Recent advances in multifunctional dendrimer-based complexes for cancer treatment.

The application of nanotechnology in biological and medical fields have resulted in the creation of new devices, supramolecular systems, structures, complexes, and composites. Dendrimers are relatively new nanotechnological polymers with unique features; they are globular in shape, with a topological structure formed by monomeric subunit branches diverging to the sides from the central nucleus. This review analyzes the main features of dendrimers and their applications in biology and medicine regarding cancer treatment. Dendrimers have applications that include drug and gene carriers, antioxidant agents, imaging agents, and adjuvants, but importantly, dendrimers can create complex nanosized constructions that combine features such as drug/gene carriers and imaging agents. Dendrimer-based nanosystems include different metals that enhance oxidative stress, polyethylene glycol to provide biosafety, an imaging agent (a fluorescent, radioactive, magnetic resonance imaging probe), a drug or/and nucleic acid that provides a single or dual action on cells or tissues. One of major benefit of dendrimers is their easy release from the body (in contrast to metal nanoparticles, fullerenes, and carbon nanotubes), allowing the creation of biosafe constructions. Some dendrimers are already clinically approved and are being used as drugs, but many nanocomplexes are currently being studied for clinical practice. In summary, dendrimers are very useful tool in the creation of complex nanoconstructions for personalized nanomedicine. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Silver Nanoparticles Modified by Carbosilane Dendrons and PEG as Delivery Vectors of Small Interfering RNA.

The fact that cancer is one of the leading causes of death requires researchers to create new systems of effective treatment for malignant tumors. One promising area is genetic therapy that uses small interfering RNA (siRNA). These molecules are capable of blocking mutant proteins in cells, but require specific systems that will deliver RNA to target cells and successfully release them into the cytoplasm. Dendronized and PEGylated silver nanoparticles as potential vectors for proapoptotic siRNA (siMCL-1) were used here. Using the methods of one-dimensional gel electrophoresis, the zeta potential, dynamic light scattering, and circular dichroism, stable siRNA and AgNP complexes were obtained. Data gathered using multicolor flow cytometry showed that AgNPs are able to deliver (up to 90%) siRNAs efficiently to some types of tumor cells, depending on the degree of PEGylation. Analysis of cell death showed that complexes of some AgNP variations with siMCL-1 lead to ~70% cell death in the populations that uptake these complexes due to apoptosis.

Dipeptide nanostructures: Synthesis, interactions, advantages and biomedical applications.

Short peptides are important in the design of self-assembled materials due to their versatility and flexibility. Self-assembled dipeptides, a group of peptide nanostructures, have highly attractive uses in the field of biomedicine. Recently these materials have proved to be important nanostructures because of their biocompatibility, low-cost and simplicity of synthesis, functionality/easy tunability and nano dimensions. Although there are different studies on peptide and protein-based nanostructures, more information about self-assembled nanostructures for dipeptides is still required to discover the advantages, challenges, importance, synthesis, interactions, and applications. This review describes and discusses the self-assembled dipeptide nanostructures especially for biomedical applications.

Activation of Ibuprofen via Ultrasonic Complexation with Silver in N-Doped Oxidized Graphene Nanoparticles for Microwave Chemotherapy of Cervix Tumor Tissues.

An ultrasonic method (20 kHz) is introduced to activate pristine ibuprofen organic molecular crystals via complexation with silver in nitrogen-doped oxidized graphene nanoplatforms (∼50 nm). Ultrasonic complexation occurs in a single-step procedure through the binding of the carboxylic groups with Ag and H-bond formation, involving noncovalent πC=C → πC=C* transitions in the altered phenyl ring and πPY → πCO* in ibuprofen occurring between the phenyl ring and C-O bonds as a result of interaction with hydroxyl radicals. The ibuprofen-silver complex in ≪NrGO≫ exhibits a ∼42 times higher acceleration rate than free ibuprofen of the charge transfer between hexacyanoferrate and thiosulfate ions. The increased acceleration rate can be caused by electron injection/ejection at the interface of the ≪Ag-NrGO≫ nanoplatform and formation of intermediate species (Fe(CN)5(CNSO3)x- with x = 4 or 5 and AgHS2O3) at the excess of produced H+ ions. Important for microwave chemotherapy, ibuprofen-silver complexes in the ≪NrGO≫ nanoplatform can produce H+ ions at ∼12.5 times higher rate at the applied voltage range from 0.53 to 0.60 V. ≪Ibu-Ag-NrGO≫ NPs develop ∼105 order higher changes of the electric field strength intensity than free ibuprofen in the microwave absorption range of 100-1000 MHz as revealed from the theoretical modeling of a cervix tumor tissue.

PAMAM-Calix-Dendrimers: Second Generation Synthesis, Fluorescent Properties and Catecholamines Binding.

A convenient method for the synthesis of the second generation of PAMAM dendrimers based on a p-tert-butylthiacalix[4]arene core in cone, partial cone and 1,3-alternate conformations was developed. Unusual fluorescence of the obtained PAMAM-calix-dendrimers has been found and explained. The binding ability of the synthesized dendrimers toward catecholamines (dopamine, L-adrenaline and L-noradrenaline) was shown by UV-Vis, fluorescence, 1D and 2D NMR spectroscopy and the binding constants (logKa 3.85-4.74) calculated. As was shown, the PAMAM-calix-dendrimers bind catecholamines by the internal cavities. All the studied hormones were most efficiently bound by the dendrimers bearing a macrocyclic core in 1,3-alternate conformation. The size of the formed supramolecular systems of dendrimer/catecholamine was established by the DLS method. A decrease in hemolytic activity of the PAMAM-calix-dendrimers with an increase in the generation number of a dendrimer was shown for the dendrimers with a core in 1,3-alternate conformation. The prospects for the use of the synthesized dendrimers with the macrocyclic core as drug delivery agents were discussed.

Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review.

Curcumin (Cur), a traditional Chinese medicine extracted from natural plant rhizomes, has become a candidate drug for the treatment of diseases due to its anti-inflammatory, anticancer, antioxidant, and antibacterial activities. However, the poor water solubility and low bioavailability of Cur limit its therapeutic effects for clinical applications. A variety of nanocarriers have been successfully developed to improve the water solubility, in vivo distribution, and pharmacokinetics of Cur, as well as to enhance the ability of Cur to polarize macrophages and relieve macrophage oxidative stress or anti-apoptosis, thus accelerating the therapeutic effects of Cur on inflammatory diseases. Herein, we review the design and development of diverse Cur nanoformulations in recent years and introduce the biomedical applications and potential therapeutic mechanisms of Cur nanoformulations in common inflammatory diseases, such as arthritis, neurodegenerative diseases, respiratory diseases, and ulcerative colitis, by regulating macrophage behaviors. Finally, the perspectives of the design and preparation of future nanocarriers aimed at efficiently exerting the biological activity of Cur are briefly discussed.

Engineered phosphorus dendrimers as powerful non-viral nanoplatforms for gene delivery: a great hope for the future of cancer therapeutics.

During the past two decades, tremendous progress has been made in the dendrimer-based delivery of therapeutic molecules including, for instance, small molecules, macromolecules, and genes. This review deals with recent successes in the development of promising biocompatible phosphorus dendrimers, a specific type of dendrimer, to deliver genes to treat cancers.

Circulating microRNAs in Medicine.

Circulating microRNAs (c-microRNAs, c-miRNAs), which are present in almost all biological fluids, are promising sensitive biomarkers for various diseases (oncological and cardiovascular diseases, neurodegenerative pathologies, etc.), and their signatures accurately reflect the state of the body. Studies of the expression of microRNA markers show that they can enable a wide range of diseases to be diagnosed before clinical symptoms are manifested, and they can help to assess a patient's response to therapy in order to correct and personalize treatments. This review discusses the latest trends in the uses of miRNAs for diagnosing and treating various diseases, viral and non-viral. It is concluded that exogenous microRNAs can be used as high-precision therapeutic agents for these purposes.

Ultrasonic Formation of Fe3O4-Reduced Graphene Oxide-Salicylic Acid Nanoparticles with Switchable Antioxidant Function.

We demonstrate a single-step ultrasonic in situ complexation of salicylic acid during the growth of Fe3O4-reduced graphene oxide nanoparticles (∼10 nm) to improve the antioxidant and antiproliferative effects of pristine drug molecules. These nanoparticles have a precisely defined electronic molecular structure with salicylic acid ligands specifically complexed to Fe(III)/Fe(II) sites, four orders of magnitude larger electric surface potential, and enzymatic activity modulated by ascorbic acid molecules. The diminishing efficiency of hydroxyl radicals by Fe3O4-rGO-SA nanoparticles is tenfold higher than that by pristine salicylic acid in the electro-Fenton process. The H+ production of these nanoparticles can be switched by the interaction with ascorbic acid ligands and cause the redox deactivation of iron or enhanced antioxidation, where rGO plays an important role in enhanced charge transfer catalysis. Fe3O4-rGO-SA nanoparticles are nontoxic to erythrocytes, i.e., human peripheral blood mononuclear cells, but surpassingly inhibit the growth of three cancer cell lines, HeLa, HepG2, and HT29, with respect to pristine salicylic acid molecules.

Blood Compatibility of Amphiphilic Phosphorous Dendrons-Prospective Drug Nanocarriers.

Dendrons are branched synthetic polymers suitable for preparation of nanosized drug delivery systems. Their interactions with biological systems are mainly predetermined by their chemical structure, terminal groups, surface charge, and the number of branched layers (generation). Any new compound intended to be used, alone or in combination, for medical purposes in humans must be compatible with blood. This study combined results from in vitro experiments on human blood and from laboratory experiments designed to assess the effect of amphiphilic phosphorous dendrons on blood components and model membranes, and to examine the presence and nature of interactions leading to a potential safety concern. The changes in hematological and coagulation parameters upon the addition of dendrons in the concentration range of 2-10 µM were monitored. We found that only the combination of higher concentration and higher generation of the dendron affected the selected clinically relevant parameters: it significantly decreased platelet count and plateletcrit, shortened thrombin time, and increased activated partial thromboplastin time. At the same time, occasional small-sized platelet clumps in blood films under the light microscope were observed. We further investigated aggregation propensity of the positively charged dendrons in model conditions using zwitterionic and negatively charged liposomes. The observed changes in size and zeta potential indicated the electrostatic nature of the interaction. Overall, we proved that the low-generation amphiphilic phosphorous dendrons were compatible with blood within the studied concentration range. However, interactions between high-generation dendrons at bulk concentrations above 10 µM and platelets and/or clotting factors cannot be excluded.

Prospects of Cationic Carbosilane Dendronized Gold Nanoparticles as Non-viral Vectors for Delivery of Anticancer siRNAs siBCL-xL and siMCL-1.

Cancer is one of the most important problems of modern medicine. At the present time, gene therapy has been developed against cancer, which includes the delivery of anticancer small interfering RNAs (siRNAs) directed at cancer proteins. The prospect of creating drugs based on RNA interference implies the use of delivery systems. Metal nanoparticles are the most studied objects for medicine, including their application as non-viral vectors. We have synthesized gold nanoparticles (AuNPs) modified with cationic carbosilane dendrons of 1-3 generations, with a positive charge on the surface, gold nanoparticles can effectively bind small interfering RNAs. Using a photometric viability test and flow cytometry, we assessed the ability of dendronized gold nanoparticles in delivering siRNAs to tumor cells. The efficiency of the complexes in initiating apoptosis was measured and, also, the overall effect of proapoptotic siRNA on cells. AuNP15 has both the highest efficacy and toxicity. The delivery efficiency in suspension cell lines was 50-60%. Complexes with targeted siRNA decreased cell viability by 20% compared to control and initiated apoptosis.

Combined therapy of ruthenium dendrimers and anti-cancer drugs against human leukemic cells.

Carbosilane ruthenium(ii) dendrimers have been complexed with conventional anti-cancer drugs. Due to its features, the presence of ruthenium within a dendrimer structure improves the anti-cancer properties of nanocomplexes containing 5-flurouracyl, methotrexate and doxorubicin. These dendrimers could be promising carriers of anti-cancer medicines. Ruthenium dendrimers that are positively charged can also enhance the cytotoxicity to cancer cells; moreover, they can form stable complexes with drugs. Results indicate that ruthenium dendrimers combined with doxorubicin and methotrexate significantly reduced the viability of leukaemia 1301 and HL-60 cancer cells.

Comparison of the effects of dendrimer, micelle and silver nanoparticles on phospholipase A2 structure.

The interaction of nanoparticles (NP) with proteins (the so-called 'protein corona') is a huge challenge in attempting to apply them in personalized nanomedicine. We have analyzed the interaction between A) two 'soft' NPs (a cationic phosphorus dendrimer of generation 3; a cationic phosphorus amphiphilic dendron of generation 2), and B) one 'hard' nanoparticle (silver NP covered with cationic carbosilane dendritic moieties); and membrane-bound protein phospholipase A2 from bovine pancreas. The hard and soft NPs have differences in the nature of their interactions with phospholipase A2. This enzyme surrounds hard AgNP, whereas dendrimer and amphiphilic dendron form aggregates/micelles with phospholipase A2. There is a difference in action of phospholipase A2 bound to the core of dendrimer, and of micelles formed from non-covalent interactions between the amphiphilic dendron. These data are important in understanding the nature of interaction between different kinds of nanoparticles and proteins.

Nanoparticles in Combating Cancer: Opportunities and Limitations. A Brief Review.

Nanomedicine is a good alternative to traditional methods of cancer treatment but does not solve all the limitations of oncology. Nanoparticles used in anticancer therapy can work as carriers of drugs, nucleic acids, imaging agents or they can sensitize cells to radiation. The present review focuses on the application of nanoparticles to treating cancer, as well as on its problems and limitations. Using nanoparticles as drug carriers, significant improvement in the efficiency of transport of compounds and their targeting directly to the tumour has been achieved; it also reduces the side effects of chemotherapeutic drugs on the body. However, nanoparticles do not significantly improve the effectiveness of the chemotherapeutic agent itself. Most nanodrugs can reduce the toxicity of chemotherapy, but do not significantly affect the effectiveness of treatment. Nanodrugs should be developed that can be effective as an anti-metastatic treatment, e.g. by enhancing the ability of nanoparticles to transport chemotherapeutic loads to sentinel lymph nodes using the immune system and developing chemotherapy in specific metastatic areas. Gene therapy, however, is the most modern method of treating cancer, the cause of cancer being tackled by altering genetic material. Other applications of nanoparticles for radiotherapy and diagnostics are discussed.

Phosphorus dendrimers as powerful nanoplatforms for drug delivery, as fluorescent probes and for liposome interaction studies: A concise overview.

Gene therapy is a new and promising tool to treat many severe diseases and the silencing of proteins is the safest and the most efficient tool to treat diseases because it does not induce changes in human genome and avoids a huge problem encompassing insertional mutagenesis. Using small RNAs to switch on/off target proteins is limited due to existence of some barriers for them in the human body (blood RNAses, serum albumins, cell walls, etc). For therapeutic applications they need the efficient and non-toxic carrier which will deliver them into cell cytoplasm. Within the huge range of carriers available, dendrimers can be underlined as new promising efficient carriers. This review summarizes several findings in phosphorus dendrimers based on in vitro and in vivo studies. As a result, we can conclude that advantages of phosphorus dendrimers are strong interaction with siRNA/DNA and formation of small and compact positively charged complexes of high and fast penetration into cells; efficient release of siRNA/pDNA in endosomes due to "proton sponge" effect; possibility of their modification including addition of fluorescent probes - in this case fluorescent dendrimer can be used both as a gene carrier and a tracer of delivery into cells. Additional benefit of using fluorescent phosphorus dendrimers is their ability to monitor the macrophage physiological status in vitro and in vivo.

A new application of inorganic sorbent for biomolecules: IMAC practice of Fe3+-nano flowers for DNA separation.

Selection of purification method and type of adsorbent has high significance for separation of a biomolecule like deoxyribonucleic acid (DNA). Nanoflowers are a newly improved class of adsorbent. Due to showing very structural similarity to plant flowers, they are named as nanoflowers. Herein, after synthesize of copper phosphate three hydrate nanoflowers [(Cu3(PO4)2.3H2O), CP-NFs], Fe3+ ions were attached to their surfaces. Obtained Fe3+-CP-NFs, before investigation of some adsorption parameters for DNA, they were characterized by scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Some attained data from the results of adsorption experiments as follows: While maximum DNA adsorption on Fe3+-CP-NFs was found as an excellent value of 845.8 mg/g, nanoflowers without Fe3+ ions adsorbed DNA as only 25.3 mg/g. Optimum media conditions for DNA adsorption were observed at pH 7 and 25 °C with an initial concentration of 1.5 mg/mL DNA. Langmuir and Freundlich adsorption equations were applied to determine which adsorption model was appropriate, and it was seen that Langmuir model was fit with a R2 of 0.9885.

Ruthenium Dendrimers against Human Lymphoblastic Leukemia 1301 Cells.

Ruthenium atoms located in the surfaces of carbosilane dendrimers markedly increase their anti-tumor properties. Carbosilane dendrimers have been widely studied as carriers of drugs and genes owing to such characteristic features as monodispersity, stability, and multivalence. The presence of ruthenium in the dendrimer structure enhances their successful use in anti-cancer therapy. In this paper, the activity of dendrimers of generation 1 and 2 against 1301 cells was evaluated using Transmission Electron Microscopy, comet assay and Real Time PCR techniques. Additionally, the level of reactive oxygen species (ROS) and changes of mitochondrial potential values were assessed. The results of the present study show that ruthenium dendrimers significantly decrease the viability of leukemia cells (1301) but show low toxicity to non-cancer cells (peripheral blood mononuclear cells-PBMCs). The in vitro test results indicate that the dendrimers injure the 1301 leukemia cells via the apoptosis pathway.