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The circadian clock controls behavior and physiology. Presently, there is clear evidence of a connection between this timing system and cancer development/progression. Moreover, circadian rhythm consideration in the therapeutic action of anticancer drugs can enhance the effectiveness of cancer therapy. Nanosized drug delivery systems (DDS) have been demonstrated to be suitable engineered platforms for drug targeted/sustained release. The investigation of the chronobiology-nanotechnology relationship, i.e., timing DDS performance according to a patient’s circadian rhythm, may greatly improve cancer clinical outcomes. In the present work, we synthesized nanosystems based on an octa-arginine (R8)-modified poly(amidoamine) dendrimer conjugated with the anticancer drug paclitaxel (PTX), G4-PTX-R8, and its physicochemical properties were revealed to be appropriate for in vitro delivery. The influence of the circadian rhythm on its cellular internalization efficiency and potential therapeutic effect on human cervical cancer cells (HeLa) was studied. Cell-internalized PTX and caspase activity, as a measure of induced apoptosis, were monitored for six time points. Higher levels of PTX and caspase-3/9 were detected at T8, suggesting that the internalization of G4-PTX-R8 into HeLa cells and apoptosis are time-specific/-regulated phenomena. For a deeper understanding, the clock protein Bmal1—the main regulator of rhythmic activity, was silenced by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. Bmal1 silencing was revealed to have an impact on both PTX release and caspase activity, evidencing a potential role for circadian rhythm on drug delivery/therapeutic effect mediated by G4-PTX-R8.

Ti3C2Tx is a particular type of MXene whose electrical properties have been studied. Specifically, its performance as a hole transport layer (HTL) in an n-type Si photovoltaic cell has been evaluated and compared to a cell without MXene. Additionally, a layer of a dipolar material, PAMAM, has been implemented alongside with MXene to improve the overall behaviour of the cell. J-V and EQE characteristics have been measured for the di↵erent cells and figures of merit have been computed to determine the e↵ect of adding layers of MXene and PAMAM. The measurements have been done at room temperature and after a 100, 2021/2022

[EN] This study presents a useful strategy for the bioconjugation of probes for developing high-performance versatile chips applied to fast-response, low-cost DNA biosensing. We herein demonstrate that the high-density immobilization of dendrimer-oligonucleotide hybrids promotes the reliable sensitive sensing of single-nucleotide variants despite their low concentration. Carboxyl-terminated poly(amidoamine) dendrimers directly coupled to amine-derivatized oligonucleotides were anchored to the activated surfaces of thermoplastics (polycarbonate and cycloolefin polymer). Surface characterization techniques and hybridization assays reported that the multiple functional sites of the oligofunctionalized dendrimer facilitated the efficient immobilization of probes and the sensitive capture of DNA targets (5 pM detection limit). Array performance was better than that of the surfaces functionalized with linear crosslinkers, such as vinyltriethoxysilane or 3-(triethoxysilyl)propyl isocyanate, as well films with unconjugated dendrimer molecules. Based on oligo-dendrimers hybrids, disposable DNA-based biosensing platforms were developed for point-ofcare diagnostics. A selective high-sensitive hybridization assay was performed that included amplification products of blocked PCR and recombinase polymerase amplification (RPA) as an isothermal reaction. The chip results indicated that the single-nucleotide mutant variant of the BRAF oncogene was correctly discriminated in colorectal tissues from cancer patients.

Semiconductor electronic devices are fundamental for technology and speci cally for solar cells. Their e ciency is crucial for the actual need of renewable energies and the resistance between semiconductor and metal are one of the factors that a ect their performance. In this article we follow the job already done by the MNT group in studying organic layers in contacts, characterizing the generation 2 dendrimer PAMAM as ETL in n-type silicon. The results show that for moderate concentrations the PAMAM acts as a good and promising contact, 2020/2021

Background: In recent years, the use of ferritins as nano-vehicles for drug delivery is taking center stage. Compared to other similar nanocarriers, Archaeoglobus fulgidus ferritin is particularly interesting due to its unique ability to assemble-disassemble under very mild conditions. Recently this ferritin was engineered to get a chimeric protein targeted to human CD71 receptor, typically overexpressed in cancer cells. Results: Archaeoglobus fulgidus chimeric ferritin was used to generate a self-assembling hybrid nanoparticle hosting an aminic dendrimer together with a small nucleic acid. The positively charged dendrimer can indeed establish electrostatic interactions with the chimeric ferritin internal surface, allowing the formation of a protein-dendrimer binary system. The 4 large triangular openings on the ferritin shell represent a gate for negatively charged small RNAs, which access the internal cavity attracted by the dense positive charge of the dendrimer. This ternary protein-dendrimer-RNA system is efficiently uptaken by acute myeloid leukemia cells, typically difficult to transfect. As a proof of concept, we used a microRNA whose cellular delivery and induced phenotypic effects can be easily detected. In this article we have demonstrated that this hybrid nanoparticle successfully delivers a pre-miRNA to leukemia cells. Once delivered, the nucleic acid is released into the cytosol and processed to mature miRNA, thus eliciting phenotypic effects and morphological changes similar to the initial stages of granulocyte differentiation. Conclusion: The results here presented pave the way for the design of a new family of protein-based transfecting agents that can specifically target a wide range of diseased cells. Graphic abstract: [Figure not available: see fulltext.].

Целью исследования является разработка полимерной системы доставки куркумина на основе биосовместимого и биодеградируемого разветвленного полимера – дендримера PAMAM и исследование физико-химических свойств комплекса.

Neonatal brain injury affects thousands of babies each year and may lead to long-term and permanent physical and neurological problems. Currently, therapeutic hypothermia is standard clinical care for term newborns with moderate to severe neonatal encephalopathy. Nevertheless, it is not completely protective, and additional strategies to restore and promote regeneration are urgently needed. One way to ensure recovery following injury to the immature brain is to augment endogenous regenerative pathways. However, novel strategies such as stem cell therapy, gene therapies and nanotechnology have not been adequately explored in this unique age group. In this perspective review, we describe current efforts that promote neuroprotection and potential targets that are unique to the developing brain, which can be leveraged to facilitate neuroregeneration.

Drug solubility could affect the therapeutic use of a drug because the biological activity of a drug is only possible if some fraction of a dissolved drug can permeate and overcome biological membranes to reach its site of action. The solubility-permeation interplay is therefore, probably the most important factor in determining a successful therapeutic outcome of any drug because more than 40% of marketed drugs and more than 70% of pipeline drugs show poor water solubility. Several solubilization techniques are used and include, balancing of pH-pKa properties, employment of cosolvents, and the solubilization by hostguest carriers. A relatively new addition to the polymer plethora of solubilizers are the poly(amidoamine) dendrimers. These highly branched, “tree-like” nanocarriers have a significant solubilization capacity for drugs in their cavities and also potentially via their terminals. Despite their successful solubilization capability, they are still plagued by some undesired properties such as cytotoxicity. Poly(amidoamine) however, seems to be a very lucrative target to develop into a pharmaceutical excipient, which will ultimately be confirmed by an official pharmacopeial monograph

We present the synthesis of polymeric amino- and guanidinoglycosides prepared by tethering neomycin and guanidinoneomycin to PAMAM dendrimers of generations 2 and 4. The ability of these conjugates to promote cellular uptake of high-molecular-weight cargo is discussed, together with their cytotoxicity and mechanisms of entry. We demonstrate that the presence of multiple guanidinoneomycin carriers on the PAMAM surface plays an important role in promoting cellular uptake of the dendrimers, maintaining the heparan sulfate specificity and negligible cytotoxicity typical of monomeric guanidinoglycoside molecular transporters.

Tato práce je zaměřena na popis struktury, syntézy a využití dendrimerů v bioaplikacích a to zejména jako nosičů bioaktivních ligandů (enzymů, značek). V práci jsou vysvětleny termíny z oblasti chemie dendrimerů a popsány jejich fyzikálně-chemické a biologické vlastnosti. Dendrimery mají vlastnosti, které jsou uplatňovány v cílené aplikaci léčiv a jako multivalentní systémy mohou být konjugovány s různými chemickými látkami, jako jsou detekční látky, zobrazovací látky, cílené komponenty, biomolekuly, radioligandy a afinitní ligandy pro různé bioanalytické aplikace., This thesis focuses on structure, synthesis and use of dendrimers in bioapplications, mostly as carriers of bioactive ligands(enzymes, signs). Terminology from field of dendrimers are explained and physico-chemical and biological properties are described. Dendrimers have features usable in targeted drug delivery and due to its multivalent nature, dendrimers can be conjugated with number of chemical substances such as detection substance, target components, biomolecules, radioligands and affinity ligands for various bioanalytical applications., Fakulta chemicko-technologická, 1. Prezentace výsledků bakalářské práce 2. Diskuze k posudku vedoucího bakalářské práce 3. Studentka zodpověděla všechny dotazy a připomínky k bakalářské práci

Herein, the synthesis of five novel ionic dendrimers and their evaluation as biological carriers is reported. The compounds include an ionic bis-MPA dendrimer and four PAMAM dendrimers of different generations decorated with negatively charged hydrophilic chains of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid as counter ions in order to increase their biocompatibility. The ionic dendrimers derived from bis-MPA have a low cytotoxicity at 0.5 mg · mL−1 against U251MG and are even less toxic against mesenchymal stem cells; however, the PAMAM derivatives show high cytotoxicity at the same concentration. The five compounds are able to form complexes with plasmid DNA at different N/P ratios. The cytotoxicity and complexation ability of the new dendrimers were also compared with jetPEI, a linear polyethylenimine derivative commercially available as transfection reagent. The results indicate that the cytotoxicity of the ionic PAMAM dendrimers remains as an important drawback, whereas the ionic I-bis-MPA compound exhibits a high ability to complex pDNA and very low toxicity compared with jetPEI.

The first synthesis of a blue fluorescent PAMAM dendrimer, comprising eight 4-N,N-dimethylaminoethyloxy-1,8-naphthalimide units in the dendrimer periphery has been described. Its functional properties have been investigated in organic solvents of different polarity. The sensor ability of the dendrimer to detect metal (Ag2+, Co2+, Pb2+ Zn2+, Ni2+, Cu2+ and Fe3+) ions has been discussed. The fluorescence intensity of the dendrimer has been investigated as a pH function of the environment. The influence of hydroxyl anions on the dendrimer spectral properties in non-aqueous medium has also been investigated. © 2014 Elsevier Ltd. All rights reserved.

In this paper, a series of iron (Fe) containing nanoparticles were prepared by employing PAMAM (Poly(amidoamine), dendrimers with different generations (G0-G3) as templates and sodium borohydride as a reducing agent. The products have been characterized by TEM, FT-IR, XRD, VSM, TGA, and XPS. XRD analysis reveal low crystallinity of formed particles within the dendrimers, however, crystallinity of the nanoparticles was observed to increase with increasing generation of dendrimers. Dominant phases were determined as magnetite (Fe3O4 or maghemite, gamma-Fe2O3). XPS analysis revealed the chemical composition of nanoparticles as iron oxide which indicated the oxidation of Fe species subsequent to the reduction process, in agreement with XRD analysis. The magnetization curves have superparamagnetic nonhysteretic characteristic at lower fields and with nonsaturation characteristic at high fields. Magnetic evaluation of samples with the 20:1 molar ratio of Fe:PAMAM showed decreasing superparamagnetic character and decreasing saturation magnetisation with increasing generation of dendrimers., QC 20120719

Small molecule chemotherapy drugs used in clinical practice are plagued by dose-limiting side effects due to off-target toxicities. In addition, because of their low water solubility and poor bioavailability, they must be administered intravenously, leading to high treatment costs and recurring hospital visits. There is a significant need for therapies that improve the bioavailability of chemotherapy agents and enhance specific drug release in the tumor environment. Dendrimers, a class of highly-branched, nanoscale polymers, share many characteristics with traditional polymeric carriers, including water solubility, high capacity of drug loading and improved biodistribution. Poly (amido amine) (PAMAM) dendrimers have shown promise as oral drug carriers due to their compact size, high surface charge density and permeation across the intestinal epithelial barrier. Attachment of chemotherapy drugs to PAMAM dendrimers has the potential to make them orally administrable and reduce off-target toxicities. In this dissertation we investigate the transport mechanisms of PAMAM dendrimers and their potential in oral drug delivery. We demonstrate that anionic G3.5 dendrimers are endocytosed by dynamin-dependent mechanisms and their transport is governed by clathrin-mediated pathways. We show that dendrimer cellular internalization may be a requisite step for tight junction opening. We also demonstrate that conjugation of small poly (ethylene glycol) chains to anionic dendrimers decreases their transport and tight junction opening due to reduction in surface charge, illustrating that small changes in surface chemistry can significantly impact transepithelial transport. Knowledge of transport mechanisms and the impact of surface chemistry will aid in rational design of dendrimer oral drug delivery systems. The potential of dendrimers as oral drug delivery carriers is demonstrated by the evaluation of G3.5 PAMAM dendrimer-SN38 conjugates for oral therapy of hepatic colorectal cance

Three conjugates based on dendrimer PAMAM generation five were synthesized and radiolabeled successfully. To investigate their tumor targeting, the in vitro and in vivo stability, cell uptake, in vivo biodistribution, and micro-SPECT imaging were evaluated, respectively. The conjugate of 99mTc labeled PEGylated dendrimer PAMAM folic acid conjugate (99mTc-G5-Ac-pegFA-DTPA) shows much higher uptake in KB cancer cells and accumulated more in the tumor area than that of the other two conjugates. The uptake in KB cells depends on the incubation time. The results of in vivo biodistribution agree with the data obtained from micro-SPECT imaging. These studies show that PEGylation of PAMAM dendrimer folic acid conjugate improves the tumor targeting. Folate-conjugated dendrimer maybe developed to be potential radiopharmaceuticals and targeted drug delivery systems.

The photophysical characteristics of a PAMAM-type dendron that utilizes a 4-ethoxy-1,8-naphthalimide donor and 4-piperidine-1,8-naphthalimide acceptor in nine organic solvents of different polarities were investigated using absorption and fluorescent spectroscopy. The 1,8-naphthalimide acceptor can be indirectly excited by the donor 1,8-naphthalimide at 372 nm whereby the only emission observed is that due to the acceptor at 517 nm; no acceptor emission at 435 nm was observed. The efficiency of energy transfer was w98%.

Dendrimere sind nanoskalige, dreidimensional verzweigte Moleküle mit sphärischer Architektur, die auf vielfältige Weise funktionalisiert und modifiziert werden können. Die speziellen Eigenschaften der Dendrimere eröffnen zahlreiche neue Anwendungsmöglichkeiten, insbesondere im Pharmabereich (drug delivery systems, tumor targeting etc.) und motivieren damit auch zu umfassenden Untersuchungen der zugrunde liegenden physiko-chemischen Prozesse. Es ist bekannt, dass die Struktur und die Komplexierungseigenschaften von Dendrimeren in wässrigen Lösungen wesentlich von den Säure-Base-Eigenschaften (Protonierungsgrad) der funktionellen Gruppen und damit vom pH-Wert bestimmt werden. Im Rahmen dieses Beitrages werden Ergebnisse kalorimetrischer und potentiometrischer pH-Titrationsexperimente in wässriger Lösung an Polyamidoamin-Dendrimeren (PAMAM), die an der Peripherie unterschiedlich funktionalisiert sind (-NH2, -OH, -COOH Gruppen), vorgestellt und diskutiert. Die potentiometrischen pH-Titrationskurven können unter Verwendung von minimal drei simultanen Protonierungsgleichgewichten mit guter Genauigkeit beschrieben werden. Die Ergebnisse sind konsistent mit dem typischen Verhalten von Polyelektrolyten. Die kalorimetrischen pH-Titrationskurven widerspiegeln die komplexe Natur der ablaufenden Prozesse wesentlich deutlicher. Neben unterschiedlichen Stufen in den kalorimetrischen Titrationskurven, die prinzipiell den Protonierungsgleichgewichten zugeordnet werden können, treten zum Teil endotherme Effekte auf, deren Ursachen noch nicht geklärt sind. Die quantitative Beschreibung der Titrationskurven auf der Basis reiner Protonierungsreaktionen gelingt dadurch nicht vollständig. Weiterhin werden erste kalorimetrische Ergebnisse zur aus pharmakologischer Sicht wichtigen Wechselwirkung von Dendrimeren mit potentiellen Targetmaterialien am Beispiel von Human Serum Albumin (HSA) präsentiert und diskutiert.