G4 Dendrimer Research Articles

Tuning the Protonation Sensitivity of Weak Acidic Groups on a Zwitterionic Dendrimer for Selectively Targeting GD2-Overexpressed Tumor Cells in an Acidic Tumor Microenvironment.

Disialoganglioside (GD2) is one of the most popular overexpressed antigens for tumor cell targeting. However, GD2-specific antibodies often show unintended targeting to GD2-expressing health-maintaining cells due to the comparable binding affinities both at physiological pH and in a slightly acidic tumor microenvironment (TME). In this work, an affinity-switchable zwitterionic PAMAM G5 dendrimer (G5-3S) is developed for selective binding to GD2 only in a slightly acidic TME. It has 3 sulfonic groups, 128 carboxylic groups, and 125 amino groups on the surface. This affinity switch is realized by multiple hydrogen bond (H-bond) formation between protonated carboxylic groups surrounding a sulfonic group and overexpressed GD2 clusters on the tumor cell membrane in the slightly acidic TME, whereas there is no stable H-bond formation at physiological pH. Thus, G5-3S shows superior selectivity to GD2-overexpressed tumor cells over anti-GD2 antibodies by avoiding targeting GD2-expressing health-maintaining cells at physiological pH. This suggests that G5-3S is a promising candidate for GD2-overexpressed cancer treatment.

Mannosylated PAMAM G2 dendrimers mediated rate programmed delivery of efavirenz target HIV viral latency at reservoirs

In this current research, we conceptualized a novel nanotechnology-enabled synthesis approach of targeting HIV-harboring tissues via second-generation (G2) polyamidoamine (PAMAM) mannosylated (MPG2) dendrimers for programmed delivery of anti-HIV drugs efavirenz (EFV) and ritonavir (RTV). Briefly, here mannose served purpose of ligand in this EFV and RTV-loaded PAMAM G2 dendrimers, synthesized by divergent techniques, denoted as MPG2ER. The developed nanocarriers were characterized by different analytical tools FTIR, NMR, zeta potential, particle size, and surface morphology. The results of confocal microscopy showed substantial alterations in the morphology of H9 cells, favored by relatively higher drug uptake through the MPG2ER. Interestingly, the drug uptake study and cytotoxicity assay of MPG2ER demonstrated that it showed no significant toxicity up to 12.5 µM. A typical flow cytometry histogram also revealed that MPG2ER efficiently internalized both drugs, with an increase in drug uptake of up to 81.2 %. It also enhanced the plasma pharmacokinetics of EFV, with Cmax7.68 μg/ml, AUC of 149.19 (μg/ml) * hr, and MRT of 26.87 hrs. Subsequently, tissue pharmacokinetics further evidence that MPG2ER accumulated more in distant Human immunodeficiency virus (HIV) reservoir tissues, such as the lymph nodes and spleen, but without exhibiting significant toxicity. Abovementioned compelling evidences strongly favored translational roles of MPG2 as a potential therapeutic strategy in the clinical eradication of HIV from viral reservoir tissue.

Unilateral Administration of Surface-Modified G1 and G4 PAMAM Dendrimers in Healthy Mice to Assess Dendrimer Migration in the Brain.

Polyamidoamine (PAMAM) dendrimers are nanoparticles that have a wide scope in the field of biomedicine. Previous evidence shows that the generation 4 (G4) dendrimers with a 100% amine surface (G4-NH2) are highly toxic to cells in vitro and in vivo due to their positively charged amine groups. To reduce the toxicity, we modified the surface of the dendrimers to have more neutral functional groups, with 10% of the surface covered with -NH2 and 90% of the surface covered with hydroxyl groups (-OH; G4-90/10). Our previous in vitro data show that these modified dendrimers are taken up by cells, neurons, and different types of stem cells in vitro and neurons and glial cells in vivo. The toxicity assay shows that these modified dendrimers are less toxic compared with G4-NH2 dendrimers. Moreover, prolonged dendrimer exposure (G1-90/10 and G4-90/10), up to 3 weeks following unilateral intrastriatal injections into the striatum of mice, showed that dendrimers have the tendency to migrate within the brain via corpus callosum at different rates depending on their size. We also found that there is a difference in migration between the G1 and G4 dendrimers based on their size differences. The G4 dendrimers migrate in the anterior and posterior directions as well as more laterally from the site of injection in the striatum compared to the G1 dendrimers. Moreover, the G4 dendrimers have unique projections from the site of injection to the cortical areas.

Discovery of a Novel Dual Targeting Peptide for Human Glioma: From In Silico Simulation to Acting as Targeting Ligand.

Receptor-mediated transcytosis (RMT) is a more specific, highly efficient, and reliable approach to crossing the blood-brain-barrier (BBB) and releasing the therapeutic cargos into the brain parenchyma. Here, we introduced and characterized a human/mouse-specific novel leptin-derived peptide using in silico, in vitro and in vivo experiments. Based on the bioinformatics analysis and molecular dynamics (MD) simulation, a 14 amino acid peptide sequence (LDP 14) was introduced and its interaction with leptin-receptor (ObR) was analyzed in comparison with an well known leptin-derived peptide, Lep 30. MD simulation data revealed a significant stable interaction between ligand binding domains (LBD) of ObR with LDP 14. Analyses demonstrated suitable cellular uptake of LDP 14 alone and its derivatives (LDP 14-modified G4 PAMAM dendrimer and LDP 14-modified G4 PAMAM/pEGFP-N1 plasmid complexes) via ObR, energy and species dependent manner (preferred uptake by human/mouse cell lines compared to rat cell line). Importantly, our findings illustrated that the entry of LDP 14-modified dendrimers in hBCEC-D3 cells not only is not affected by protein corona (PC) formation, as the main reason for diminishing the cellular uptake, but also PC per se can enhance uptake rate. Finally, fluorescein labeled LDP 14-modified G4 PAMAM dendrimers efficiently accumulated in the mice brain with lower biodistribution in other organs, in our in vivo study. LDP 14 introduced as a novel and highly efficient ligand, which can be used for drugs/genes delivery to brain tissue in different central nervous system (CNS) disorders.

A Molecular Dynamics Simulation of Complexes of Fullerenes and Lysine-Based Peptide Dendrimers with and without Glycine Spacers.

The development of new nanocontainers for hydrophobic drugs is one of the most important tasks of drug delivery. Dendrimers with hydrophobic interiors and soluble terminal groups have already been used as drug carriers. However, the most convenient candidates for this purpose are peptide dendrimers since their interiors could be modified by hydrophobic amino acid residues with a greater affinity for the transported molecules. The goal of this work is to perform the first molecular dynamics study of the complex formation of fullerenes C60 and C70 with Lys-2Gly, Lys G2, and Lys G3 peptide dendrimers in water. We carried out such simulations for six different systems and demonstrated that both fullerenes penetrate all these dendrimers and form stable complexes with them. The density and hydrophobicity inside the complex are greater than in dendrimers without fullerene, especially for complexes with Lys-2Gly dendrimers. It makes the internal regions of complexes less accessible to water and counterions and increases electrostatic and zeta potential compared to single dendrimers. The results for complexes based on Lys G2 and Lys G3 dendrimers are similar but less pronounced. Thus, all considered peptide dendrimers and especially the Lys-2Gly dendrimer could be used as nanocontainers for the delivery of fullerenes.

Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers.

Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties of farnesyl monophosphate prodrug farnesyltransferase inhibitors (FTIs) on human NF1 malignant peripheral nerve sheath tumor (MPNST) cells are potentiated by co-treatment with lovastatin. Unfortunately, such prodrug FTIs have poor aqueous solubility. In this study, we synthesized a series of prodrug FTI polyamidoamine generation 4 (PAMAM G4) dendrimers that compete with farnesyl pyrophosphate for farnesyltransferase (Ftase) and assessed their effects on human NF1 MPNST S462TY cells. The prodrug 3-tert-butylfarnesyl monophosphate FTI-dendrimer (i.e., IG 2) exhibited improved aqueous solubility. Concentrations of IG 2 and lovastatin (as low as 0.1 μM) having little to no effect when used singularly synergistically suppressed cell proliferation, colony formation, and induced N-RAS, RAP1A, and RAB5A deprenylation when used in combination. Combinational treatment had no additive or synergistic effects on the proliferation/viability of immortalized normal rat Schwann cells, primary rat hepatocytes, or normal human mammary epithelial MCF10A cells. Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations.

Anti-quorum sensing activity of poly-amidoamine dendrimer generation 5 dendrimer loaded kinase inhibitor peptide against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a significant concern in both healthcare and community settings, as it causes numerous infections worldwide with high morbidity and mortality rates. One promising strategy is to target the quorum sensing (QS) system of MRSA using a dendrimer loaded with kinase inhibitor peptide. The present investigation has formulated a poly-amidoamine dendrimer (PAMAM) G5 dendrimer that is loaded with Quorum Quencher (QQ) peptide, which functions as a histidine kinase inhibitor. The particle average size of the formulated G5-QQ3 complex was determined to be 276 nm, and polydispersity index values of 0.33. The MIC50 for the formulated nanoparticles was 18 μM as demonstrated by a growth assay. Furthermore, the G5-QQ3 complex was able to inhibit the hemolysis activity of the MRSA with a concentration of 10 μM, and for Staphylococcus aureus was 3 μM. The G5-QQ3 complex possesses the ability to inhibit, penetrate, and eradicate biofilm in MRSA, Staphylococcus aureus, and different agr mutants with inhibition percentages ranging from 60 to 72%. Furthermore, live/dead viability assay confirmed the ability of the formulated nanoparticles to effectively kill all strains within the biofilm structure as evidenced by a confocal microscope, and the cytotoxicity of the G5-QQ3 complex was dose-dependent (p < 0.05). against RAW 264.7 cells. In general, the study confirmed that encapsulating QQ3 peptide within PAMAM G5 dendrimer results in a potent anti-virulence and anti-bacterial action and suggests a synergistic effect. The findings of this study have significant implications for the development of new treatments for MRSA infections, which are a major public health concern.

High-Throughput Screening of Surface Engineered Cyanine Nanodots for Active Transport of Therapeutic Antibodies into Solid Tumor.

The successful delivery of therapeutic biomacromolecules into solid tumorholds great challenge due to their high resistance to penetrate through the complex tumor microenvironments. Here, active-transporting nanoparticles are harnessed to efficiently deliver biomacromolecular drugs into solid tumors through cell transcytosis. A series of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids (G5-AA) is prepared. The capability of these positively charged nanodots to induce cell endocytosis, exocytosis, and transcytosis is evaluated via fluorescence-based high-throughput screen. The optimized nanodots (G5-R) are conjugated with αPD-L1 (a therapeutic monoclonal antibody binding to programmed-death ligand 1) (αPD-L1-G5-R) to demonstrate the nanoparticle-mediated tumor active transport. The αPD-L1-G5-R can greatly enhance the tumor-penetration capability through adsorption-mediated transcytosis (AMT). The effectiveness of αPD-L1-G5-R is tested in treating mice bearing partially resected CT26 tumors, mimicking the local immunotherapy of residual tumors post-surgery in clinic. The αPD-L1-G5-R embedded in fibrin gel can efficiently mediate tumor cell transcytosis, and deliver αPD-L1 throughout the tumor, thereby enhancing immune checkpoint blockade, reducing tumor recurrence, and significantly prolonging the survival time. The active-transporting nanodots are promising platforms for efficient tumor delivery of therapeutic biomacromolecules.

Fucoidan and dendrimer-based nanocapsule exhibiting effectiveness in methotrexate controlled delivery towards rheumatoid arthritis treatment

In recent years, nanomaterials have been intensively studied and applied in various fields, including pharmaceutical applications. This platform can act as a carrier for anticancer drugs or for insoluble bioactive compounds. To increase the stability and prolong the effect of anticancer drugs, we have incorporated a sulfated polysaccharide fucoidan (Fu) into PAMAM dendrimer G3.0 to form a G3.0-Fu complex. Then, a nano-sized encapsulated anticancer drug, methotrexate (MTX), was successfully embedded in the synthesised dendrimer complex namely G3.0-Fu/MTX. Newly synthesised G3.0-Fu/MTX was characterised by transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential measurement.Additionally, the loading efficiency of MTX was assessed via UV spectroscopy. Our findings revealed that upon combining with Fu, the G3.0 nanoparticle size increased from 4.3 ± 1.1 nm to 56 ± 6 nm. The changes in zeta potential aligned with drug entrapment efficiency and the results from TEM and DLS. The drug release activity of G3.0-Fu/MTX was increased compared to free MTX after 24 h. G3.0-Fu also showed high cytocompatibility in fibroblast cells. Taken together, the G3.0-Fu could be used to increase the encapsulation of several kinds of hydrophobic drugs and G3.0-Fu/MTX could be further studied in rheumatoid arthritis treatment.

Pyromellitic acid grafted to cross-linked LDH by dendritic units: An efficient and recyclable heterogeneous catalyst for green synthesis of 2,3-dihydro quinazoline and dihydropyrimidinones derivatives

In this work, using layered double hydroxide (LDH) inorganic substrate, melamine as binding agent and dendrimer G1 and also pyromellitic acid (PMA) organic catalytic agent a heterogeneous acid catalyst was designed and prepared. After that, the prepared organic-inorganic catalyst was evaluated by various identification techniques such as FTIR, EDX, XRD, TGA, FESEM, and BET, and the results showed that the desired structure was successfully prepared. Also, in order to investigate the efficiency of the LDH@Me-PMA nanocatalyst as an efficient and heterogeneous catalyst, it was used for green and one-pot synthesis of 2,3-dihydro quinazoline and 3,4-dihydropyrimidinone-2-(1H)-ones derivatives. The use of LDH@Me-PMA catalyst led to the synthesis of the desired derivatives with higher efficiency and shorter reaction time than previously reported works. In addition, the prepared LDH@Me-PMA acid catalyst has the ability to be recycled and reused for 5 consecutive periods and has high stability, which is well consistent with the principles of green chemistry.

Metallodendrimers Unveiled: Investigating the Formation and Features of Double-Decker Silsesquioxane-Based Silylferrocene Dendrimers.

Dendrimers exhibiting reversible redox properties have attracted extensive attention for their potential as electron transfer mediators, catalysts, and molecular sensors. In this study, we introduce intriguing G1 and G2 dendrimers featuring double-decker silsesquioxane cores and silylferrocene moieties. Through a carefully orchestrated sequence of condensation, reduction, and hydrosilylation reactions, these compounds were synthesized and comprehensively characterized spectroscopically and spectrometrically. Our investigation also encompassed the examination of their properties, including thermal stability, solubility in common organic solvents, and electrochemical behavior. We determined that these dendrimers possess the capability to form monolayers on platinum electrodes, which we conclusively demonstrated through the probing of cyclic voltammetry, electrochemical impedance spectroscopy, and scanning electron microscopy imaging. Notably, this study marks the first-ever example of modifying double-decker silsesquioxane cores with ferrocene groups while simultaneously representing one of the scarce instances of dendrimers exhibiting an open double-decker silsesquioxane core.

Synthesis and characterization of Fulvestrant and Paclitaxel conjugates with polyamidoamine dendrimer fourth generation

Introduction and aim. Poorly soluble anticancer drugs can be attached covalently into biologically inert macromolecule in order to administrate a drug as water soluble form. It was proven that covalent linkers, for instance amide or carbamate bonds are susceptible to hydrolysis. Thus the attached drug can be released from the conjugates in tissue, specifically within the targeted cell. We aimed at construction of water soluble conjugates of Fulvestrant and Paclitaxel with PAMAM G4 dendrimer. In order to obtain water soluble conjugates the amine groups were substituted with R-glycidol. Material and methods. Polyamidoamine dendrimer of fourth generation was synthesized and examined by detailed NMR analysis in water and in DMSO. The conjugates were covalently linked to amine groups of PAMAM after activation of Fulvestrant 17-OH group with 4-nitrophenylchloroformate and activation of end-carboxyl group of Paclitaxel succinate. Results. The method of binary conjugate PAMAMG4-Fulvestrant-Paclitaxel synthesis was elaborated and the product was characterized by physicochemical methods. Conclusion. The glycidylated PAMAMG4-Fulvestrant-Paclitaxel conjugate is better soluble in water than unconverted drugs.

Exploring the Potential of Lapatinib, Fulvestrant, and Paclitaxel Conjugated with Glycidylated PAMAM G4 Dendrimers for Cancer and Parasite Treatment.

Fulvestrant (F), lapatinib (L), and paclitaxel (P) are hydrophobic, anticancer drugs used in the treatment of estrogen receptor (ER) and epidermal growth factor receptor (EGFR)-positive breast cancer. In this study, glycidylated PAMAM G4 dendrimers, substituted with F, L, and/or P and targeting tumor cells, were synthesized and characterized, and their antitumor activity against glioma U-118 MG and non-small cell lung cancer A549 cells was tested comparatively with human non-tumorogenic keratinocytes (HaCaT). All cell lines were ER+ and EGFR+. In addition, the described drugs were tested in the context of antinematode therapy on C. elegans. The results show that the water-soluble conjugates of G4P, G4F, G4L, and G4PFL actively entered the tested cells via endocytosis due to the positive zeta potential (between 13.57-40.29 mV) and the nanoparticle diameter of 99-138 nm. The conjugates of G4P and G4PFL at nanomolar concentrations were the most active, and the least active conjugate was G4F. The tested conjugates inhibited the proliferation of HaCaT and A549 cells; in glioma cells, cytotoxicity was associated mainly with cell damage (mitochondria and membrane transport). The toxicity of the conjugates was proportional to the number of drug residues attached, with the exception of G4L; its action was two- and eight-fold stronger against glioma and keratinocytes, respectively, than the equivalent of lapatinib alone. Unfortunately, non-cancer HaCaT cells were the most sensitive to the tested constructs, which forced a change in the approach to the use of ER and EGFR receptors as a goal in cancer therapy. In vivo studies on C. elegans have shown that all compounds, most notably G4PFL, may be potentially useful in anthelmintic therapy.

Lysine-Dendrimer, a New Non-Aggressive Solution to Rebalance the Microbiota of Acne-Prone Skin.

Acne is a chronic inflammatory skin disease that affects the quality of life of patients. Several treatments exist for acne, but their effectiveness tends to decrease over time due to increasing resistance to treatment and associated side effects. To circumvent these issues, a new approach has emerged that involves combating the pathogen Cutibacterium acnes while maintaining the homeostasis of the skin microbiome. Recently, it was shown that the use of a G2 lysine dendrigraft (G2 dendrimer) could specifically decrease the C. acnes phylotype (IAI) involved in acne, compared to non-acne-causing C. acnes (phylotype II) bacteria. In the present study, we demonstrate that the efficacy of this technology is related to its 3D structure, which, in contrast to the linear form, significantly decreases the inflammation factor (IL-8) linked to acne. In addition, our in-vitro data confirm the specific activity of the G2 dendrimer: after treatment of bacterial cultures and biofilms, the G2 dendrimer affected neither non-acneic C. acnes nor commensal bacteria of the skin (Staphylococcus epidermidis, S. hominis, and Corynebacterium minutissimum). In parallel, comparative in-vitro and in-vivo studies with traditional over-the-counter molecules showed G2's effects on the survival of commensal bacteria and the reduction of acne outbreaks. Finally, metagenomic analysis of the cutaneous microbiota of volunteers who applied a finished cosmetic product containing the G2 dendrimer confirmed the ability of G2 to rebalance cutaneous acne microbiota dysbiosis while maintaining commensal bacteria. These results confirm the value of using this G2 dendrimer to gently prevent the appearance of acne vulgaris while respecting the cutaneous microbiota.

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.

Core-shell tecto dendrimer-mediated cooperative chemoimmunotherapy of breast cancer.

Development of effective nanomedicines to deal with tumor immunogenicity and immunosuppression is vital to improve the immunotherapy efficacy. Herein, we developed a programmed strategy not only to activate the tumoral immune microenvironment through immunogenic cell death (ICD) effect but also to promote the maturation of dendritic cells (DCs) in lymph nodes through two modules of core-shell tecto dendrimer (CSTD)-based nanomedicines. The CSTDs with amplified tumor enhanced permeability and retention effect and improved gene delivery efficiency were formed by supramolecular self-assembly of generation 5 (G5) poly(amidoamine) dendrimers as cores and G3 dendrimers as shells. One module was employed to load doxorubicin for cancer cell chemotherapy to generate ICD, while the other module with partial surface modification of zwitterions and mannose was used for serum-enhanced YTHDF1 siRNA delivery to DCs to stimulate their maturation. These two modular CSTD-based nanomedicine formulations enable enhanced chemoimmunotherapy of an orthotopic breast tumor model through programmed treatment of cancer cells and DCs, and synergistic modulation of the maturation of DCs to activate the CD8+/CD4+ T cells for tumor killing. The developed CSTD-enabled nanomodules with improved drug/gene delivery performance may be applicable to tackle other cancer types via collaborative chemoimmunotherapy.

Cu(II)/citric acid grafted to chitosan by dendritic units of melamine as a novel and highly efficient heterogeneous catalyst for the synthesis of 2-aminobenzothiazole derivatives

In this paper, a new cross-linked chitosan by G1 dendrimer from melamine terminated by citric acid groups to support Cu(II) nanoparticles (CS@CA-Me-CA@Cu) was designed and prepared. Subsequently, the prepared nanocomposite was characterized using different spectroscopic, microscopic and analytical techniques such as FTIR, XRD, FESEM, TGA and EDX. The supramolecular CS@CA-Me-CA@Cu demonstrates higher thermal and chemical stability than its components. In addition, in order to investigate the catalytic performance of the CS@CA-Me-CA@Cu bio-based nanocomposite it was used, as a Lewis acidic and green heterogeneous catalyst, for the preparation of 2-aminobenzothiazole derivatives under green conditions. Also, other advantages of this new bio-based nanocomposite include easy preparation, high catalytic activity, recyclability, and reuse with a gradual decreasing in its catalytic activity.

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.

Effect of PEGylation on drug uptake, biodistribution, and tissue toxicity of efavirenz–ritonavir loaded PAMAM G4 dendrimers

The present investigations aimed to compare the efficiency of PAMAM G4 (PG4) and PEGylated PAMAM G4 (PPG4) dendrimers as novel nanocarriers for the treatment of HIV-1. Synthesized PG4 and PPG4 dendrimers were confirmed by electrospray ionization and particle size with its morphology. The anti-human immunodeficiency virus (HIV) drug efavirenz (EFV) with a booster dose of ritonavir (RTV) was encapsulated into PG4 and PPG4 formerly noted as PG4ER and PPG4ER, respectively. Further, evaluated for dendrimers mediated solubilization, drug release, cytotoxicity, drug uptake, plasma, and tissue pharmacokinetics, and histopathology. PG4ER and PPG4ER both promoted a prolonged release of EFV in weakly acidic pH 4 up to 84 h and 132 h, respectively. The results of the cytotoxicity assay and drug uptake study showed that PPG4ER was safe and biocompatible up to 12.5 µg/ml. The plasma pharmacokinetic profile of EFV and RTV was significantly increased by PPG4ER with prolonged t 1/2 up to three times as compared to free EFV–RTV and PG4ER. Histopathological analysis showed remarkably lower tissue toxicity in PPG4ER as compared to free EFV–RTV. Therefore, overall data suggested that PPG4 has a great potential for prolonged release of EFV and RTV with enhanced bioavailability and lower toxicity.

Sulfamic acid grafted to cross-linked chitosan by dendritic units: a bio-based, highly efficient and heterogeneous organocatalyst for green synthesis of 2,3-dihydroquinazoline derivatives.

In this work, novel cross-linked chitosan by the G1 dendrimer from condensation of melamine and toluene-2,4-diisocyante terminated by sulfamic acid groups (CS-TDI-Me-TDI-NHSO3H), as a bio-based and heterogeneous acidic organocatalyst, was designed and prepared. Also, the structure of the prepared organocatalyst was characterized by Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD) and thermogravimetric analysis/derivative thermogravimetry (TGA/DTA). Subsequently, the catalytic performance of the biobased and dendritic CS-TDI-Me-TDI-NHSO3H, as a multifunctional solid acid, was evaluated for the preparation of 2,3-dihydroquinazoline derivatives through a three-component reaction by following green chemistry principles. Some of the advantages of this new protocol include high to excellent yields and short reaction times as well as easy preparation and remarkable catalyst stability of the introduced acidic organocatalyst. The CS-TDI-Me-TDI-SO3H catalyst can be used for up to five cycles for the preparation of quinazoline derivatives with a slight decrease in its catalytic activity.