Prednisone and ibuprofen conjugate Janus dendrimers and their anticancer activity.

Drug release from hyperbranched Janus dendrimer-drug conjugates and their subsequent activity are influenced by the different drugs in each dendron and the linker. To understand these effects, we synthetized new Janus-type dendrimers of first and second generation. One dendron with 2,2-Bis(hydroxymethyl)propionic acid functionalized with ibuprofen and the second dendron was obtained with 3-aminopropanol-amidoamine and prednisone. The dendrimers were obtained by copper(I)-catalyzed Click azide-alkyne cycloaddition for the formation of a triazole as a dendrimeric nucleus of Janus dendrimer conjugates are reported. The influence of ibuprofen, prednisone, and spacer on cancer activity of Janus dendrimers conjugates is reported. The IC50 values of the anticancer activity on cancer cell lines the Janus dendrimer of second generation was higher in comparison to the first generation dendrimer. Similarly, the anticancer activity was higher compared to the dendron conjugates. Also, no cytotoxic effects of dendrons and dendrimers on non-cancerous kidney COS-7 cell line was observed. The interesting anticancer activity of the prepared prednisone-ibuprofen Janus dendrimer conjugates suggest that the dendrimers could be of potential use as new anticancer drug.

Janus Dendrimers as Nanocarriers of Ibuprofen, Chlorambucil and Their Anticancer Activity.

BACKGROUND: Janus Dendrimer represents a novel class of synthetic nanocarriers. Since it is possible to introduce multiple drugs and target moieties, this helps the designing of new biocompatible forms with pharmacological activities comprised of different drugs with tailor-made functionalities, such as anticancer and nonsteroidal anti-inflammatory, which could improve the anticancer activity with less toxicity. AIMS: This study aimed to determine the anticancer activity of the Janus dendrimers formed by two dendrons. One dendron conjugates with chlorambucil, and the other dendron conjugates with Ibuprofen. METHODS: The cytotoxicity of the drug carriers was determined by the sulforhodamine B (SRB) assay for three cell lines. PC-3 (human prostatic adenocarcinoma), HCT-15 (human colorectal adenocarcinoma), MFC-7 (human breast cancer) and the COS-7 African green monkey kidney (used as a control) cell lines were seeded into 96-well plates at a density of 5x103 cells/well and cultured for 24 h before use. All the obtained compounds were characterized by 1H and 13C NMR one and two dimensions, UV-vis, FTIR, MALDI-TOF, Electrospray mass, and FAB+. Microscopic images were taken in an Inverted microscope Nikon, Diaphot 300, 10x4 in culture medium. RESULTS: Janus dendrimers (G1 and G2) were synthesized via an azide-alkyne click-chemistry reaction attaching on one face dendrons with ibuprofen molecules and, on the other face, attached a chlorambucil-derivative. The IC50 behavior of the conjugates of the first and second generations showed anticancer activity against PC-3, HCT-15, and MFC-7 cell lines. The second generation was more active against PC-3, HCT-15 and MFC-7 with IC50 of 3.8±0.5, 3.0±0.2 and 3.7±1.1 M, respectively Conclusion: The new Janus dendrimers with anticancer chlorambucil and nonsteroidal anti-inflammatory Ibuprofen can improve the anticancer activity of chlorambucil with less toxicity.

Anticancer Activity of 3,5-Bis(dodecyloxy)Benzoate-PAMAM Conjugates with Indomethacin or Mefenamic Acid.

BACKGROUND: The synthesis of conjugates with nonsteroidal anti-inflammatory drugs could improve their activity with less toxicity and these compounds could be used for the treatment of cancer. OBJECTIVE: The aim of the present investigation was the synthesis of 3,5-bis(dodecyloxy)benzoate - PAMAM conjugates with indomethacin and mefenamic acid to examine their anticancer activity. METHODS: The anticancer activity was studied of the conjugates against six human cancer cells U- 251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and the COS-7 (as a control) cell lines. The conjugates with indomethacin and mefenamic acid were characterized by 1H, 13C NMR one- and twodimension spectroscopy. RESULTS: All the conjugates synthetized with indomethacin or mefenamic acid showed anticancer activity against all the human cancer cell lines. The first generation of indomethacin conjugates showed better activity against the PC-3 (human prostatic adenocarcinoma) cell line than the second generation. But the second generation with indomethacin showed better activity against PC-3 than the first generation. The second-generation conjugate with mefenamic acid had strong selectivity to PC-3 cells with an IC50 value of 10.23 ± 1.2 µM in vitro. CONCLUSION: In the paper, we report the synthesis and spectroscopic analyses of new indomethacin or mefenamic acid conjugates. The overall results showed that the conjugate of the second generation with mefenamic acid could be a potential nanocarrier for human prostatic adenocarcinoma cancer treatment, our research will be continued.

Polymer-dendrimer Hybrids as Carriers of Anticancer Agents.

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is important and interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, improve the solubility of drugs, have active molecules in their outer layer, and, due to their nanometric size, they can take advantage of the EPR effect, prolong circulation time and avoid renal clearance. Furthermore, bioactive molecules (could be joined covalently or by host-host interaction), such as drugs, bioimaging molecules, proteins, targeting ligands, "cross-linkable" molecules, or linkages sensitive to internal or external stimuli, can be incorporated into them. The confined multivalent cooperativity and the ability to modify the dendritic structure provide versatility to create and improve the amphiphiles used in the micellar supramolecular field. As discussed in this review, the most studied structures are hybrid copolymers, which are formed by the combination of linear polymers and dendrons. Amphiphilic dendrimer micelles have achieved efficient and promising results in both in vitro and in vivo tests, and this encourages research for their future application in nanotherapies.

Click Reaction in the Synthesis of Dendrimer Drug-delivery Systems.

Drug delivery systems are designed for the targeted delivery and controlled release of medicinal agents. Among the materials employed as drug delivery systems, dendrimers have gained increasing interest in recent years because of their properties and structural characteristics. The use of dendrimer-nanocarrier formulations enhances the safety and bioavailability, increases the solubility in water, improves stability and pharmacokinetic profile, and enables efficient delivery of the target drug to a specific site. However, the synthesis of dendritic architectures through convergent or divergent methods has drawbacks and limitations that disrupt aspects related to design and construction, and consequently, slow down the transfer from academia to industry. In that sense, the implementation of click chemistry has received increasing attention in the last years, as it offers new efficient approaches to obtain dendritic species in good yields and higher monodispersity. This review focuses on recent strategies for building dendrimer drug delivery systems using click reactions from 2015 to early 2021. The dendritic structures showed in this review are based on ß -cyclodextrins (ß-CD), poly(amidoamine) (PAMAM), dendritic poly (lysine) (PLLD), dimethylolpropionic acid (bis-MPA), phosphoramidate (PAD), and poly(propargyl alcohol-4-mercaptobutyric (PPMA).

Nanomedical Applications of Amphiphilic Dendrimeric Micelles.

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, have active molecules in their outer layer, and due to their nanometric size, can take advantage of the enhanced permeability and retention (EPR) effect, prolong the time in circulation and avoid renal clearance. In addition, nanobioactive molecules (joined in covalent form or by host-host interaction), such as drugs, bioimaging molecules, targeting ligands, "crosslinkable" molecules or bonds, sensitive to internal or external stimuli, can be incorporated into them and showed better activity as anticancer agents, siRNA delivery agents as well as antiviral and antiparasitic compounds. The present work is a review of the information published, which is the most important about the synthesis and biological importance of the confined multivalent cooperation and the ability to modify the dendritic structure, provide the versatility to create and improve the amphiphiles used in the micellar supramolecular field. The most studied structures are the hybrid copolymers formed by the combination of linear polymers and dendrons. However, small dendritic molecules that do not involve linear polymers have also been developed, such as Janus dendrimers, facial dendrons, and dendritic amphiphiles with only one dendron. Amphiphilic dendrimer micelles have achieved efficient and promising results, both in in vitro and in vivo tests, which encourage their research for future application in nanotherapies.

Synthesis of flutamide-conjugates.

In this paper, we designed and extended modification basing on the flutamide structure. A series of flutamide-conjugates were obtained with methyl bromoacetate and ethylenediamine. Through the synthesis of two conjugates with 3,5-bis(dodecyloxy)benzoate derivatives, these flutamide conjugates were tested for anticancer activity. Among the compounds tested, the flutamide-conjugates showed good inhibition activity against cancer cell lines U-251, PC-3 and K-562. The conjugates showed a better inhibitory effect than free flutamide and did not show activity against normal COS-7 monkey kidney fibroblast cells. It was also observed that the flutamide conjugates had an inhibitory effect against human colorectal adenocarcinoma HCT-15.

Synthesis and anticancer activity of open-resorcinarene conjugates.

The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.

Improvement of the Anticancer Activity of Chlorambucil and Ibuprofen via Calix[4]arene Conjugates.

BACKGROUND: One of the possible ways of improving the activity and selectivity profile of anticancer agents is to design drug carrier systems employing nanomolecules. Calix[4]arene derivatives and chlorambucil and ibuprofen are important compounds that exhibit interesting anticancer properties. OBJECTIVE: The objective of this article is the synthesis of new calix[4]arene-derivative conjugates of chlorambucil or ibuprofen with potential anticancer activity. METHODS: Cytotoxicity assays were determined using the protein-binding dye sulforhodamine B (SRB) in microculture to measure cell growth as described [19, 20]. Conjugates of chlorambucil and resorcinarene-dendrimers were prepared in 2% DMSO and added into the culture medium immediately before use. Control cells were treated with 2% DMSO. RESULTS: Thus, calix[4]arene-derivative conjugates of chlorambucil or ibuprofen showed good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the calix[4]arene chlorambucil or ibuprofen conjugates employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) and U-251 (human glioblastoma cells) demonstrated that the conjugate was more potent as an antiproliferative agent than free chlorambucil and ibuprofen. The conjugates did not show any activity against the COS-7 African green monkey kidney fibroblast cell line. CONCLUSION: In the paper, we report the synthesis and spectroscopic analyses of new calix[4]arene derivative conjugates of chlorambucil or ibuprofen. Cytotoxicity assays revealed that at 10 µM, the conjugates were very active against K-562 (human chronic myelogenous leukemia cells) and U- 251 (human glioblastoma cells) cancer cells' proliferation. In order to explain the molecular mechanisms involved in the anticancer activity of calix[4]arene chlorambucil or ibuprofen conjugates, our research will be continued.

Anticancer Activity of Water-Soluble Olsalazine-PAMAM-Dendrimer-Salicylic Acid-Conjugates.

Improving the activity and selectivity profile of anticancer agents will require designing drug carrier systems that employ soluble macromolecules. Olsalazine-PAMAM-dendrimer-salicylic acid-conjugates with dendritic arms of different lengths have shown good stability regarding the chemical link between drug and spacer. In this study, the drug release was followed in vitro by ultraviolet (UV) studies. Evaluation of the cytotoxicity of the olsalazine-PAMAM-dendrimer-salicylic acid-conjugates employing a sulforhodamine B (SRB) assay in PC-3 (human prostatic adenocarcinoma) and MCF-7 (human mammary adenocarcinoma) cell lines demonstrated that conjugate 9 was more active as an antiproliferative agent than cisplatin, and no cytotoxicity towards the African green monkey kidney fibroblast (COS-7) cell line was observed in any of the conjugates synthesized in the present work.

In vitro activity of resorcinarene-chlorambucil conjugates for therapy in human chronic myelogenous leukemia cells.

A possible way of improving the activity and selectivity profile of antitumor agents is to design drug carrier systems employing soluble macromolecules. Thus, four resorcinarene-PAMAM-dendrimer conjugates of chlorambucil with different groups in the lower part of the macrocycle and different length dendritic arms showed a good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the resorcinarene-PAMAM-dendrimer-chlorambucil conjugate employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) demonstrated that the conjugate was more potent as an antiproliferative agent than chlorambucil.

Telemonitoring system for patients with chronic kidney disease undergoing peritoneal dialysis: Usability assessment based on a case study.

There are two million people with chronic kidney disease (CKD) worldwide. In Mexico, it is estimated that by 2025, there will be 212 thousand CKD cases. Among the renal replacement treatments, peritoneal dialysis (PD) exists either in the continuous ambulatory (CAPD) or automated (APD) mode, which requires continuous monitoring and strict control. Thus, several software systems have been proposed to perform reliable remote monitoring of patients using PD but also to achieve the goal with effectiveness, efficiency and satisfaction; i.e., in software engineering, this is called usability. However, few studies have addressed usability issues using case studies with patients and medical staff in real domains. In this paper, we present a usability assessment of a telemonitoring system for patients with CKD on peritoneal dialysis treatment through a case study with patients and medical staff of the Mexican Institute of Social Security (IMSS). The usability evaluation was carried out through the application of two satisfaction instruments. These instruments evaluated multiple usability criteria, such as navigability, interactivity, motivation, satisfaction, and applicability. The results obtained from the usability evaluation show that, on average, the services offered by the system have 91.3% acceptance by users (patient-doctors), with the APD and CAPD exchange data registration services having the highest acceptance for patients, with a positive perception of 94.5% and 92.3%, respectively. Meanwhile, for the doctors and nurses, the alarm reception for patients in a risk situation was highest with 95% acceptance. Based on the obtained results, the evaluated telemonitoring system holds wide acceptance, satisfaction, and applicability from patients' and doctors' perspectives. It is also noted that the evaluated system considers and satisfies the requirements and suitable parameters that should be monitored in PD treatment according to studies presented in the literature.

Water-soluble porphyrin-PAMAM-conjugates of melphalan and their anticancer activity.

p-[bis(chloro-2-ethyl)amino]-L-phenylalanine (melphalan) is an approved anti-cancer agent with a broad spectrum of antitumor activity. However, it has some disadvantages, such as poor water-solubility followed by rapid elimination, which reduce the target specificity. To solve these problems, porphyrin- poly(amidoamine) or PAMAM-conjugates of melphalan were synthesized and characterized. The dendrimeric conjugates showed satisfactory water solubility. It was found that the size of the dendrimer played a crucial role in controlling the drug content and diameter of the melphalan-conjugates. The in vitro studies of cell cytotoxicity revealed that by employing the dendrimeric conjugation strategy and using the PAMAM dendritic arms as spacers, the conjugates had good anti-cancer activity and lower toxicity than free melphalan.

Anticancer Activity of Resorcinarene-PAMAM-Dendrimer Conjugates of Flutamide.

METHODS: The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. RESULTS: The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug. CONCLUSION: This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.

Synthesis, Characterization, and Nanomedical Applications of Conjugates between Resorcinarene-Dendrimers and Ibuprofen.

Ibuprofen has been reported to possess anticancer activity. In the present work, four ibuprofen conjugates of resorcinarene-Polyamidoamine PAMAM-dendrimers were synthesized with eight or 16 ibuprofen moieties. The ibuprofen was released from the dendrimers in a dependent manner. The drug-conjugated nanoresorcinarene-dendrimers showed higher cellular uptake than free ibuprofen. In vitro cytotoxicity studies were performed with free ibuprofen and with the synthesized conjugates in U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and MDA-MB-231 (human mammary adenocarcinoma) cancer cell lines by different cytotoxicity assays. Ibuprofen conjugates of the first and second generations showed significant cytotoxic effects towards the human glioblastoma (U251) and human mammary adenocarcinoma (MCF-7, MDA) cell lines. Moreover, the ibuprofen conjugates improved cytotoxicity compared to free ibuprofen. Increased therapeutic efficacy was observed with specific ibuprofen conjugates of the second generation using low doses.

Electrical Properties of Multi-Pyrene/Porphyrin-Dendrimers.

Dendrimers bearing pyrene donor groups have been obtained and act as efficient light-harvesting antennae capable of transferring light energy through space from their periphery to their core. The light-harvesting ability increases with each generation due to an increase in the number of peripheral pyrenes. In order to evaluate the photovoltaic properties of the compounds, thermal evaporated thin films were produced and the voltage response in the presence of visible light was obtained. The energy transfer efficiency was found to be almost quantitative for the first and second generations. The dendrimers have the potential to become integral components of molecular photonic devices.

High Fluorescent Porphyrin-PAMAM-Fluorene Dendrimers.

Two new classes of dendrimers bearing 8 and 32 fluorene donor groups have been synthesized. The first and second generations of these porphyrin-PAMAM-fluorene dendrimers were characterized by 1H-NMR, 13C-NMR, FTIR, UV-vis spectroscopy, elemental analyses and MALDI-TOF mass spectrometry. The UV-vis spectra showed that the individual properties of donor and acceptor moieties were preserved, indicating that the new dendrimers could be used as photosynthetic antennae. Furthermore, for fluorescent spectroscopy, these dendrimers showed good energy transfer.

Synthesis of 5-aryl-1,4-benzodiazepine derivatives attached in resorcinaren-PAMAM dendrimers and their anti-cancer activity.

A series of resorcinaren-PAMAM dendrimers with benzodiazepines in the periphery were synthesized and their anticancer properties studied. The synthesized dendrimers showed potential anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4-benzodiazepine. The dendrimers were characterized by IR, (1)H and (13)C NMR, UV-vis absorption, electrospray (ES) and/or MALDI-TOF mass spectrometries.

Synthesis of porphyrin-dendrimers with a pyrene in the periphery and their cubic nonlinear optical properties.

Dendrons of pyrene derivatives were attached to a porphyrin core. A marked effect in solution for the dendrimers was observed in the absorption spectra. All the compounds obtained were characterized by (1)H-, (13)C-NMR, FTIR, UV-vis, MALDI-TOF or FAB+ mass spectrometry and elemental analysis. The cubic nonlinear optical behavior of some the synthesized compounds was tested via Z-Scan measurements in spin-coated film samples.

Dendrimers containing ferrocene and porphyrin moieties: synthesis and cubic non-linear optical behavior.

Dendrons with ferrocenyl ended groups joined by styryl moieties were attached to a porphyrin core. All the dendrons used for dendrimer synthesis showed trans configuration. The chemical structure of the first generation dendron was confirmed by X-ray crystallographic studies. The structure of the synthesized dendrimers was confirmed by 1H- and 13C-NMR, electrospray mass spectrometry and elemental analysis. Cubic non-linear optical behavior of the ferrocene and porphyrin-containing dendrimers was studied in solid thin films by THG Maker-Fringe technique at 1,260 nm.