PAMAM Dendrimers Research Articles

Dendrimer platform against prostate cancer: Recent update on new horizon of treatment

Prostate malignancy is regarded as one of the most lethal disorders in men. In the last two decades, new cases of prostate cancer have risen swiftly worldwide. Currently, the conventional strategies to treat prostate cancer are none other than chemotherapy, prostatectomy, and radiation therapy. However, these methods exist with their drawbacks, including the adverse effects and risks which could potentially outweigh the treatment efficacy. With that, the advancement of nanoparticles (NPs) as modern approaches for prostate cancer treatment is being extensively explored to eradicate the malignancy effectively. The notable nano-formulations that have presented significant development in prostate cancer treatment are abiraterone liposomes, lycopene loaded in polymeric nanoparticles, curcumin nano-emulsions, and so forth. These formulations have an important driving force to discover and advance the use of NPs in prostate cancer therapy. Currently, various research focuses on dendrimers as novel nanoparticles in prostate cancer. Dendrimers are globular macromolecules in the nanoscale that can be applied in the delivery of nano-formulations to overcome the limitations of conventional treatments. In this study, some of the significant dendrimers, including PAMAM dendrimers, magneto-dendrimers, self-assembling amphiphilic peptide dendrimers (AmPDDs), siRNA dendrimers, heterofunctional carbosilane metallodendrimers, gold nanoparticles (AuNPs)-(PAMAM) dendrimers as well as DNA dendrimers were analysed and discussed based on past research. The efficacies and mechanisms of each dendrimer are reviewed to understand their operations in the human body. Although the dendrimers vary from one to another in terms of bioavailability, functional groups, and other properties, all of them met the criteria as vehicles of anticancer agents and serve the main purpose of delivering the drugs to the desired target site for the potential cure of prostate cancer.

Manganese nanocarrier for matrix metalloproteinase 9 responsive delivery of irinotecan for colon cancer treatment

Enzyme responsive nanocarriers are reactive or sensitive towards a specific enzyme and, therefore, have the advantages of low systemic toxicity, targeted delivery, and superior therapeutic effect with high efficiency. In this study, we have developed a matrix metalloproteinase 9 (MMP9) enzyme responsive manganese nanocarrier for the site-specific delivery of anticancer drugs. Manganese nanoparticles were coated with G5 PAMAM dendrimers and loaded with irinotecan hydrochloride (IRI). The drug loaded nanoparticles were further coated with collagen-IV (Col-IV) peptide, an MMP9 substrate, to make them MMP9 responsive (Col-IV@IRI-G5MNP). The developed nanoparticles were monodispersed with size of about 12 nm and high IRI encapsulation efficiency (80%). A faster but controlled IRI release was observed from Col-IV@IRI-G5MNP in HEPES buffer containing MMP9 enzyme. When incubated with human red blood cells, the nanoformulation was hemocompatible and caused <2% hemolysis. The anticancer activity of Col-IV@IRI-G5MNP against HCT116 human colon cancer cells was better than free IRI. The cell viability of HCT116 cells incubated with 25 µg/mL Col-IV@IRI-G5MNP was significantly lower (p < 0.001) than the cells incubated with free IRI. Further, Col-IV@IRI-G5MNP showed paramagnetic nature and good T2 relaxivity at a very low concentration, suggesting its potential use for diagnosis through magnetic resonance imaging.

Physiochemical Properties of Benzophenone and Curcumin-conjugated PAMAM Dendrimers Using Topological Indices

Curcumin longa (Turmeric) contains an extremely strong phytochemical called curcumin, which has various medicinal and industrial benefits, including anti-inflammatory and anti-cancer effects, textile dyeing, and food and beverage colorants. However, due to its poor bioavailability and low aqueous solubility, it is unstable. These physiochemical properties limit curcumin’s clinical application. In order to solve this problem, scientists recently made new PAMAM dendrimers of the zero, first, and second generations conjugated with curcumin and benzophenone, which is a water-soluble secondary metabolite. Here, we use topological indices to examine these novel PAMAM dendrimers. Adriatic indices, which are a subclass of topological indices, can be used to measure how the arrangement of atoms in a chemical structure affects its most important physical properties. In this study, the parameters of the aforementioned dendrimer, including its density, retention duration, enthalpy, and lipophilicity, are calculated and analyzed based on 16 distinct adriatic indices. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for the treatment of human diseases.

Aptamer-grafted, cell membrane-coated dendrimer loaded with doxorubicin as a targeted nanosystem against epithelial cellular adhesion molecule (EpCAM) for triple negative breast cancer therapy

The major issue associated with chemotherapeutics is the non-specific distribution, extended range of toxicity, and low intratumoral accumulation. Targeted therapy using aptamers could be a ground-breaking approach in cancer treatment. Poly(amidoamine) PAMAM dendrimers are a type of nanocarriers with a well-defined structure, higher encapsulation efficiency and modification surface groups. However, the toxicity of cationic dendrimers and non-targetability poses a great risk to patients' health. Considering this, we developed a EpCAM aptamer-functionalized, red blood cell (RBC) membrane-camouflaged PAMAM dendrimer loaded with doxorubicin to selectively target EpCAM-positive triple-negative breast cancer (TNBC) cells. An increase in size of doxorubicin (Dox) loaded PAMAM was observed from 11.34 nm to 108.4 nm post coating with RBC membrane and aptamer, respectively. The biocompatibility and blood circulation time were enhanced by the coating of the RBC membrane on the surface of the dendrimers while functionalization with aptamers improved its cancer cell internalization. The results obtained suggested that the coating with RBC provided controlled and sustained release during the 140 h of study. In vitro cell viability study showed enhanced apoptosis and significantly elevated uptake by the cancer cells as compared with the non-targeted preparation. Furthermore, the volume of the tumor was significantly reduced in groups treated with aptamer-modified, cell membrane-coated dendrimer due to selective internalization in the cancer cells only. This novel, personalized, and targeted therapy could be a potent platform for TNBC therapy.

Multicolor flow cytometry-based immunophenotyping for preclinical characterization of nanotechnology-based formulations: an insight into structure activity relationship and nanoparticle biocompatibility profiles.

Immunophenotyping, which is the identification of immune cell subsets based on antigen expression, is an integral technique used to determine changes of cell composition and activation in various disease states or as a response to different stimuli. As nanoparticles are increasingly utilized for diagnostic and therapeutic applications, it is important to develop methodology that allows for the evaluation of their immunological impact. Therefore, the development of techniques such as immunophenotyping are desirable. Currently, the most common technique used to perform immunophenotyping is multicolor flow cytometry. We developed two distinct multicolor flow cytometry immunophenotyping panels which allow for the evaluation of the effects of nanoparticles on the composition and activation status of treated human peripheral blood mononuclear cells. These two panels assess the presence of various lymphoid and myeloid-derived cell populations as well as aspects of their activation statuses-including proliferation, adhesion, co-stimulation/presentation, and early activation-after treatment with controls or nanoparticles. To conduct assay performance qualification and determine the applicability of this method to preclinical characterization of nanoparticles, we used clinical-grade nanoformulations (AmBisome, Doxil and Feraheme) and research-grade PAMAM dendrimers of different sizes (G3, G4 and G5) and surface functionalities (amine-, carboxy- and hydroxy-). We found that formulations possessing intrinsic fluorescent properties (e.g., Doxil and AmBisome) interfere with accurate immunophenotyping; such interference may be partially overcome by dilution. In the absence of interference (e.g., in the case of dendrimers), nanoparticle size and surface functionalities determine their effects on the cells with large amine-terminated dendrimers being the most reactive.

Novel fluorescein isothiocyanate (FITC) cored PAMAM dendrimers as drug delivery agent

Fluorescent dyes, or fluorophores, enable researchers to visualize specific biological molecules by fluorescence microscopy. Herein, a novel fluorescent FITC-poly(amidoamine) (FITC-PAMAM) dendrimers have been synthesized via divergent approach. The molecular structure of the FITC-PAMAM dendrimers (G-0 to G5) was characterized by 1H NMR, 13C NMR spectroscopy and by FTIR. In order to emphasize the structural efficacy of FITC-PAMAM dendrimer, the drug delivery behavior has been evaluated by using 5-fluorouracil (5-FU) as a model cancer therapy drug. Anti-proliferative activity of FITC-cored PAMAM dendrimers in all generations (G0-G5) with or without 5-FU were analyzed on human gastric carcinoma cells (AGS) by WST-1 cell proliferation assay. Initially, the nontoxic dose of unloaded FITC-PAMAM dendrimers was assessed for further drug loading experiments. Loading of 5-FU into FITC-PAMAM dendrimers, regardless of generation, increased the toxicity of the drug. Besides, 5-FU loaded FITC-PAMAM dendrimers induced a generation-based gradual inhibition of cell proliferation. FITC and phase contrast merged images indicated that FITC-PAMAM dendrimers facilitate the entry of the drug into the cells, in a generation-dependent manner. The FITC- dendrimers may serve as a promising intracellular drug delivery agent for 5-FU by increasing cell uptake into cells and thereby, enhancing antiproliferative activity on AGS cells in a generation-dependent manner.

Methotrexate and sulforaphane loaded PBA-G5-PAMAM dendrimers as a combination therapy for anti-inflammatory response in an intra-articular joint arthritic animal model

L-sulforaphane (LSF), a natural product developed from cruciferous vegetables, have shown potent anti-inflammatory effect in cancer as well as arthritis. However, the stable delivery of LSF remains a major challenge. Methotrexate (MTX) is currently the first line treatment for managing RA and is most effective in patients when used in combination with other anti-inflammatory or anti-rheumatic drugs. Here we developed phenylboronic acid-PAMAM dendrimer (PBA-G5D) nanoparticles conjugated MTX (MTX-PBA-G5D), and L-sulforaphane (LSF/PBA-G5D) loaded dendrimers. The MTX and LSF drug loading and release kinetics was analyzed using HPLC. The lipopolysaccharide (LPS) stimulated macrophages were treated with the formulations to study the inflammatory response in vitro. For in vivo studies, arthritis was induced in five-week-old female Wistar rats, and the MTX- and LSF/PBA-G5-D were injected via intra-articular injection for treatment and the arthritis reduction was scored by weight, knee diameter, and serum cytokine level measurement. The average size of the drug-nanoparticle conjugates ranged from 135 to 250 nm, with mostly cationic surface charges. The encapsulation efficiency of the drugs to the modified dendrimer was more than 60% with a slow release of drugs from the nanoparticles within 24 h at pH 7.4. Drugs in the nanoparticle formulation were biocompatible, with promising anti-inflammatory effects in vitro against LPS-activated murine macrophages. Further in vivo studies on arthritis induced female Wistar rats, revealed significant anti-arthritic effects based on the arthritic scoring from the knee diameter reading, and anti-inflammatory effects based on the serum cytokine levels. This study provides a promising strategy for utilizing PAMAM dendrimers as a nanocarrier for LSF delivery for RA therapy.

Angiopep-2 Grafted PAMAM Dendrimers for the Targeted Delivery of Temozolomide: In Vitro and In Vivo Effects of PEGylation in the Management of Glioblastoma Multiforme.

The present study was aimed to synthesize, characterize, and evaluate the angiopep-2 grafted PAMAM dendrimers (Den, G 3.0 NH2) with and without PEGylation for the targeted and better delivery approach of temozolomide (TMZ) for the management of glioblastoma multiforme (GBM). Den-ANG and Den-PEG2-ANG conjugates were synthesized and characterized by 1H NMR spectroscopy. The PEGylated (TMZ@Den-PEG2-ANG) and non-PEGylated (TMZ@Den-ANG) drug loaded formulations were prepared and characterized for particle size, zeta potential, entrapment efficiency, and drug loading. An in vitro release study at physiological (pH 7.4) and acidic pH (pH 5.0) was performed. Preliminary toxicity studies were performed through hemolytic assay in human RBCs. MTT assay, cell uptake, and cell cycle analysis were performed to evaluate the in vitro efficacy against GBM cell lines (U87MG). Finally, the formulations were evaluated in vivo in a Sprague-Dawley rat model for pharmacokinetics and organ distribution analysis. The 1H NMR spectra confirmed the conjugation of angiopep-2 to both PAMAM and PEGylated PAMAM dendrimers, as the characteristic chemical shifts were observed in the range of 2.1 to 3.9 ppm. AFM results revealed that the surface of Den-ANG and Den-PEG2-ANG conjugates were rough. The particle size and zeta potential of TMZ@Den-ANG were observed to be 229.0 ± 17.8 nm and 9.06 ± 0.4 mV, respectively, whereas the same for TMZ@Den-PEG2-ANG were found to be 249.6 ± 12.9 nm and 10.9 ± 0.6 mV, respectively. The entrapment efficiency of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were calculated to be 63.27 ± 5.1% and 71.48 ± 4.3%, respectively. Moreover, TMZ@Den-PEG2-ANG showed a better drug release profile with a controlled and sustained pattern at PBS pH 5.0 than at pH 7.4. The ex vivo hemolytic study revealed that TMZ@Den-PEG2-ANG was biocompatible in nature as it showed 2.78 ± 0.1% hemolysis compared to 4.12 ± 0.2% hemolysis displayed by TMZ@Den-ANG. The outcomes of the MTT assay inferred that TMZ@Den-PEG2-ANG possessed maximum cytotoxic effects against U87MG cells with IC50 values of 106.62 ± 11.43 μM (24 h) and 85.90 ± 9.12 μM (48 h). In the case of TMZ@Den-PEG2-ANG, the IC50 values were reduced by 2.23-fold (24 h) and 1.36-fold (48 h) in comparison to pure TMZ. The cytotoxicity findings were further confirmed by significantly higher cellular uptake of TMZ@Den-PEG2-ANG. Cell cycle analysis of the formulations suggested that the PEGylated formulation halts the cell cycle at G2/M phase with S-phase inhibition. In the in vivo studies, the half-life (t1/2) values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were enhanced by 2.22 and 2.76 times, respectively, than the pure TMZ. After 4 h of administration, the brain uptake values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were found to be 2.55 and 3.35 times, respectively, higher than that of pure TMZ. The outcomes of various in vitro and ex vivo experiments promoted the use of PEGylated nanocarriers for the management of GBM. Angiopep-2 grafted PEGylated PAMAM dendrimers can be potential and promising drug carriers for the targeted delivery of antiglioma drugs directly to the brain.

Dyeability of Surface-Modified Cotton and Silk Fabrics with PAMAM Dendrimer Using Sargassum sp. Seaweed Extract

In this study, a PAMAM dendrimer was used as a surface-modifier to study the dyeability of cotton and silk fabrics using a sustainable dye generated from Sargassum sp. seaweed extracts. PAMAM dendrimer is a polymeric molecule characterized with multiple branched monomers containing numerous functional primary amino groups on the surface. These amine groups would readily act as a functional group similar to the structure of the natural protein fibers which is capable to improve the dyeability of textile fibers, especially with natural dyes. The crushed powder of dry Sargassum sp. was macerated for 48 h at 60 ℃ in methanol. The cotton and silk materials were pre-treated with a PAMAM dendrimer at concentrations that were determined in advance before the dyeing process began. The electrokinetic capabilities of these surface-modified fabrics were next investigated by measuring their zeta potential with a SurPASS Electrokinetic Analyzer. Exhaust dyeing and simultaneous mordanting with vinegar, alum and iron were done on both untreated and treated cotton and silk fabrics with a certain amount of PAMAM dendrimer. The dyeing process was carried out at 85 ℃ for intervals of 40, 60 and 80 min. It was discovered that surface-modified cotton and silk materials had a lower negative charge zeta potential, which enhanced their dyeability as well as the percent exhaustion and K/S values of the dyed fabrics. As a result of the surface modification, the zeta potential of the cotton fabric went from −20.40 to −14.63 mV. Similarly, the zeta potential of the surface-modified silk fabric, on the other hand, went from −36.80 to −26.85 mV. However, the percent exhaustion of surface-modified cotton and silk fabrics was increased to 21.17 and 39.99, respectively. Likewise, the K/S ratio of the surface-modified cotton fabric was raised from 0.06 to 0.20. Although the K/S value of the surface-modified silk fabric increased from 0.15 to 0.24. Additionally, the fastness properties of the dyed fabrics were graded as good to exceptional (between 4 and 5), except for lightfastness, which was classified as poor (rated between 3 to 5). Consequently, the sustainable dye from Sargassum sp. seaweed was successfully applied to cotton and silk fabrics. GRAPHICAL ABSTRACT

Macromolecular Conformation of Low-Generation PAMAM Dendrimers Probed by Pyrene Excimer Formation

A series of pyrene-labeled PAMAM dendrimers (PyCX-PAMAM-GY, where X (=4, 8, or 12) and Y (=0, 1, or 2) represent the number of atoms in the pyrenyl linker and the dendrimer generation, respectively) were studied by acquiring their time-resolved fluorescence decays in N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The fluorescence decays were fitted globally according to the model-free analysis (MFA), which yielded the average rate constant ⟨k⟩ for pyrene excimer formation (PEF). ⟨k⟩ was compared with the local pyrene concentration [Py]loc inside the dendrimers, which was calculated by assuming that the segments constituting the dendrimer interior obey Gaussian statistics. ⟨k⟩ was found to increase linearly with [Py]loc in both solvents, but the straight lines had different slopes due to differences in solvent viscosity and polarity. These differences were accounted for by dividing ⟨k⟩ by kdiff, which is the bimolecular rate constant for PEF generated by n-hexyl-1-pyrenebutyramide used as a model compound. The ⟨k⟩/kdiff ratios obtained for all the PyCX-PAMAM-GY samples in DMF and DMSO collapsed onto a single master line where ⟨k⟩/kdiff increased linearly with [Py]loc. The strong correlation found between ⟨k⟩ and [Py]loc suggested that the oligomeric segments constituting the interior of the low-generation (Y = 0, 1, and 2) PAMAM dendrimers obeyed Gaussian statistics. This fact was further supported by using the Gaussian approximation to calculate the radius of gyration (Rg) of PAMAM dendrimers and compare them to the Rg values obtained by molecular dynamics simulations. The excellent agreement obtained between the two sets of Rg values validated the assumption. Furthermore, the direct relationship between ⟨k⟩ and [Py]loc established in this study demonstrates that ⟨k⟩ provides a quantitative measure of the internal density of the dendrimers, an observation with considerable implications for the quantitative conformational characterization of macromolecules with a complex architecture in solution.

Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes-A More Selective Anticancer Treatment?

Based on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH2 moieties of PAMAM dendrimers of generation 2 (G2) and 4 (G4) via amide bonds. Conjugates were characterized by 1H and 195Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC50 values in the low micromolar to high picomolar range. The synergistic combination of PAMAM dendrimers and platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded platinum(IV) units compared to their platinum(IV) counterparts. The lowest IC50 value of 780 ± 260 pM in the CH1/PA-1 cancer cell line was detected for an oxaliplatin-based G4 PAMAM dendrimer conjugate. Finally, in vivo experiments of a cisplatin-based G4 PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum tumor growth inhibition effect of 65.6% compared to 47.6% for cisplatin was observed as well as a trend of prolonged animal survival.

Interaction between dirhodium(II) tetraacetate and PAMAM dendrimer grafted onto magnetite nanoparticles: Effects on magnetic properties

In this study, we report on fabrication and characterization of a novel magnetic nanocarrier based on association of magnetite nanoparticles (NPs) with poly(amidoamine) (PAMAM) dendrimers loading dirhodium(II) tetraacetate complex (DiRh(II)). The pristine magnetite NP was coated with ATPS (3-aminopropyltriethoxysilane). The interaction between PAMAM dendrimer and DiRh(II) and its effects on magnetic properties were investigated. The magnetite spinel phase is confirmed via x-ray diffraction (XRD) and Raman spectroscopy data analysis. A mean crystallite size of 9.5 ± 0.3 nm of magnetite particles is assessed from XRD data, which is close to the values obtained via dynamic light scattering (DLS) and transmission electron microscopy micrographs. Our findings strongly suggest that the Rh(II) ions interact with lone electron pairs of nitrogen atoms in amide-II and primary amines of PAMAM surface-terminated moieties. The onset of an absorption peak at 283 nm in DiRh(II) containing sample, assigned to σRh-L→σ∗Rh-Rh electronic transition, revealed a direct interaction between Rh(II) ions and L moieties of PAMAM dendrimer. Magnetization results indicate that the presence of DiRh(II) attached to PAMAM dendrimer leads to the strong weakening of magnetic dipole–dipole interactions in ATPS- and ATPS + PAMAM coated magnetite nanoparticles.

NIR Laser Irradiation-Controlled Docetaxel Release from Nanodiamond Decorated with Temperature Stimuli Responsive Polymer Containing PAMAM Dendrimer

NIR Laser Irradiation-Controlled Docetaxel Release from Nanodiamond Decorated with Temperature Stimuli Responsive Polymer Containing PAMAM Dendrimer

Poly(amidoamine) Dendrimer as an Interfacial Dipole Modification in Crystalline Silicon Solar Cells.

Poly(amidoamine) (PAMAM) dendrimers are used to modify the interface of metal-semiconductor junctions. The large number of protonated amines contributes to the formation of a dipole layer, which finally serves to form electron-selective contacts in silicon heterojunction solar cells. By modification of the work function of the contacts, the addition of the PAMAM dendrimer interlayer quenches Fermi level pinning, thus creating an ohmic contact between the metal and the semiconductor. This is supported by the observation of a low contact resistivity of 4.5 mΩ cm2, the shift in work function, and the n-type behavior of PAMAM dendrimer films on the surface of crystalline silicon. A silicon heterojunction solar cell containing the PAMAM dendrimer interlayer is presented, which achieved a power conversion efficiency of 14.5%, an increase of 8.3% over the reference device without the dipole interlayer.

Polyamidoamine dendrimer decorated graphene oxide as a pH-sensitive nanocarrier for the delivery of hydrophobic anticancer drug quercetin: a remedy for breast cancer.

The aim of this study was to investigate the potential of poly(amido amine) (PAMAM) dendrimer decorated graphene oxide (GO) based nanocarrier for targeted delivery of a hydrophobic anticancer drug, quercetin (QSR). GO-PAMAM was successfully synthesized by covalent bonding between GO and NH2-terminated PAMAM dendrimer (zero generation). To investigate drug loading performance, QSR was loaded on the surface of GO as well as GO-PAMAM. Further, the release behaviour of QSR-loaded GO-PAMAM was studied. Finally, an in-vitro sulforhodamine B assay was performed in HEK 293T epithelial cells and MDA MB 231 breast cancer cells. It was observed that GO-PAMAM shows higher QSR loading capacity compared to GO. Also, synthesized nanocarrier exhibits controlled as well as pH-responsive release of QSR and the amount of QSR released at pH 4 was approximately two times higher than the release at pH 7.4. Furthermore, GO-PAMAM was found to be biocompatible for HEK 293T cells, and a high cytotoxic effect was observed for QSR-loaded GO-PAMAM on MDA MB 231 cells. The present investigation highlights the potential application of synthesized hybrid materials as a nanocarrier with excellent loading and controlled releasing efficiency for the delivery of the hydrophobic anticancer drug.

Efficient Removal of Uranyl Ions Using PAMAM Dendrimer: Simulation and Experiment

In this work, using atomistic molecular dynamics (MD) simulations and polymer-assisted ultrafiltration experiments, we explore the adsorption and removal of uranyl ions from aqueous solutions using poly(amidoamine) (PAMAM) dendrimers. The effects of uranyl ion concentration and the pH of the solution were examined for PAMAM dendrimers of generations 3, 4, and 5. Our simulation results show that PAMAM has a high adsorption capacity for the uranyl ions. The adsorption capacity increases with increasing concentration of uranyl ions for all 3 generations of PAMAM in agreement with experimental findings. We find that the number of uranyl ions bound to PAMAM is significantly higher in acidic solutions (pH < 3) as compared to neutral solutions (pH ∼ 7) for all uranyl ion concentrations. Additionally, we find an increase in the number of adsorbed uranyl ions to PAMAM with the increase in the dendrimer generation. This increase is due to the greater number of binding sites present for higher-generation PAMAM dendrimers. Our simulation study shows that nitrate ions form a solvation shell around uranyl ions, which allows them to bind to PAMAM binding sites, including the amide, amine, and carbonyl groups. In polymer-assisted ultrafiltration (PAUF) experiments, the removal percentage of uranyl ions by G3 PAMAM dendrimer increased from 36.3% to 42.6% as the metal ion concentration increased from 2.1 × 10-5 M to 10.5 × 10-5 M at a pH of 2. Our combined experiment and simulation study suggests that PAMAM is an effective adsorbent for removing uranyl ions from aqueous solutions.

A UiO-66-NH2 MOF/PAMAM Dendrimer Nanocomposite for Electrochemical Detection of Tramadol in the Presence of Acetaminophen in Pharmaceutical Formulations

In this work, we prepared a novel electrochemical sensor for the detection of tramadol based on a UiO-66-NH2 metal-organic framework (UiO-66-NH2 MOF)/third-generation poly(amidoamine) dendrimer (G3-PAMAM dendrimer) nanocomposite drop-cast onto a glassy carbon electrode (GCE) surface. After the synthesis of the nanocomposite, the functionalization of the UiO-66-NH2 MOF by G3-PAMAM was confirmed by various techniques including X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), field emission-scanning electron microscopy (FE-SEM), and Fourier transform infrared (FT-IR) spectroscopy. The UiO-66-NH2 MOF/PAMAM-modified GCE exhibited commendable electrocatalytic performance toward the tramadol oxidation owing to the integration of the UiO-66-NH2 MOF with the PAMAM dendrimer. According to differential pulse voltammetry (DPV), it was possible to detect tramadol under optimized circumstances in a broad concentration range (0.5 μM-500.0 μM) and a narrow limit of detection (0.2 μM). In addition, the stability, repeatability, and reproducibility of the presented UiO-66-NH2 MOF/PAMAM/GCE sensor were also studied. The sensor also possessed an acceptable catalytic behavior for the tramadol determination in the co-existence of acetaminophen, with the separated oxidation potential of ΔE = 410 mV. Finally, the UiO-66-NH2 MOF/PAMAM-modified GCE exhibited satisfactory practical ability in pharmaceutical formulations (tramadol tablets and acetaminophen tablets).

Phenylboronic acid conjugated PAMAM G4 dendrimers augmented usnic acid delivery to gastric cancer cells

Here we report on the synthesis, characterization, and biological evaluation of Siglec’s targeted G4 PAMAM dendrimers loaded with usnic acid (UA). Siglec's targeted G4 dendrimers were obtained by conjugation of 4-carboxy phenylboronic acid (PBA) to the periphery of the G4 PAMAM dendrimer (PBA-PAMAM). UA-loaded PBA-PAMAM dendrimers (UA@PBA-PAMAM) showed average particle size (18 nm) without any sign of aggregation with amorphous nature, stability of the drug, and PBA-mediated anticancer efficacy. The UA@PBA-PAMAM dendrimer formulation showed a site-specific drug release profile. After 12 h, 17.6% and 95.7% of UA was released from UA@PBA-PAMAM dendrimer formulation in pH 7.4 and pH 5.0, respectively. In vitro anticancer results suggested the no cytotoxicity of G4 dendrimers after PBA conjugation. The cell viability of AGS cells was observed as 88.9 ± 0.7% (12 h) and 50.4 ± 1.9% (24 h) after pure UA treatment and 37.3 ± 0.6% (12 h) and 14.4% ± 1.2 (24 h) after treatment with UA@PBA-PAMAM. The pure UA had IC50 values of 44.9 ± 3.1 μg/mL (for 12 h) and 8.2 ± 1.1 μg/mL (for 24 h) while UA@PBA-PAMAM had an IC50 value of 8.4 ± 0.3 μg/mL (for 12 h) and 2.7 ± 0.4 μg/mL (for 24 h) in AGS cells. As a result of cytotoxicity studies, the dendrimer formulation UA@PBA-PAMAM maintained its effectiveness and was able to produce a long-term anticancer effect over time compared to the pure UA dose. The PBA-PAMAM dendrimer also significantly enhanced the cellular internalization in AGS gastric cancer cells. The new PBA-PAMAM design appears to be suitable nanocarriers for the UA to deliver gastric cancer cells.

Hybrid Nanoparticle System Integrating Tumor-Derived Exosomes and Poly(amidoamine) Dendrimers: Implications for an Effective Gene Delivery Platform

Nanoscale drug delivery systems for cancer treatment have demonstrated promising results in enhancing the selectivity of therapeutic agents while reducing their toxic side effects. However, several biological and physical barriers, such as the immunogenicity and undesirable biodistributions of such delivery systems, have hindered their fast translation. To address these issues, we have developed an exosome–dendrimer hybrid nanoparticle (NP) platform to combine the advantageous biological properties of natural exosomes and synthetic dendrimers into a single NP system. The novel hybrid NPs, consisting of exosomes derived from MCF7 cells and functionalized poly(amidoamine) (PAMAM) dendrimers, were prepared using sonication and characterized in terms of loading efficiency, size, cytotoxicity, and cellular interactions. Our results indicate that the loading of dendrimers into exosomes is dependent on dendrimer size and charge. The hybrid NPs inherited the size (∼150 nm), surface charge (−10 mV), and surface protein markers (CD81 and CD63) of exosomes. Importantly, the hybrid NPs enhanced the cellular internalization of amine-terminated PAMAM dendrimers (p < 0.05) while exhibiting substantially lower cytotoxicity than the free positively charged dendrimers (113.3 vs 35.6% of cell viability at 500 nM, p < 0.05). These advantageous properties of hybrid NPs were leveraged for use as a gene delivery vehicle, resulting in enhanced oligonucleotide delivery (over 2-fold) to cancer cells, compared to dendrimers alone. Furthermore, the hybrid NPs effectively delivered small interfering RNA (siRNA) as well, downregulating programmed death-ligand 1 (PD-L1) expression significantly more (3.8-fold) than dendrimers alone (p < 0.05). Our results demonstrate that the individual characteristics of both exosomes and dendrimers can be integrated to generate a multifaceted NP platform, proposing a novel NP design strategy.

Precise and systematic end group chemistry modifications on PAMAM and poly(l-lysine) dendrimers to improve cytosolic delivery of mRNA.

Here, we aimed to chemically modify PAMAM dendrimers using lysine as a site-selective anchor for successfully delivering mRNA while maintaining a low toxicity profile. PAMAM dendrimers were multi-functionalised by amidation reactions in a regioselective, quantitative and stepwise manner with carefully selected property-modifying surface groups. Alternatively, novel lysine-based dendrimers were prepared in the same manner with the aim to unlock their potential in gene delivery. The modified dendrimers were then formulated with Cy5-EGFP mRNA by bulk mixing via liquid handling robotics across different nitrogen to phosphate ratios. The resulting dendriplexes were characterised by size, charge, mRNA encapsulation, and mRNA binding affinity. Finally, their in-vitro delivery activity was systematically investigated across key cellular trafficking stages to relate chemical design to cellular effect. We demonstrate our findings in different cell lines and benchmarked relative to a commercially available transfection agent, jetPEI®. We demonstrate that specific surface modifications are required to generate small, reliable and well-encapsulated positively charged dendriplex complexes. Furthermore, we show that introduction of fusogenic groups is essential for driving endosomal escape and achieving cellular delivery and translation of mRNA in these cell lines.