cells and rapid release of DTX to exert its therapeutic effect. Compared to free DTX, HADD showed much higher tumor growth inhibition in the MDA-MB-231 tumor-bearing mice model (up to 99.71%), and no toxicity was observed. Therefore, HADD could be employed as an efficacious nano-agent for treating triple negative breast cancer (TNBC).

Modulation of inflammation by anti-TNF α mAb-dendrimer nanoparticles loaded in tyramine-modified gellan gum hydrogels in a cartilage-on-a-chip model.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease characterized by joint inflammation. Since the inflammatory condition plays an important role in the disease process, it is important to develop and test new therapeutic approaches that specifically target and treat joint inflammation. In this study, a human 3D inflammatory cartilage-on-a-chip model was established to test the therapeutic efficacy of anti-TNFα mAb-CS/PAMAM dendrimer NPs loaded-Tyramine-Gellan Gum in the treatment of inflammation. The results showed that the proposed therapeutic approach applied to the human monocyte cell line (THP-1) and human chondrogenic primary cells (hCH) cell-based inflammation system revealed an anti-inflammatory capacity that increased over 14 days. It was also possible to observe that Coll type II was highly expressed by inflamed hCH upon the culture with anti-TNF α mAb-CS/PAMAM dendrimer NPs, indicating that the hCH cells were able maintain their biological function. The developed preclinical model allowed us to provide more robust data on the potential therapeutic effect of anti-TNF α mAb-CS/PAMAM dendrimer NPs loaded-Ty-GG hydrogel in a physiologically relevant model.

A metastasis suppressor Pt-dendrimer nanozyme for the alleviation of glioblastoma.

Nanozymes are nanostructure-based materials which mimic the enzymatic characteristics of natural enzymes. Biological applications of nanozymes have been highlighted in basic research, industry, and translational medicine as a new cutting-edge tool. In this work, and for the first time, we disclose a tumor alleviation property of a nanozyme that is made up of amine-terminated sixth-generation polyamidoamine dendrimers with encapsulated tiny platinum nanoparticles. We systematically conducted the synthesis and characterization of the dendrimer-encapsulated Pt nanoparticles (denoted Pt-dendrimer) and confirmed their enzymatic function (hydrogen peroxide (H2O2) decomposition) within various cell lines (normal, cancerous), including glioblastoma (GBM) cells. By understanding the effects of the Pt-dendrimer at the gene level, especially related to cancer cell metastasis, we have thoroughly demonstrated its ability for tumor alleviation and suppressing GBM migration, invasion, and adhesion. The present findings show great promise for the application of the nanozyme for use in GBM-related basic research as well as at clinical sites.

Facial Solid-Phase Synthesis of Well-Defined Zwitterionic Amphiphiles for Enhanced Anticancer Drug Delivery.

Serum protein adsorption on the nanoparticle surface determines the biological identity of polymeric nanocarriers and critically impacts the in vivo stability following intravenous injection. Ultrahydrophilic surfaces are desired in delivery systems to reduce the serum protein corona formation, prolong drug pharmacokinetics, and improve the in vivo performance of nanotherapeutics. Zwitterionic polymers have been explored as alternative stealth materials for biomedical applications. In this study, we employed facial solid-phase peptide chemistry (SPPC) to synthesize multifunctional zwitterionic amphiphiles for application as a drug delivery vehicle. SPPC facilitates synthesis and purification of the well-defined dendritic amphiphiles, yielding high-purity and precise architecture. Zwitterionic glycerylphosphorylcholine (GPC) was selected as a surface moiety for the construction of a ultrahydrophilic dendron, which was coupled on solid phase to a hydrophobic dendron using multiple rhein (Rh) molecules as drug-binding moieties (DBMs) for doxorubicin (DOX) loading via pi-pi stacking and hydrogen bonding. The resulting zwitterionic amphiphilic Janus dendrimer (denoted as GPC8-Rh4) showed improved stabilities and sustained drug release compared to the analogue with poly(ethylene glycol) (PEG) surface (PEG5k-Rh4). In vivo studies in xenograft mouse tumor models demonstrated that the DOX-GPC8-Rh4 nanoformulation significantly improved anticancer effects compared to DOX-PEG5k-Rh4, owing to the improved in vivo pharmacokinetics and increased tumor accumulation.

Design, Synthetic Strategies, and Therapeutic Applications of Heterofunctional Glycodendrimers.

Glycodendrimers have attracted considerable interest in the field of dendrimer sciences owing to their plethora of implications in biomedical applications. This is primarily due to the fact that cell surfaces expose a wide range of highly diversified glycan architectures varying by the nature of the sugars, their number, and their natural multiantennary structures. This particular situation has led to cancer cell metastasis, pathogen recognition and adhesion, and immune cell communications that are implicated in vaccine development. The diverse nature and complexity of multivalent carbohydrate-protein interactions have been the impetus toward the syntheses of glycodendrimers. Since their inception in 1993, chemical strategies toward glycodendrimers have constantly evolved into highly sophisticated methodologies. This review constitutes the first part of a series of papers dedicated to the design, synthesis, and biological applications of heterofunctional glycodendrimers. Herein, we highlight the most common synthetic approaches toward these complex molecular architectures and present modern applications in nanomolecular therapeutics and synthetic vaccines.

On-cell saturation transfer difference NMR for the identification of FimH ligands and inhibitors.

We describe the development of an on-cell NMR method for the rapid screening of FimH ligands and the structural identification of ligand binding epitopes. FimH is a mannose-binding bacterial adhesin expressed at the apical end of type 1 pili of uropathogenic bacterial strains and responsible for their d-mannose sensitive adhesion to host mammalian epithelial cells. Because of these properties, FimH is a key virulence factor and an attractive therapeutic target for urinary tract infection. We prepared synthetic d-mannose decorated dendrimers, we tested their ability to prevent the FimH-mediated yeast agglutination, and thus we used the compounds showing the best inhibitory activity as models of FimH multivalent ligands to set up our NMR methodology. Our experimental protocol, based on on-cell STD NMR techniques, is a suitable tool for the screening and the epitope mapping of FimH ligands aimed at the development of new antiadhesive and diagnostic tools against urinary tract infection pathogens. Notably, the study is carried out in a physiological environment, i.e. at the surface of living pathogen cells expressing FimH.

Peptide Dendrimers with Non-Symmetric Bola Structure Exert Long Term Effect on Glioblastoma and Neuroblastoma Cell Lines.

BACKGROUND: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS). Neuroblastoma (NB) is one of the most common cancers of childhood derived from the neural crest cells. The survival rate for patients with GBM and high-risk NB is poor; therefore, novel therapeutic approaches are needed. Increasing evidence suggests a dual role of redox-active compounds in both tumorigenesis and cancer treatment. Therefore, in this study, polyfunctional peptide-based dendrimeric molecules of the bola structure carrying residues with antiproliferative potential on one side and the antioxidant residues on the other side were designed. METHODS: We synthesized non-symmetric bola dendrimers and assessed their radical scavenging potency as well as redox capability. The influence of dendrimers on viability of rat primary cerebellar neurons (CGC) and normal human astrocytes (NHA) was determined by propidium iodide staining and cell counting. Cytotoxicity against human GBM cell lines, T98G and LN229, and NB cell line SH-SY5Y was assessed by cell counting and colony forming assay. RESULTS: Testing of CGC and NHA viability allowed to establish a range of optimal dendrimers structure and concentration for further evaluation of their impact on two human GBM and one human NB cell lines. According to ABTS, DPPH, FRAP, and CUPRAC antioxidant tests, the most toxic for normal cells were dendrimers with high charge and an excess of antioxidant residues (Trp and PABA) on both sides of the bola structure. At 5 µM concentration, most of the tested dendrimers neither reduced rat CGC viability below 50-40%, nor harmed human neurons (NHA). The same dose of compounds 16 or 22, after 30 min treatment decreased the number of SH-SY5Y and LN229 cells, but did not affect the number of T98G cells 48 h post treatment. However, either compound significantly reduced the number of colonies formed by SH-SY5Y, LN229, and T98G cells measured 14 days after treatment. CONCLUSIONS: Peptide dendrimers with non-symmetric bola structure are excellent scaffolds for design of molecules with pro/antioxidant functionality. Design of molecules with an excess of positive charges and antioxidant residues rendered molecules with high neurotoxicity. Single, 30 min exposition of the GBM and NB cell lines to the selected bola dendrimers significantly suppressed their clonogenic potential.

Recent Advances in Preclinical Research Using PAMAM Dendrimers for Cancer Gene Therapy.

Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, namely, their low capacity and complex manufacturing process, based on biological systems, are major limitations prior to their broad implementation in the clinical setting. The application of non-viral carriers in gene therapy is one of the available approaches. Poly(amidoamine) (PAMAM) dendrimers are repetitively branched, three-dimensional molecules, made of amide and amine subunits, possessing unique physiochemical properties. Surface and internal modifications improve their physicochemical properties, enabling the increase in cellular specificity and transfection efficiency and a reduction in cytotoxicity toward healthy cells. During the last 10 years of research on PAMAM dendrimers, three modification strategies have commonly been used: (1) surface modification with functional groups; (2) hybrid vector formation; (3) creation of supramolecular self-assemblies. This review describes and summarizes recent studies exploring the development of PAMAM dendrimers in anticancer gene therapies, evaluating the advantages and disadvantages of the modification approaches and the nanomedicine regulatory issues preventing their translation into the clinical setting, and highlighting important areas for further development and possible steps that seem promising in terms of development of PAMAM as a carrier of genetic material.

Increased Valency Improves Inhibitory Activity of Peptides Targeting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9).

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a clinically validated target for treating hypercholesterolemia. Peptide-based PCSK9 inhibitors have attracted pharmaceutical interest, but the effect of multivalency on bioactivity is poorly understood. Here we designed bivalent and tetravalent dendrimers, decorated with the PCSK9 inhibitory peptides Pep2-8[RRG] or P9-38, to study relationships between peptide binding affinity, peptide valency, and PCSK9 inhibition. Increased valency resulted in improved PCSK9 inhibition for both peptides, with activity improvements of up to 100-fold achieved for the P9-38-decorated dendrimers compared to monomeric P9-38 in in vitro competition binding assays. Furthermore, the P9-38-decorated dendrimers showed improved potency at restoring functional low-density lipoprotein (LDL) receptor levels and internalizing LDL in the presence of PCSK9, demonstrating significant cell-based activity at picomolar concentrations. This study demonstrates the potential of increasing valency as a strategy for increasing the efficacy of peptide-based PCSK9 therapeutics.

Polyphosphorhydrazone-Based Radical Dendrimers.

The search for new biomedical applications of dendrimers has promoted the synthesis of new radical-based molecules. Specifically, obtaining radical dendrimers has opened the door to their use in various fields such as magnetic resonance imaging, as anti-tumor or antioxidant agents, or the possibility of developing new types of devices based on the paramagnetic properties of organic radicals. Herein, we present a mini review of radical dendrimers based on polyphosphorhydrazone, a new type of macromolecule with which, thanks to their versatility, new metal-free contrast agents are being obtained, among other possible applications.