Dendrimer Surface Research Articles

Theoretical and Experimental Analyses of the Interfacial Mechanism of Dendrimer-Doxorubicin Complexes Formation.

The work presents correlations between the physicochemical properties of the carrier and the active substance and optimization of the conditions for creating an active system based on PAMAM dendrimers and doxorubicin. The study monitored the influence of the ionized form of the doxorubicin molecule on the efficiency of complex formation. The deprotonated form of doxorubicin occurs under basic conditions in the pH range of 9.0-10.0. In the presence of doxorubicin, changes in the zeta potential of the complex concerning the initial system are observed. These changes result from electrostatic interactions between the drug molecules and external functional groups. Based on changes in the absorbance intensity of UV-vis spectra, the binding of the drug in the polymer structure is observed depending on the pH of the environment and the molar ratio. Optimal conditions for forming complexes occur under alkaline conditions. UV-vis, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy confirmed the stability of the formed dendrimer-DOX complex. Molecular dynamics simulations were conducted to gain a deeper insight into the molecular mechanism of DOX adsorption on and within the G4.0 PAMAM dendrimers. It was observed that the protonation state of both the dendrimer and DOX significantly influences the adsorption stability. The system exhibited high stability at high pH values (∼9-10), with DOX molecules strongly adsorbed on the dendrimer surface and partially within its bulk. However, under lower pH conditions, a reduction in adsorption strength was observed, leading to the detachment of DOX clusters from the dendrimer structure.

Systemically targeting monocytic myeloid-derived suppressor cells using dendrimers and their cell-level biodistribution kinetics

The focus of nanoparticles in vivo trafficking has been mostly on their tissue-level biodistribution and clearance. Recent progress in the nanomedicine field suggests that the targeting of nanoparticles to immune cells can be used to modulate the immune response and enhance therapeutic delivery to the diseased tissue. In the presence of tumor lesions, monocytic-myeloid-derived suppressor cells (M-MDSCs) expand significantly in the bone marrow, egress into peripheral blood, and traffic to the solid tumor, where they help maintain an immuno-suppressive tumor microenvironment. In this study, we investigated the interaction between PAMAM dendrimers and M-MDSCs in two murine models of glioblastoma, by examining the cell-level biodistribution kinetics of the systemically injected dendrimers. We found that M-MDSCs in the tumor and lymphoid organs can efficiently endocytose hydroxyl dendrimers. Interestingly, the trafficking of M-MDSCs from the bone marrow to the tumor contributed to the deposition of hydroxyl dendrimers in the tumor. M-MDSCs showed different capacities of endocytosing dendrimers of different functionalities in vivo. This differential uptake was mediated by the unique serum proteins associated with each dendrimer surface functionality. The results of this study set up the framework for developing dendrimer-based immunotherapy to target M-MDSCs for cancer treatment.

Therapeutic Effects of PEG-Modified Polyamide Amine Dendrimer for Cell Free DNA Adsorption in Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJ OA) is characterized by the degeneration of cartilage and subchondral bone. In this study, we observed a significant increase in cell-free DNA (cfDNA) levels during the progression of TMJ OA. Bioinformatics analysis identified TLR9 as a pivotal molecule in TMJ OA pathogenesis. The polyamidoamine (PAMAM) dendrimer characterized by a well-structured, highly branched, and reactive nature, exhibits robust binding and clearance capabilities for cfDNA. However, the abundant amino groups on the surface of PAMAM lead to its inherent toxicity. To mitigate this, PEG-5000 was conjugated to the surface of PAMAM dendrimers, enhancing safety. Our results indicate that PEG-PAMAM effectively inhibits the upregulation of the TLR9 protein in TMJ OA, significantly suppressing the activation of the p-IκBα/p-NF-κB signaling pathway and subsequently decreasing chondrocyte inflammation and apoptosis, as evidenced by both in vivo and in vitro experiments. We conclude that PEG-PAMAM is a safe and effective material for in vivo applications, offering a promising therapeutic strategy for TMJ OA by targeting cfDNA clearance.

Diverse Approaches for the Difunctionalization of PPH Dendrimers, Precise Versus Stochastic: How Does this Influence Catalytic Performance?

Random difunctionalization of dendrimer surfaces, frequently employed in biological applications, provides the advantage of dual functional groups through a synthetic pathway that is simpler compared to precise difunctionalization. However, is the random difunctionalization as efficient as the precise difunctionalization on the surface of dendrimers? This question is unanswered to date because most dendrimer families face challenges in achieving precise functionalization. Polyphosphorhydrazone (PPH) dendrimers present a unique opportunity to obtain precise difunctionalization at each terminal branching point. The work concerning catalysis we report with PPH dendrimers, whether precisely or randomly functionalized, addresses this question. Across PPH dendrimers, from generations 1 to 3, precise functionalization consistently outperforms random functionalization in terms of efficiency. This finding introduces a novel concept in dendrimer science, emphasizing the superiority of precise over random functionalization methodologies. Introducing a groundbreaking concept in the field of dendrimers.

Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson's disease treatment via cooperative modulation of microglia

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.

Dendritic Pyridine-Imine Copper Complexes as Metallo-Drugs.

Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine-imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.

Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery.

Dendrimers are a family of polymers with highly branched structure, well-defined composition, and extensive functional groups, which have attracted great attention in biomedical applications. Micelles formed by dendrimers are ideal nanocarriers for delivering anticancer agents due to the explicit study of their characteristics of particle size, charge, and biological properties such as toxicity, blood circulation time, biodistribution, and cellular internalization. Here, the classification, preparation, and structure of dendrimer micelles are reviewed, and the specific functional groups modified on the surface of dendrimers for tumor active targeting, stimuli-responsive drug release, reduced toxicity, and prolonged blood circulation time are discussed. In addition, their applications are summarized as various platforms for biomedical applications related to cancer therapy including drug delivery, gene transfection, nano-contrast for imaging, and combined therapy. Other applications such as tissue engineering and biosensor are also involved. Finally, the possible challenges and perspectives of dendrimer micelles for their further applications are discussed.

Computer simulation of the structural properties of fatty-acid modified PAMAM dendrimers at pH 5 and 7

In this work, we performed coarse-grained molecular dynamics (CGMD) simulations of G3, G4, and G5 polyamidoamine (PAMAM) dendrimers grafting with fatty acid (FTA) chains. The FTA chains of varying length and grafting densities (50% and 100% of surface terminals) correspond to pH 7 and 5, respectively. Our findings suggested that the structural properties of dendrimers were determined by dendrimer generation, polymerization degrees, and pH. With one exception, the size of the FTA grafting dendrimer shrank after fatty acid attachment. Because of the protonation of the dendrimer's interior amines at low pH, the FTA chains are distributed at the dendrimer's surface group. At pH 7, the FTA chains that have aggregated in the interior of the dendrimer cause chain crowding. Our research provided references on drug encapsulation and the lower toxicity of these hydrophobically modified nanoparticles.

An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation-Mediated Combination Tumor Therapy.

Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP-1 peptide is reported. The resulting generation 5 (G5) dendrimer-based nanodevice, known as G5-PEG-LyP-1-CuS-DMXAA NPs (GLCD NPs), possess good colloidal stability, pH-sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP-1-targeted killing effect on breast tumors by combining CuS-mediated photothermal therapy (PTT) and DMXAA-induced vascular disruption, while also triggering antitumor immune responses through PTT-induced immunogenic cell death and DMXAA-mediated immune regulation via M1 polarization of tumor-associated macrophages and dendritic cell maturation. In addition, with the LyP-1-mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two-pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation-mediated combination tumor therapy with potential for clinical translations.

Effect of Alkaline Conditions on Forming an Effective G4.0 PAMAM Complex with Doxorubicin.

In this study, special attention was paid to the correlation between the degree of ionization of the components and the effective formation of the complex under alkaline conditions. Using UV-Vis, 1H NMR, and CD, structural changes of the drug depending on the pH were monitored. In the pH range of 9.0 to 10.0, the G4.0 PAMAM dendrimer can bind 1 to 10 DOX molecules, while the efficiency increases with the concentration of the drug relative to the carrier. The binding efficiency was described by the parameters of loading content (LC = 4.80-39.20%) and encapsulation efficiency (EE = 17.21-40.16%), whose values increased twofold or even fourfold depending on the conditions. The highest efficiency was obtained for G4.0PAMAM-DOX at a molar ratio of 1:24. Nevertheless, regardless of the conditions, the DLS study indicates system aggregation. Changes in the zeta potential confirm the immobilization of an average of two drug molecules on the dendrimer's surface. Circular dichroism spectra analysis shows a stable dendrimer-drug complex for all the systems obtained. Since the doxorubicin molecule can simultaneously act as a therapeutic and an imaging agent, the theranostic properties of the PAMAM-DOX system have been demonstrated by the high fluorescence intensity observable on fluorescence microscopy.

Helical micelle of an achiral surfactant from the template interaction with dendrimer

The electrostatic interaction between of poly(amidoamine) (PAMAM) G9 dendrimer and an achiral surfactant, dodecylbenzenesulfonic acid (DBSA), leads to the formation of nucleosome-like structure, where the globular dendrimer molecule directs the DBSA cylindrical micelle to wrap around it spirally with a regular pitch length of 3.2 ∼ 4.3 nm. Molecular dynamics simulation demonstrates that the spherical micelles of DBSA in the aqueous solution first condense on the dendrimer surface via the electrostatic attraction. The micelles then merge with their neighbors to form cylinders bending around the dendrimer, which further connect with one another to form a spring-like helix wrapping around the dendrimer. The discovery of the helical supramolecular structure attests the universality of soft cylindrical building block such as DNA and micelle to twist and wrap helically around the oppositely charged particle such as histone protein and dendrimer for attaining the optimal charge matching at the expense of the bending energy of the cylinder.

Dendrimer-Mediated Delivery of Anticancer Drugs for Colon Cancer Treatment.

The third most common cancer worldwide is colon cancer (CC). Every year, there more cases are reported, yet there are not enough effective treatments. This emphasizes the need for new drug delivery strategies to increase the success rate and reduce side effects. Recently, a lot of trials have been done for developing natural and synthetic medicines for CC, among which the nanoparticle-based approach is the most trending. Dendrimers are one of the most utilized nanomaterials that are accessible and offer several benefits in the chemotherapy-based treatment of CC by improving the stability, solubility, and bioavailability of drugs. They are highly branched polymers, making it simple to conjugate and encapsulate medicines. Dendrimers have nanoscale features that enable the differentiation of inherent metabolic disparities between cancer cells and healthy cells, enabling the passive targeting of CC. Moreover, dendrimer surfaces can be easily functionalized to improve the specificity and enable active targeting of colon cancer. Therefore, dendrimers can be explored as smart nanocarriers for CC chemotherapy.

Effect of dendrimer generation and surface groups on the optoelectronic properties of green emitting bis-tridentate iridium(iii) complexes designed for OLEDs

The role of surface groups (t-butyl versus 2-ethylhexyloxy) and dendron generation (first versus second) on the photoluminescent and electroluminescent properties of solution-processable bis-tridentate iridium(iii) complexes has been investigated.

Mitigating Cardiotoxicity of Dendrimers: Angiotensin-(1-7) via Its Mas Receptor Ameliorates PAMAM-Induced Cardiac Dysfunction in the Isolated Mammalian Heart.

The influence of the physiochemical properties of dendrimer nanoparticles on cardiac contractility and hemodynamics are not known. Herein, we investigated (a) the effect of polyamidoamine (PAMAM) dendrimer generation (G7, G6, G5, G4 and G3) and surface chemistry (-NH2, -COOH and -OH) on cardiac function in mammalian hearts following ischemia-reperfusion (I/R) injury, and (b) determined if any PAMAM-induced cardiotoxicity could be mitigated by Angiotensin-(1-7) (Ang-(1-7), a cardioprotective agent. Hearts isolated from male Wistar rats underwent regional I/R and/or treatment with different PAMAM dendrimers, Ang-(1-7) or its MAS receptors antagonists. Thirty minutes of regional ischemia through ligation of the left anterior descending coronary artery was followed by 30 min of reperfusion. All treatments were initiated 5 min prior to reperfusion and maintained during the first 10 min of reperfusion. Cardiac function parameters for left ventricular contractility, hemodynamics and vascular dynamics data were acquired digitally, whereas cardiac enzymes and infarct size were used as measures of cardiac injury. Treatment of isolated hearts with increasing doses of G7 PAMAM dendrimer progressively exacerbated recovery of cardiac contractility and hemodynamic parameters post-I/R injury. Impairment of cardiac function was progressively less on decreasing dendrimer generation with G3 exhibiting little or no cardiotoxicity. Cationic PAMAMs (-NH2) were more toxic than anionic (-COOH), with neutral PAMAMs (-OH) exhibiting the least cardiotoxicity. Cationic G7 PAMAM-induced cardiac dysfunction was significantly reversed by Ang-(1-7) administration. These cardioprotective effects of Ang-(1-7) were significantly revoked by administration of the MAS receptor antagonists, A779 and D-Pro7-Ang-(1-7). PAMAM dendrimers can impair the recovery of hearts from I/R injury in a dose-, dendrimer-generation-(size) and surface-charge dependent manner. Importantly, PAMAM-induced cardiotoxicity could be mitigated by Ang-(1-7) acting through its MAS receptor. Thus, this study highlights the activation of Ang-(1-7)/Mas receptor axis as a novel strategy to overcome dendrimer-induced cardiotoxicity.

Toxicity of polyamidoamine dendrimers in vivo

The development of effective drug delivery systems is a crusial task for modern medicine. The main problem is the occurrence of non-specific toxicity leading to undesirable side effects in vivo.This article aims at reviewing resent research on the toxicity of polyamidoamine (PAMAM) dendrimers in vivo. The research results show that the toxicity of PAMAM dendrimers and modified nanoparticles depends both on the characteristics of the particles themselves (size, generation and surface charge) and on the administration parameters. It has been shown that cationic PAMAM dendrimers of small and medium generations are non-toxic in vivo when administered intravenously and intraperitoneally to mice at doses up to 10 mg/kg. In turn, anionic, neutral, and modified PAMAM dendrimers do not exhibit toxicity, regardless of the route of administration. Thus, by varying methods of administration, the dose, and modifying the surface of dendrimers, the decrease in toxicity can be achieved, promising a path towards their successfully aplication as drug carriers.

Polymeric Dendrimers as Nanocarrier Vectors for Neurotheranostics.

Dendrimers are polymers with well-defined 3D branched structures that are vastly utilized in various neurotheranostics and biomedical applications, particularly as nanocarrier vectors. Imaging agents can be loaded into dendrimers to improve the accuracy of diagnostic imaging processes. Likewise, combining pharmaceutical agents and anticancer drugs with dendrimers can enhance their solubility, biocompatibility, and efficiency. Practically, by modifying ligands on the surface of dendrimers, effective therapeutic and diagnostic platforms can be constructed and implemented for targeted delivery. Dendrimer-based nanocarriers also show great potential in gene delivery. Since enzymes can degrade genetic materials during their blood circulation, dendrimers exhibit promising packaging and delivery alternatives, particularly for central nervous system (CNS) treatments. The DNA and RNA encapsulated in dendrimers represented by polyamidoamine that are used for targeted brain delivery, via chemical-structural adjustments and appropriate generation, significantly improve the correlation between transfection efficiency and cytotoxicity. This article reports a comprehensive review of dendrimers' structures, synthesis processes, and biological applications. Recent progress in diagnostic imaging processes and therapeutic applications for cancers and other CNS diseases are presented. Potential challenges and future directions in the development of dendrimers, which provide the theoretical basis for their broader applications in healthcare, are also discussed.

Lipophilic PAMAM Dendrimer: Conceptualization of Targeted Cosmetics and Drug Delivery

Abstract: The structure, properties, synthesis, negligible toxicity, and surface modification of PAMAM (polyamidoamine dendrimers) are all discussed in this review. The properties of supramolecular PAMAM dendrimers in nanopolymer science have shown great progress in delivering medicines. A divergent strategy was used to construct a Generation four (G4.0) PAMAM dendrimer with an ethylenediaminetetraacetic acid core and repeating units of acrylic acid and ethylenediamine. PAMAM dendrimers, have an aminodoamine repeat branching architecture that starts with an ethylene diamine initiator core. A generation [G] is a set of branching steps that follow each other. Drug molecules can be transferred either as covalently bonded to the functional groups on the dendrimer surface or by forming non-covalent complexes with dendrimers. Full generation PAMAM dendrimers are terminated with amine surface [G0, G1, G2, G3, G4], whereas half-generation dendrimers are terminated with carboxylate [G1.5, G2.5, etc]. PAMAM dendrimers appear to have negligible toxicity and immunogenicity, as well as favorable biodistribution-: according to the current study they can improve drug solubility, prevent drug degradation, increase circulation time, and potentially target drugs. According to the characterization study, they exhibit strong lipophilic qualities, allowing them to easily pass the blood-brain barrier. Due to cheaper polydispersity index of dendrimers, they possess greater stability and the void spaces of dendrimers are accessible for drug loading. The existence of a duplet functional group on the dendrimers enables appending vectors, ligands and devices for targed the drug delivery in the body.

Specific Bifunctionalization on the Surface of Phosphorus Dendrimers Syntheses and Properties

Dendrimers are highly branched macromolecules possessing, in most cases, identical terminal functions. However, it is sometimes desirable to have two types of surface functions in order to fulfil specific properties. The stochastic functionalization is frequently used for such purposes, but the presence of an uncontrolled number of each type of terminal function, albeit acceptable for research purposes, has no practical use. Thus, it is highly desirable to find strategies suitable for the precise grafting of two different functional groups on the surface of dendrimers. The easiest way, and the most widely used, consists in using a bifunctional monomer to be grafted to all of the surface functions of the dendrimers. Two other strategies are known but are rarely used: the modification of an existing function, to generate two functions, and the sequential grafting of one function then of a second function. The three methods are illustrated in this review with polyphosphorhydrazone (PPH) dendrimers, together with their properties as catalysts, for materials, and as biological tools.

β‐Cyclodextrin PAMAM Dendrimer Surface Doped with Silver and Hexacyanoferrate (III) and its Applications for Dopamine Detection in Synthetic Samples

AbstractA synthesis of β‐cyclodextrin (β‐Cd) functionalized with polyamide dendrimer PAMAM G.0 complexed with silver and potassium hexacyanoferrate (III) forming a mixed‐valence complex (β‐Cd‐PAMAM‐Ag/Fe) was proposed. This material was characterized by scanning electron microscopy (SEM), infrared spectroscopy (FT‐IR), X‐Ray diffraction (XRD), Energy Dispersion Spectroscopy (EDS) and Electron Paramagnetic Resonance (EPR). The hybrid complex was electrochemically investigated using cyclic voltammetry and some parameters (electrolyte, concentration of electrolyte, pH and scan rate) were evaluate in order to obtain optimum analytical responses. The β‐Cd‐PAMAM‐Ag/Fe material was successfully applied in the electrocatalytic oxidation of dopamine (DOP) using Cyclic Voltammetry (CV) and Square Wave Voltammetry (SWV).

DENDRIMERS: A REVIEW ON ITS SNYTHESIS, TYPES, PROPERTIES AND APPLICATIONS

Dendrimers are monodisperse macromolecules with a lot of branches. Dendrimers' structural advantages enable them to play a key role in the field of nano-drug delivery. Dendrimers are ideal for a wide range of biological and industrial applications due to their unique behaviour. The bioactive substances may be readily encapsulated into the inside of the dendrimers or chemically conjugated or physically adsorbed onto the dendrimer surface, tailoring the carrier's desirable features to the active material's unique demands and therapeutic uses. This review summarizes on dendrimer production, characterization, advantages, and potential applications in drug delivery.