Tumor cells with stem cell properties are considered to play major roles in promoting the development and malignant behavior of aggressive cancers. Therapeutic strategies that efficiently eradicate ...such tumor stem cells are of highest clinical need. Herein, we performed the validation of the polycationic phosphorus dendrimer-based approach for small interfering RNAs delivery in in vitro stem-like cells as models. As a therapeutic target, we chose Lyn, a member of the Src family kinases as an example of a prominent enzyme class widely discussed as a potent anti-cancer intervention point. Our selection is guided by our discovery that Lyn mRNA expression level in glioma, a class of brain tumors, possesses significant negative clinical predictive value, promoting its potential as a therapeutic target for future molecular-targeted treatments. We then showed that anti-Lyn siRNA, delivered into Lyn-expressing glioma cell model reduces the cell viability, a fact that was not observed in a cell model that lacks Lyn-expression. Furthermore, we have found that the dendrimer itself influences various parameters of the cells such as the expression of surface markers PD-L1, TIM-3 and CD47, targets for immune recognition and other biological processes suggested to be regulating glioblastoma cell invasion. Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.
Dendritic molecules bearing metal complexes in their structure (metallodendrimers and metallodendrons) are considered prospective therapeutic entities. In particular, metallodendrons raise interest ...as antitumor agents for the treatment of poorly curable or drug-resistant tumors. Herein, we have synthesized amphiphilic triazine-phosphorus dendrons bearing multiple copper (II) or gold (III) complexes on the periphery and a branched hydrophobic fragment at the focal point. Due to their amphiphilic nature, metallodendrons formed single micelles (mean diameter ~9 nm) or multi-micellar aggregates (mean diameter ~60 nm) in a water solution. We have tested the antitumor activity of amphiphilic metallodendrons towards glioblastoma, a malignant brain tumor with a notoriously high level of therapy resistance, as a model disease. The metallodendrons exhibit higher cytotoxic activity towards glioblastoma stem cells (BTSC233, JHH520, NCH644, and SF188 cell lines) and U87 glioblastoma cells (IC50 was 3-6 µM for copper-containing dendron and 11-15 µM for gold-containing dendron) in comparison with temozolomide (IC50 >100 µM)-the clinical standard of care for glioblastoma. Our findings show the potential of metallodendron-based nanoformulations as antitumor entities.
In this review, we summarize the recent advances in the use of pyrene-modified oligonucleotides as a platform for functional nucleic acid-based constructs. Pyrene is of special interest for the ...development of nucleic acid-based tools due to its unique fluorescent properties (sensitivity of fluorescence to the microenvironment, ability to form excimers and exciplexes, long fluorescence lifetime, high quantum yield), ability to intercalate into the nucleic acid duplex, to act as a π-π-stacking (including anchoring) moiety, and others. These properties of pyrene have been used to construct novel sensitive fluorescent probes for the sequence-specific detection of nucleic acids and the discrimination of single nucleotide polymorphisms (SNPs), aptamer-based biosensors, agents for binding of double-stranded DNAs, and building blocks for supramolecular complexes. Special attention is paid to the influence of the design of pyrene-modified oligonucleotides on their properties, i.e., the structure-function relationships. The perspectives for the applications of pyrene-modified oligonucleotides in biomolecular studies, diagnostics, and nanotechnology are discussed.
The lack of an appropriate intracellular delivery system for therapeutic nucleic acids (TNAs) is a major problem in molecular biology, biotechnology, and medicine. A relatively new class of highly ...symmetrical hyperbranched polymers, called dendrimers, shows promise for transporting small TNAs into both cells and target tissues. Dendrimers have intrinsic advantages for this purpose: their physico-chemical and biological properties can be controlled during synthesis, and they are able to transport large numbers of TNA molecules that can specifically suppress the expression of single or multiple targeted genes. Numerous chemical modifications of dendrimers extend the biocompatibility of synthetic materials and allow targeted vectors to be designed for particular therapeutic purposes. This review summarizes the latest experimental data and trends in the medical application of various types of dendrimers and dendrimer-based nanoconstructions as delivery systems for short small interfering RNAs (siRNAs) and microRNAs at the cell and organism levels. It provides an overview of the structural features of dendrimers, indicating their advantages over other types of TNA transporters.
DNA and RNA vaccines (nucleic acid-based vaccines) are a promising platform for vaccine development. The first mRNA vaccines (Moderna and Pfizer/BioNTech) were approved in 2020, and a DNA vaccine ...(Zydus Cadila, India), in 2021. They display unique benefits in the current COVID-19 pandemic. Nucleic acid-based vaccines have a number of advantages, such as safety, efficacy, and low cost. They are potentially faster to develop, cheaper to produce, and easier to store and transport. A crucial step in the technology of DNA or RNA vaccines is choosing an efficient delivery method. Nucleic acid delivery using liposomes is the most popular approach today, but this method has certain disadvantages. Therefore, studies are actively underway to develop various alternative delivery methods, among which synthetic cationic polymers such as dendrimers are very attractive. Dendrimers are three-dimensional nanostructures with a high degree of molecular homogeneity, adjustable size, multivalence, high surface functionality, and high aqueous solubility. The biosafety of some dendrimers has been evaluated in several clinical trials presented in this review. Due to these important and attractive properties, dendrimers are already being used to deliver a number of drugs and are being explored as promising carriers for nucleic acid-based vaccines. This review summarizes the literature data on the development of dendrimer-based delivery systems for DNA and mRNA vaccines.
Supramolecular chemistry holds great potential for the design of versatile and safe carriers for therapeutic proteins and peptides. Nanocarriers can be designed to meet specific criteria for given ...application (exact drug, administration route, target tissue, etc.). However, alterations in the topology of formulation components can drastically change their activity. This is why the supramolecular topology of therapeutic nanoconstructions has to be considered. Herein, we discuss several topological groups used for the design of nanoformulations for peptide and protein delivery: modification of polypeptide chains by host-guest interactions; packaging of proteins and peptides into liposomes; complexation and conjugation with dendrimers. Each topological type has its own advantages and disadvantages, so careful design of nanoformulations is needed. Ideally, each case where nanomedicine is needed requires a therapeutic construction specially created for that taking into account features of the administration route, target tissue, or organ, properties of a drug, its bioavailability, etc. The wide number of studies in the field of protein delivery by supramolecular and nanocarriers for proteins and peptides evidence their increasing potential for different aspects of the innovative medicine. Although significant progress has been achieved in the field, there are several remaining challenges to be overcome in future.
Hydrogels are hydrophilic, three-dimensional networks able to imprison large amounts of water and are largely used in pharmaceutical formulations. Hydrogels are frequently obtained from hydrophilic ...polymers, either natural, biohybrid, or synthetic. Owing to their peculiar structure, dendrimers can be considered prospective building blocks for hydrogel networks. This review gathers the use of different types of amphiphilic dendritic structures able to generate physical hydrogels alone. Such dendritic structures comprise dendrimers, Janus dendrimers, and dendrons. The first part concerns different types of positively charged phosphorus dendrimers used to generate hydrogels, which are also suitable to form fibers, and for encapsulating diverse substances, or forming complexes with genetic materials for their slow delivery. The second part concerns PAMAM dendrimers functionalized with collagen mimetics. The third part concerns amphiphilic Janus dendrimers, whereas the fourth part displays different types of amphiphilic dendrons and their use, in particular in the fields of materials and drug delivery.
The failure of a long-lasting curative therapeutic benefit of currently applied chemotherapies against malignant cancers is suggested to be caused by the ineffectiveness of such interventions on ...cancer stem cells (CSCs). CD133/AC133 is a cell surface protein previously shown to have potential to identify CSCs in various tumors, including brain tumors. Moreover, an increase in the rate of cellular metabolism of glutamine and glucose are contributors to the fast cellular proliferation of some high-grade malignancies. Inhibition of glutaminolysis by utilizing pharmacological inhibitors of the enzyme glutaminase 1 (GLS1) can be an effective anti-CSC strategy. In this study, the clinical-stage GLS1 inhibitor Telaglenastat (CB-839) was loaded into PEGylated gold nanoparticles equipped with the covalently conjugated CD133 aptamer (Au-PEG-CD133-CB-839) and exposed to a collection of CD133-positive brain tumor models in vitro. Our results show that Au-PEG-CD133-CB-839 significantly decreased the viability of CD133-postive cancer cells in a dose-dependent manner, which was higher as compared to the effects of treatment of the cells with the individual components of the assembled nanodrug. Interestingly, the treatment effect was observed in glioblastoma stem cells modeling different transcriptomic subtypes of the disease. The presented platform is the fundament for subsequent target specificity characterization and in vivo application.
This paper examines the complexation of anti-cancer small interfering RNAs (siRNAs) by cationic carbosilane dendrimers, and the interaction of the formed complexes with HeLa and HL-60 cancer cells. ...Stepwise formation of the complexes accompanied by the evolution of their properties has been observed through the increase of the charge ratio (dendrimer/siRNA). The complexes decrease the viability of both "easy-to-transfect" cells (HeLa) and "hard-to transfect" ones (HL-60), indicating a high potential of the cationic carbosilane dendrimers for siRNA delivery into tumor cells.
PDF
