G4 Dendrimer Research Articles

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.

Site-Specific Evaluation of Bioactive Coumarin-Loaded Dendrimer G4 Nanoparticles against Methicillin Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a foremost treatment challenge in today’s clinical practice. Natural coumarins contain a variety of bioactivities and have the ability to alter resistance in several ways. In developing effective drug delivery methods, the goal is to maximize biocompatibility while minimizing toxicity. With this in mind, this work investigated the site-specific potential of dendrimer G4 poloxamer nanoparticles loaded with bioactive coumarin. The goal of the current work is to deliver a complete evaluation of dendrimer G4 poloxamer nanoparticles against MRSA. Coumarin-loaded dendrimer G4 poloxamer nanoparticles were thoroughly investigated and characterized using various techniques, including particle size, shape, entrapment efficiency, in vitro drug release, hemolysis assay, cytotoxicity, antibacterial activity, and bactericidal kinetics. Studies showed that the newly developed dendrimer G4 poloxamer nanoparticles exhibited significantly lower levels of hemolysis and cytotoxicity. The results showed that the in vitro drug release of coumarin from dendrimer G4 poloxamer nanoparticles was slower compared to coumarin in its free form. This innovative therapeutic delivery technology may enhance the defense of coumarin against MRSA.

PEGylated G4 dendrimers as a promising nanocarrier for piperlongumine delivery: Synthesis, characterization, and anticancer activity

PAMAM dendrimers are well-known delivery vehicles for various therapeutic agents like synthetic drugs, natural phytoconstituents, and genetic materials. The tunable physicochemical properties and variety of surface interactions make them attractive nano delivery system. However, plain dendrimers particularly higher generation dendrimers are reported to cause dose-dependent toxicities. Therefore, in this study, PEGylated G4 PAMAM dendrimers were synthesized via a click chemistry approach and used for the delivery piperlongumine (PL) for the treatment of colon cancer. PL is an amide alkaloid and potential anticancer agent, but it has poor aqueous solubility. PL was loaded into the dendrimer cavity through both physical loading and electrostatic chemical interactions. The prepared PL-loaded PEGylated G4 PAMAM dendrimers (PL@PEGylated G4) possessed a nanoscale size about 20 nm, monodispersity with a PDI value of 0.098 ± 0.002 and high drug solubility 226 ± 9.4 μg/mL. The drug release profile of PL@PEGylated G4 indicated a sustained release of encapsulated PL. After 24 h, about 43.2 ± 4.2 % and 64.9 ± 4.5 % of PL was released in PBS and SAB, respectively. The PEGylated dendrimers showed good biocompatibility during hemolytic toxicity study. In cytotoxicity studies, PL@PEGylated G4 showed potential cytotoxicity (IC50 = 5.8 μg/mL, p < 0.05) and greater induction of apoptosis in HCT 116 human colon cancer cells in comparison to pure PL, as demonstrated by the MTT and AO/EB assay, respectively. Overall, this biocompatible PEGylated G4 dendrimer-based formulation of PL could be a potential nanomedicine for cancer therapy.

Lapatinib- and fulvestrant-PAMAM dendrimer conjugates promote apoptosis in chemotherapy-induced senescent breast cancer cells with different receptor status.

Lapatinib (L) and fulvestrant (F) are used in targeted anticancer therapies, in particular, against phenotypically different breast cancer cells. L, a dual inhibitor of EGFR and HER2 tyrosine kinases, is active against HER2-positive breast cancer cells, while F, a selective estrogen receptor degrader (SERD), is active against ER-positive breast cancer cells. However, the action of L and F can be limited due to their relatively low water solubility and bioavailability. In the present study, poly(amidoamine) (PAMAM) dendrimer G3 was functionalized with L or F or L and F to compare their effects with free L or F against breast cancer cells with different receptor status (ER-positive MCF-7, triple negative MDA-MB-231 and HER2-positive SK-BR-3 cells). L-PAMAM and F-PAMAM conjugates potentiated cytostatic and cytotoxic action of L and F that was accompanied by elevated levels of autophagy. TRDMT1, RNA methyltransferase, was also involved in this response as judged by TRDMT1 nuclear translocation and nano-drug resistance of TRDMT1 gene knockout cells. Nano-drugs also promoted elimination of doxorubicin-induced senescent breast cancer cells by apoptosis-mediated senolysis regardless of receptor status. In conclusion, we propose a novel anticancer approach based on L-PAMAM and F-PAMAM nanoplatforms being effective, at least, against breast cancer cells with different phenotypic features.

Fabrication of TPGS-Grafted Polyamidoamine Dendrimer for Enhanced Piperine Brain Delivery and Pharmacokinetics.

Piperine (PIP) is a neuroprotective phytomedicine that has profound acetylcholine esterase and reactive oxygen species inhibition effect in Alzheimer's disease (AD) model. However, the oral delivery of PIP is limited by poor aqueous solubility and low bioavailability in systemic circulation. To improve the PIP bioavailability, the polyamidoamine (PAMAM) G4 dendrimer is grafted with tocopheryl polyethylene glycol succinate-1000 (TPGS) through carbodiimide chemistry to form TPGS-PAMAM conjugate. The TPGS-PAMAM coupling was confirmed through proton NMR and FTIR techniques. PIP was encapsulated in the TPGS-PAMAM through solvent diffusion method to form PIP-TPGS-PAMAM. The particle size for PIP-TPGS-PAMAM found the less than 50nm, whereas entrapment efficiency found to 87 ± 3.5% and 10.6 ± 2.9% drug loading. The powder differential scanning calorimetry and powder X-ray diffraction characterization were employed to evaluate the amorphous encapsulation of the PIP in TPGS-PAMAM. The PIP-TPGS-PAMAM stability was studied in the gastric fluids which showed no drastic differencein particle size and encapsulation efficiency compared to PIP-PAMAM. The in vitro release analysis revealed 37 ± 4.1% PIP release from the PIP-TPGS-PAMAM matrix, and 71 ± 4.9% PIP release from the PIP-PAMAM dendrimer was observed in 48h. The single-dose oral gavage to Wistar rats of PIP-TPGS-PAMAM showed the AUC0-∞ 14.38µg/mL.h, Cmax 7.77 ± 1.65µg/mL, Tmax, 1.6 ± 0.18h, and half-life 3.47 ± 0.64h for PIP in systemic circulation. PIP-PAMAM and free PIP showed significantly poor AUC0-∞ compared to PIP-TPGS-PAMAM. The brain uptake studies revealed PIP-TPGS-PAMAM treated group showed 2.2 ± 0.37µg/g PIP content compared to free PIP administeredgroup which was 0.4 ± 0.10µg/g. Therefore, PIP-TPGS-PAMAM can offer excellent prospect for the delivery hydrophobic drugs to brain in AD.

Improvement in Bioavailability and Pharmacokinetic Characteristics of Efavirenz with Booster Dose of Ritonavir in PEGylated PAMAM G4 Dendrimers.

Efavirenz (EFV) with a booster dose of ritonavir (RTV) (EFV-RTV) inhibits the metabolism of EFV and improves its bioavailability. However, inadequate organ perfusion with surface permeability glycoprotein (P-gp) efflux sustains the viable HIV. Hence, the present investigations were aimed to evaluate the pharmacokinetics and tissue distribution efficiency of EFV by encapsulating it into PEGyalated PAMAM (polyamidoamine) G4 dendrimers with a booster dose of RTV (PPG4ER). The entrapment efficiency of PEGylated PAMAM G4 dendrimers was found to be 94% and 92.12% for EFV and RTV respectively with a zeta potential of 0.277mV. The pharmacokinetics and tissue distribution behavior of EFV within PPG4ER was determined by developing and validating a simple, sensitive, and reliable bioanalytical method of RP-HPLC. The developed bioanalytical method was very sensitive with a quantification limit of 18.5ng/ml and 139.2ng/ml for EFV and RTV, respectively. The comparative noncompartmental pharmacokinetic parameters of EFV were determined by administrating a single intraperitoneal dose of EFV, EFV-RTV, and PPG4ER to Wistar rats. The PPG4ER produced prolonged release of EFV with a mean residential time (MRT) of 24h with Cmax 7.68µg/ml in plasma against EFV-RTV with MRT 11h and Cmax 3.633µg/ml. The PPG4ER was also detected in viral reservoir tissues (lymph node and spleen) for 3-4days, whereas free EFV and EFV-RTV were cleared within 72h. The pharmacokinetic data including Cmax, t1/2, AUCtot, and MRT were significantly improved in PPG4ER as compared with single EFV and EFV-RTV. This reveals that the PPG4ER has great potential to target the virus harbors tissues and improve bioavailability.

Electrostatic interactions between cationic dendrimers and anionic model biomembrane

The electrostatic interactions between cationic poly(amidoamine) (PAMAM) dendrimers of different generations, G3, G4, and G6, with net anionic model biomembranes have been predicted by adopting an analytical model based on two dissimilar soft spheres. The influence of bilayer surface charge density, ionic strength, pH, temperature, membrane softness (modeled as changes in bilayer thickness), and dendrimer generation on the attractive interaction was investigated. The attraction was found to decrease with increasing salt concentration, dendrimer charge, and thickness (or softness) of the membrane. On the other hand, the attraction increased with the surface charge density of the membrane, and the size of dendrimer generation. In fact, the attraction was found to be much larger for large generations, like G6 dendrimer that have a higher charge, than it is with small ones like G3 and G4 dendrimers. These results have implications for the use of PAMAM dendrimers as potential gene transfection vectors.

Margetuximab conjugated-PEG-PAMAM G4 nano-complex: a smart nano-device for suppression of breast cancer.

Breast cancer due to its high incidence and mortality is the second leading cause of death among females. On the other hand, nanoparticle-based drug delivery is one of the most promising approaches in cancer therapy, nowadays. Hence, margetuximab- and polyethylene glycol-conjugated PAMAM G4 dendrimers were efficiently synthesized for targeted delivery of quercetin (therapeutic agent) to MDA-MB-231 breast cancer cells. Synthesized nano-complexes were characterized using analytical devices such as FT-IR, TGA, DLS, Zeta potential analyzer, and TEM. The size less than 40nm, - 18.8 mV surface charge, efficient drug loading capacity (21.48%), and controlled drug release (about 45% of drug release normal pH after 8h) were determined for the nano-complex. In the biomedical test, the cell viability was obtained 14.67% at 24h of post-treatment for 800 nM concentration, and IC50 was ascertained at 100 nM for the nano-complex. The expression of apoptotic Bax and Caspase9 genes was increased by more than eightfolds and more than fivefolds after treatment with an optimal concentration of nanocarrier. Also, more than threefolds of cell cycle arrest was observed at the optimal concentration synthetics, and 27.5% breast cancer cell apoptosis was detected after treatment with 100 nM nano-complex. These outputs have been indicating the potential capacity of synthesized nano-complex in inhibiting the growth of breast cancer cells.

Synthesis and Properties of α-Mangostin and Vadimezan Conjugates with Glucoheptoamidated and Biotinylated 3rd Generation Poly(amidoamine) Dendrimer, and Conjugation Effect on Their Anticancer and Anti-Nematode Activities.

α-Mangostin and vadimezan are widely studied potential anticancer agents. Their biological activities may be improved by covalent bonding by amide or ester bonds with the third generation poly(amidoamine) (PAMAM) dendrimer, substituted with α-D-glucoheptono-1,4-lactone and biotin. Thus, conjugates of either ester- (G3gh4B5V) or amide-linked (G32B12gh5V) vadimezan, and equivalents of α-mangostin (G3gh2B5M and G32B12gh5M, respectively), were synthesized, characterized and tested in vitro against cancer cells: U-118 MG glioma, SCC-15 squamous carcinoma, and BJ normal human fibroblasts growth, as well as against C. elegans development. α-Mangostin cytotoxicity, stronger than that of Vadimezan, was increased (by 2.5–9-fold) by conjugation with the PAMAM dendrimer (with the amide-linking being slightly more effective), and the strongest effect was observed with SCC-15 cells. Similar enhancement of toxicity resulting from the drug conjugation was observed with C. elegans. Vadimezan (up to 200 µM), as well as both its dendrimer conjugates, was not toxic against both the studied cells and nematodes. It showed an antiproliferative effect against cancer cells at concentrations ≥100 µM. This effect was significantly enhanced after conjugation of the drug with the dendrimer via the amide, but not the ester bond, with G32B12gh5V inhibiting the proliferation of SCC-15 and U-118 MG cells at concentrations ≥4 and ≥12 μM, respectively, without a visible effect in normal BJ cells. Thus, the drug delivery system based on the PAMAM G3 dendrimer containing amide bonds, partially-blocked amino groups on the surface, larger particle diameter and higher zeta potential can be a useful tool to improve the biological properties of transported drug molecules.

Polylysine dendrigraft is able to differentially impact Cutibacterium acnes strains preventing acneic skin.

With a view to reducing the impact of Cutibacteriumacnes (C.acnes) on acne vulgaris, it now appears interesting to modify the balance between acneic and non-acneic strains of C.acnes using moderate approach. In the present study, we identified that a G2 dendrigraft of lysine dendrimer (G2 dendrimer) was able to modify membrane fluidity and biofilm formation of a C.acnes acneic strain (RT5), whereas it appeared no or less active on a C.acnes non-acneic strain (RT6). Moreover, skin ex vivo data indicated that the G2 is able to decrease inflammation (IL1α and TLR-2) and improve skin desquamation after of C.acnes acneic strains colonization. Then, in vivo data confirmed, after C.acnes quantification by metagenomic analysis that the G2 cream after 28days of treatment was able to increase the diversity of C.acnes strains versus placebo cream. The data also showed a modification of the balance expression between C.acnes phylotype IA1 and phylotype II abundances. Taken together, the results confirm the interest of using soft compounds in cosmetic product for modifying phylotype abundances and diversity of C.acnes strains could be a new strategy for prevent acne vulgaris outbreak.

New method of identifying morphine in urine samples using nanoparticle-dendrimer-enzyme hybrid system

The incorporation of morphine (MOR) into the nanoparticle structure is a viable alternative to traditional enzyme usage. It has good biological potential to separate MOR from real urine samples. In this study, a new method of MOR identification in real urine samples was synthesized using the β-glucuronidase-dendrimer poly amidoamine (PAMAM) enzyme hybrid system. Replacing MOR in dendrimer cavities significantly reduces enzyme consumption. The replacement technique is done in dendrimer cavities in two stages as an alternative to β-glucuronidase enzyme and even MOR. In this paper, firstly, PAMAM dendrimer G2 was synthesized based on silica. The β-glucuronidase enzyme was replaced inside its dendrimer cavities and the compound was released into a real urine sample containing MOR. The enzyme was extracted from dendrimer cavities. The MOR- β-glucuronidase enzyme bond broke. In the next stage of the process, free MOR entered the PAMAM dendrimer G2 cavities. MOR was detected in real urine samples.

Synthesis of Biotinylated PAMAM G3 Dendrimers Substituted with R-Glycidol and Celecoxib/Simvastatin as Repurposed Drugs and Evaluation of Their Increased Additive Cytotoxicity for Cancer Cell Lines.

Simple SummaryNew anti-cancer drugs can be created through the combination of well-known substances acting on different molecular targets. Repurposed drugs selected in this way can then be attached to special carriers that have specific, high affinity for cancer cells. In this study, two anti-glioma drugs, celecoxib and simvastatin, were chosen and linked to the PAMAM G3 dendrimer targeted to cancer cells by attached biotin and R-glycidol. In vitro studies performed with human glioblastoma (U-118 MG) and squamous cell carcinoma (SCC-15) cells revealed that dendrimer conjugate containing both celecoxib and simvastatin was 20–50 times more potent than either drug administered alone or in combination. Thus, the obtained combined conjugate can be considered as a potential candidate for a new therapy of malignant glioblastoma.Recent achievement in anticancer therapy considers the application of repurposed drugs in optimal combinations with the use of specific carriers for their targeted delivery. As a result, new optimized medications with reduced side effects can be obtained. In this study, two known anticancer drugs, celecoxib and/or simvastatin, were conjugated covalently with PAMAM G3 dendrimer and tested in vitro against human squamous carcinoma (SCC-15-15) and glioblastoma (U-118 MG) cells, as well as normal human fibroblasts (BJ). The obtained conjugates were also substituted with biotin and R-glycidol to increase their affinity for cancer cells and were characterized with NMR spectroscopy and dynamic light scattering technique. Conjugates furnished with two celecoxib and four simvastatin residues revealed the very high effectiveness and dramatically decreased the SCC-15 and U-118 MG cell viability at very low concentrations with IC50 equal to about 3 µM. Its action was 20–50-fold stronger than that of either drug alone or as a mixture. Combined conjugate revealed also additive action since it was 2–8-fold more effective than conjugates with either single drug. The combined conjugate revealed rather low specificity since it was also highly cytotoxic for BJ cells. Despite this, it may be concluded that biotinylated and R-glycidylated PAMAM G3 dendrimers substituted with both celecoxib and simvastatin can be considered as a new perspective anticancer agent, effective in therapy of malignant, incurable glioblastomas.

Reaction of Amino-Terminated PAMAM Dendrimers with Carbon Dioxide in Aqueous and Methanol Solutions.

Polyamines have been used as active materials to capture carbon dioxide gas based on its well-known reaction with amines to form carbamates. This work investigates the reactions between three amino-terminated poly(amidoamine) (PAMAM) dendrimers (G1, G3 and G5) and CO2(g) in aqueous (D2O) and methanolic (CD3OD) solutions. The reactions were monitored using 1H NMR spectroscopy, and yielded dendrimers with a combination of terminal carbamate and terminal ammonium groups. In aqueous media the reaction was complicated by the generation of soluble carbonate and bicarbonate ions. The reaction was cleaner in CD3OD, where the larger G5 dendrimer solution formed a gel upon exposure to CO2(g). All reactions were reversible, and the trapped CO2 could be released by treatment with N2(g) and mild heating. These results highlight the importance of the polyamine dendrimer size in terms of driving changes to the solution’s physical properties (viscosity, gel formation) generated by exposure to CO2(g).

Accelerated synthesis of dendrimers by thermal azide–alkyne cycloaddition with internal alkynes

Optimized reaction conditions and a strict alignment to green chemistry principles allow the accelerated preparation of a G5 dendrimer in less than 12 h by combining the thermal azide–alkyne cycloaddition and azide substitution reactions.

Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms

The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G32B12gh5M) or 17 (G32B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G32B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G32B12gh5M and G32B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G32B10gh17M than for G32B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy.

Corneal endothelial cell sheet bioengineering from neural crest cell-derived adipose stem cells on novel thermo-responsive elastin-mimetic dendrimers decorated with RGD

Due to the limitations in in vivo division of Human Corneal Endothelial Cells (HCECs), and a shortage of cornea donations, there is increasing focus on bioengineering Corneal endothelium (CE) using alternative cells. Cell sheet engineering allows for the maintenance of the cellular junctions necessary for CE function. The aim of this study was to generate CE-like cell sheets on innovative thermo-responsive biopolymer, using hADSC-derived CE-like cells.Thermo-responsive biopolymers were fabricated by conjugating Elastin-like polypeptide (ELP) functionalized with RGD to a G4 dendrimer as a nanoplatform, named elastin-mimetic dendrimer (EMD). The hADSCs were first reprogrammed into neurospheres on Poly-L-lysine, induced by small molecules. Then, neural crest cells (NCCs) were differentiated into CE-like cells on EMD, and cultured until the CE-like cell sheet formed.EMD exhibited excellent biocompatibility improving cell spreading, adhesion, proliferation and NCCs differentiation into CE-like cells, and Lower critical solution temperature (LCST) near physiological temperature ideal for CE-like cell sheet harvesting. NCCs and CE-like cells markers were confirmed by qRT-PCR, immunocytochemistry, and western blot. After 18 days, cell sheets with cellular junctions were harvested by decreasing the temperature. This study thus represents the successful generation of CE-like cell sheets from hADSC-derived CE-like cells on EMD.

Surface modified and rituximab functionalized PAMAM G4 nanoparticle for targeted imatinib delivery to leukemia cells: In vitro studies

Cancer therapy is one of the most important issues in human beings’ life since it is the determining cause of death all over the world. In this research, polyethylene glycol (P: PEG) modified and rituximab (Ab: antibody) functionalized polyamidoamine (P: PAMAM) G4 dendrimers were developed for the efficient delivery of imatinib (D: drug) to leukemia cancer cells. The Ab-P-P-D nano-complex was effectively synthesized and subsequently, characterized with analytical devices, including Nano-drop UV–vis, FT-IR, TGA, DLS, and TEM. The drug loading efficiency of the Ab-P-P-D sample was calculated at 37.87 % and the size less than 40 nm in diameter was detected via TEM. Additionally, the drug release profile of nano-complex was investigated and the controlled release behavior of nano-complex was determined at various pHs. In the next phase, the sorts of biomedical tests such as cell viability, gene expression, cell cycle arrest, and apoptosis analyses were carried out to evaluate cancer cell inhibition potency of the nano-complex. The Ab-P-P-D nano-complex showed 13.84 ± 2.34 % cell viability after 72 h of treatment, more than 6 folds expression values in the caspase3 gene, 23.26 % of cells in the sub-G1 phase, and 39 % apoptosis in cancer cells. These results are presenting Ab-P-P-D nano-complex as an effective drug delivery system (DDS) for cancer therapy.

Antiplasmodial Effect of Nano Dendrimer G2 Loaded with Chloroquine in Mice Infected with Plasmodium berghei.

Malaria is a parasitic lethal disease caused by Plasmodium protozoa. The resistance and drugs' side effects have led to numerous researches for alternative suitable drugs with better efficiency and lower toxicity PURPOSE: In the present study, we investigated in vivo antimalarial effects of G2 linear dendrimer-based nano-chloroquine. After the preparation of nano dendrimer G2, chloroquine loading was done. Determine the characterization of particles were specified by DLS, SLS and SEM. The LC-MS and FTIR were used for verifying the nano dendrimer G2 and the loading of chloroquine into the compound. The Solubility N-chloroquine and measurement of drug release rate were done. Antiplasmodial activity of N-chloroquine on BALB/c mice was performed by the microscope and enzymatic methods. At the end, In vivo toxicity of N-chloroquine on tissues was assayed. The RBC morphology and enzyme levels were identified. The results showed the synthesized N-chloroquine had suitable size and solubility. Highest inhibitory effect on Plasmodium parasitic growth was observed at 16mg/kg dose of N-chloroquine, which eliminated 95% of the parasites (p > 0.05). ED50 is observed at 7.7mg/kg of N-chloroquine dose. Biochemical findings showed the synthesized N-chloroquine was safer than chloroquine. The N-chloroquine no adverse effects were observed in examined tissues. Due to the better effect of the synthesized N-chloroquine on Plasmodium berghei in mice compared to chloroquine, this nanoparticle can be considered as an effective anti-plasmodium compound while more comprehensive research is recommended.