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- Gene delivery into mesenchymal stem cells: a biomimetic approach using RGD nanoclusters based on poly(amidoamine) dendrimersPublication . Pandita, Deepti; Santos, José L.; Rodrigues, João; Pêgo, Ana P.; Granja, Pedro L.; Tomás, HelenaPoly(amidoamine) dendrimers (generations 5 and 6) with amine termini were conjugated with peptides containing the arginine-glycine-aspartic acid (RGD) sequence having in view their application as gene delivery vectors. The idea behind the work was to take advantage of the cationic nature of dendrimers and of the integrin targeting capabilities of the RGD motif to improve gene delivery. Dendrimers were used as scaffolds for RGD clustering and, by controlling the number of peptides (4, 8, and 16) linked to each dendrimer, it was possible to evaluate the effect of RGD density on the gene delivery process. The new vectors were characterized in respect to their ability to neutralize and compact plasmid DNA (pDNA). The complexes formed by the vectors and pDNA were studied concerning their size, zeta potential, capacity of being internalized by cells and ability of transferring genes. Transfection efficiency was analyzed, first, by using a pDNA encoding for Enhanced Green Fluorescent Protein and Firefly Luciferase and, second, by using a pDNA encoding for Bone Morphogenetic Protein-2. Gene expression in mesenchymal stem cells was enhanced using the new vectors in comparison to native dendrimers and was shown to be dependent on the electrostatic interaction established between the dendrimer moiety and the cell surface, as well as on the RGD density of nanoclusters. The use of dendrimer scaffolds for RGD cluster formation is a new approach that can be extended beyond gene delivery applications, whenever RGD clustering is important for modulating cellular responses.
- Amphiphilic polymer-mediated formation of laponite-based nanohybrids with robust stability and pH sensitivity for anticancer drug deliveryPublication . Wang, Guoying; Maciel, Dina; Wu, Yilun; Rodrigues, João; Shi, Xiangyang; Yuan, Yuan; Liu, Changsheng; Tomás, Helena; Li, YulinThe development of pH-sensitive drug delivery nanosystems that present a low drug release at the physiological pH and are able to increase the extent of the release at a lower pH value (like those existent in the interstitial space of solid tumors (pH 6.5) and in the intracellular endolysosomal compartments (pH 5.0)) is very important for an efficient and safe cancer therapy. Laponite (LP) is a synthetic silicate nanoparticle with a nanodisk structure (25 nm in diameter and 0.92 nm in thickness) and negative-charged surface, which can be used for the encapsulation of doxorubicin (DOX, a cationic drug) through electrostatic interactions and exhibit good pH sensitivity in drug delivery. However, the colloidal instability of LP still limits its potential clinical applications. In this study, we demonstrate an elegant strategy to develop stable Laponite-based nanohybrids through the functionalization of its surface with an amphiphile PEG-PLA copolymer by a self-assembly process. The hydrophobic block of PEG-PLA acts as an anchor that binds to the surface of drug-loaded LP nanodisks, maintaining the core structure, whereas the hydrophilic PEG part serves as a protective stealth shell that improves the whole stability of the nanohybrids under physiological conditions. The resulting nanocarriers can effectively load the DOX drug (the encapsulation efficiency is 85%), and display a pH-enhanced drug release behavior in a sustained way. In vitro biological evaluation indicated that the DOX-loaded nanocarriers can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher anticancer cytotoxicity than free DOX. The merits of Laponite/PEG-PLA nanohybrids, such as good cytocompatibility, excellent physiological stability, sustained pH-responsive release properties, and improved anticancer activity, make them a promising platform for the delivery of other therapeutic agents beyond DOX.
- Gene delivery using dendrimer/pDNA complexes immobilized in electrospun fibers using the Layer-by-Layer techniquePublication . Ramalingam, Kirthiga; Castro, Rita; Pires, Pedro; Shi, Xiangyang; Rodrigues, João; Xiao, Shili; Tomás, HelenaA gene delivery platform for potential use in tissue engineering applications was developed by surface functionalization of biodegradable electrospun poly(lactic-co-glycolic acid) (PLGA) fibers with nanolayers of chitosan (cationic polymer) and alginate (anionic polymer) using the Layer-by-Layer (LbL) technique. The developed system not only supported the attachment and growth of human Mesenchymal Stem Cells (hMSCs), but also was capable of delivering pDNA/dendrimer complexes and inducing cell differentiation towards the osteogenic lineage when a pDNA codifying for human Bone Morphogenetic Protein-2 (BMP-2) was used. Beyond providing a means for pDNA/dendrimer complex immobilization, the polyelectrolyte coating conferred sustained release properties to the scaffold that resulted in pDNA protection from degradation. The polyelectrolyte coating, by itself, also contributed to enhance cell differentiation.
- Recent therapeutic applications of the theranostic principle with dendrimers in oncologyPublication . Mignani, Serge; Rodrigues, João; Tomás, Helena; Caminade, Anne-marie; Laurent, Régis; Shi, Xiangyang; Majoral, Jean-PierreAt the intersection between treatment and diagnosis,nanoparticlestechnologiesarestronglyimpactingthe development of both therapeutic and diagnostic agents. Consequently, the development of novel modalities for concomitant noninvasive therapy and diagnostics known as theranostics as a single platform has gained significant interests. These multifunctional theranostic platforms include carbon-based nanomaterials (e.g., carbon nanotubes), drug conjugates, aliphatic polymers, micelles, vesicles, core-shell nanoparticles,microbubblesanddendrimersbearingdifferent contrastagentsanddrugs,suchascytotoxiccompoundsinthe oncology domain. Dendrimers emerged as a new class of highly tunable hyperbranched polymers, and have been developed as useful theranostic platforms. Magnetic resonance imaging, gamma scintigraphy, computed tomography and optical imaging are the main techniques developed with dendrimers in the theranostic domain in oncology. Different imaging agents have been used such as Gd(III), 19F, Fe2O3 (MRI), 76Br (PET), 111In, 88Y, 153Gd, 188Re, 131I (SPECT), 177Lu, gold (CT) and boronated groups, siliconnaphthalocyanines, dialkylcarbocyanines and QDs (optical imaging dyes).
- Antitumor efficacy of doxorubicin-loaded laponite/alginate hybrid hydrogelsPublication . Gonçalves, Mara; Figueira, Priscilla; Maciel, Dina; Rodrigues, João; Shi, Xiangyang; Tomás, Helena; Li, YulinDegradable hybrid hydrogels with improved stability are prepared by incorporating nanodisks of biocompatible laponite (LP) in alginate (AG) hydrogels using Ca2+ as a crosslinker. The Dox‐loaded hybrid hydrogels give a controlled Dox release at physiological environment in a sustained manner. Under conditions that mimic the tumor environment, both the sustainability in the Dox release (up to 17 d) and the release efficiency from LP/AG‐Dox hydrogels are improved. The in situ degradation of these hybrid hydrogels gives rise to nanohybrids that might serve as vehicles for carrying Dox through the cell membrane and diminish the effect of Dox ion‐trapping in the acidic extracellular environment of the tumor and/or in the endo‐lysosomal cell compartments.
- Engineered non-invasive functionalized dendrimer/dendron-entrapped/complexed gold nanoparticles as a novel class of theranostic (radio)pharmaceuticals in cancer therapyPublication . Mignani, Serge; Shi, Xiangyang; Ceña, Valentin; Rodrigues, João; Tomás, Helena; Majoral, Jean-PierreNanomedicine represents a very significant contribution in current cancer treatment; in addition to surgical intervention, radiation and chemotherapeutic agents that unfortunately also kill healthy cells, inducing highly deleterious and often life-threatening side effects in the patient. Of the numerous nanoparticles used against cancer, gold nanoparticles had been developed for therapeutic applications. Inter alia, a large variety of den drimers, i.e. soft artificial macromolecules, have turned up as non-viral functional nanocarriers for entrapping drugs, imaging agents, and targeting molecules. This review will provide insights into the design, synthesis, functionalization, and development in biomedicine of engineered functionalized hybrid dendrimer-tangled gold nanoparticles in the domain of cancer theranostic. Several aspects are highlighted and discussed such as 1) dendrimer-entrapped gold(0) hybrid nanoparticles for the targeted imaging and treatment of cancer cells, 2) dendrimer encapsulating gold(0) nanoparticles (Au DENPs) for the delivery of genes, 3) Au DENPs for drug delivery applications, 4) dendrimer encapsulating gold radioactive nanoparticles for radiotherapy, and 5) dendrimer/dendron-complexed gold(III) nanoparticles as technologies to take down cancer cells.
- Poly(alkylidenimine) Dendrimers Functionalized with the Organometallic Moiety [Ru(η5-C5H5)(PPh3)2]+ as Promising Drugs Against Cisplatin-Resistant Cancer Cells and Human Mesenchymal Stem CellsPublication . Gouveia, Marisol; Figueira, João; Jardim, Manuel G.; Castro, Rita; Tomás, Helena; Rissanen, Kari; Rodrigues, JoãoHere and for the first time, we show that the organometallic compound [Ru(η5-C5H5)(PPh3)2Cl] (RuCp) has potential to be used as a metallodrug in anticancer therapy, and further present a new approach for the cellular delivery of the [Ru(η5-C5H5)(PPh3)2]+ fragment via coordination on the periphery of low-generation poly(alkylidenimine) dendrimers through nitrile terminal groups. Importantly, both the RuCp and the dendrimers functionalized with [Ru(η5-C5H5)(PPh3)2]+ fragments present remarkable toxicity towards a wide set of cancer cells (Caco-2, MCF-7, CAL-72, and A2780 cells), including cisplatin-resistant human ovarian carcinoma celllines(A2780cisRcells). Also,RuCpandthepreparedmetallodendrimersareactiveagainsthuman mesenchymal stem cells (hMSCs), which are often found in the tumor microenvironment where they seem to play a role in tumor progression and drug resistance.
- Fine tuning of the pH-sensitivity of laponite–doxorubicin nanohybrids by polyelectrolyte multilayer coatingPublication . Xiao, Shili; Castro, Rita; Maciel, Dina; Gonçalves, Mara; Shi, Xiangyang; Rodrigues, João; Tomás, HelenaDespite the wide research done in the field, the development of advanced drug delivery systems with improved drug delivery properties and effective anticancer capability still remains a great challenge. Based on previous work that showed the potentialities of the nanoclay Laponite as a pH-sensitive doxorubicin (Dox) delivery vehicle, herein we report a simple method to modulate its extent of drug release at different pH values. This was achieved by alternate deposition of cationic poly(allylamine) hydrochloride and anionic poly(sodium styrene sulfonate) (PAH/PSS) polyelectrolytes over the surface of Dox-loaded Laponite nanoparticles using the electrostatic layer-by-layer (LbL) self-assembly approach. The successful formation of polyelectrolyte multilayer-coated Dox/Laponite systems was confirmed by Dynamic Light Scattering and zeta potential measurements. Systematic studies were performed to evaluate their drug release profiles and anticancer efficiency. Our results showed that the presence of the polyelectrolyte multilayers improved the sustained release properties of Laponite and allowed a fine tuning of the extension of drug release at neutral and acidic pH values. The cytotoxicity presented by polyelectrolyte multilayer-coated Dox/Laponite systems towards MCF-7 cells was in accordance with the drug delivery profiles. Furthermore, cellular uptake studies revealed that polyelectrolyte multilayer-coated Dox/Laponite nanoparticles can be effectively internalized by cells conducting to Dox accumulation in cell nucleus.
- Electrochemical characterization of cobalt-based alloys using the mini-cell systemPublication . Nascimento, M. Lúcia; Mueller, Wolf-Dieter; Carvalho, Ana C.; Tomás, HelenaThe aim of this work was to investigate the electrochemical behavior of cobaltbased alloys of different compositions using the mini-cell system (MCS) and to test the sensitivity of this technique in the detection of variations in the electrochemical behavior caused by the different compositions of cobalt-based alloys. Methods. The electrochemical measurements were performed on two cobalt-based alloys, having a small content of gold (B¨arlight and Gold Core); one cobalt–platinum–ruthenium alloy (Porta Smart) and one classical Co-based alloy (Wironit), in two different electrolytes, 1% NaCl and phosphate buffered solution (PBS). Results. Based on I versus E curves, enhanced pitting corrosion capability was observed for the cobalt-based alloys, especially for those with lower chromium content and with the addition of a small amount of gold. The alloying of Co with Pt and Ru (Porta Smart), and the standard Co-based alloy do not show any critical instability; in contrast, a small addition of Au enhanced the pitting corrosion activity and reduced the corrosion stability. For higher alloy stability, a minimum 30% atomic ratio of chromium in the alloy composition is necessary. Furthermore, it was shown that MCS has sensitivity for the qualitative comparison of the alloys as well as in the electrochemical characterization of each alloy. Significance. Electrochemical measurements are essential to assess the quality of an alloy. MCSmighthelpinunderstandingtheroletheelementsplayintheelectrochemicalbehavior of the alloys and at the same time contribute to the selection of the alloys in terms of their quality,evenbeforemorecomplextestsinvitroorinvivoareapplied,andmightreducethe costs for materials research.
- Green polymers toward nanobiotechnology(I): synthesis of glycopolypeptides and their analoguesPublication . Wang, Zhao; Neves, Ana Rute; Olim, Filipe; Tomás, Helena; Tang, Shi; Sheng, RuilongHarnessing natural-based renewable molecular resources to construct functional synthetic green polymers is a promising research frontier at the interface of sustainable/green chemistry, polymer chemistry and nanobiotechnology. As natural glycoprotein mimics/analogues and biocompatible building blocks of nanobio- materials, synthetic functional glycopolypeptides and their structural/functional analogues have attracted great attentions in recent years. This mini-perspective article reviewed current synthetic strategies and methods of glycopolypeptides and their analogues. The pros and cons of the synthesis protocols were discussed, moreover, possible future perspectives in this field were also stated.