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- 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.
- An integrative approach based on GC–qMS and NMR metabolomics data as a comprehensive strategy to search potential breast cancer biomarkersPublication . Silva, Catarina Luís; Perestrelo, Rosa; Capelinha, Filipa; Tomás, Helena; Câmara, José S.Introduction Globally, breast cancer (BC) is leading at the top of women's diseases and, as a multifactorial disease, there is the need for the development of new approaches to aid clinicians on monitoring BC treatments. In this sense, metabo lomic studies have become an essential tool allowing the establishment of interdependency among metabolites in biological samples. Objective The combination of nuclear magnetic resonance (NMR) and gas chromatography–quadrupole mass spectrometry (GC–qMS) based metabolomic analyses of urine and breast tissue samples from BC patients and cancer-free individuals was used. Methods Multivariate statistical tools were used in order to obtain a panel of metabolites that could discriminate malignant from healthy status assisting in the diagnostic feld. Urine samples (n=30), cancer tissues (n=30) were collected from BC patients, cancer-free tissues were resected outside the tumor margin from the same donors (n=30) while cancer-free urine samples (n=40) where obtained from healthy subjects and analysed by NMR and GC–qMS methodologies. Results The orthogonal partial least square discriminant analysis model showed a clear separation between BC patients and cancer-free subjects for both classes of samples. Specifcally, for urine samples, the goodness of ft (R2 Y) and predictive ability (Q2 ) was 0.946 and 0.910, respectively, whereas for tissue was 0.888 and 0.813, revealing a good predictable accuracy. The discrimination efciency and accuracy of tissue and urine metabolites was ascertained by receiver operating charac teristic curve analysis that allowed the identifcation of metabolites with high sensitivity and specifcity. The metabolomic pathway analysis identifed several dysregulated pathways in BC, including those related with lactate, valine, aspartate and glutamine metabolism. Additionally, correlations between urine and tissue metabolites were investigated and fve metabo lites (e.g. acetone, 3-hexanone, 4-heptanone, 2-methyl-5-(methylthio)-furan and acetate) were found to be signifcant using a dual platform approach. Conclusion Overall, this study suggests that an improved metabolic profle combining NMR and GC–qMS may be useful to achieve more insights regarding the mechanisms underlying cancer.
- Polyethylenimine nanogels incorporated with ultrasmall iron oxide nanoparticles and doxorubicin for MR imaging-guided chemotherapy of tumorsPublication . Zou, Yu; Li, Du; Wang, Yue; Ouyang, Zhijun; Peng, Yucheng; Tomás, Helena; Xia, Jindong; Rodrigues, João; Shen, Mingwu; Shi, XiangyangDevelopment of versatile nanoplatforms for cancer theranostics remains a hot topic in the area of nanomedicine. We report here a general approach to create polyethylenimine (PEI)-based hybrid nanogels (NGs) incorporated with ultrasmall iron oxide (Fe3O4) nanoparticles (NPs) and doxorubicin for T1-weighted MR imaging guided chemotherapy of tumors. In this study, PEI NGs were first prepared using an inverse emulsion approach along with Michael addition reaction to cross-link the NGs, modified with citric acid stabilized ultrasmall Fe3O4 NPs through 1-ethyl-3-(3-(dimethylamino)- propyl) carbodiimide hydrochloride (EDC) coupling, and physically loaded with anticancer drug doxorubicin (DOX). The formed hybrid NGs possess good water dispersibility and colloidal stability, excellent DOX loading efficiency (51.4%), pH-dependent release profile of DOX with an accelerated release rate under acidic pH, and much higher r1 relaxivity (2.29 mM−1 s −1 ) than free ultrasmall Fe3O4 NPs (1.15 mM−1 s −1 ). In addition, in contrast to the drug-free NGs that possess good cytocompatibility, the DOX-loaded hybrid NGs display appreciable therapeutic activity and can be taken up by cancer cells in vitro. With these properties, the developed hybrid NGs enabled effective inhibition of tumor growth under the guidance of T1-weighted MR imaging. The developed hybrid NGs may be applied as a versatile nanoplatform for MR imaging-guided chemotherapy of tumors.
- Use of half-generation PAMAM dendrimers (G0. 5–G3. 5) with carboxylate end-groups to improve the DACHPtCl2 and 5-FU efficacy as anticancer drugsPublication . Camacho, Cláudia; Tomás, Helena; Rodrigues, JoãoThe DACHPtCl2 compound (trans-(R,R)-1,2-diaminocyclohexanedichloroplatinum(II)) is a potent anticancer drug with a broad spectrum of activity and is less toxic than oxaliplatin (trans-l-diaminocyclohexane oxalate platinum II), with which it shares the active metal fragment DACHPt. Nevertheless, due to poor water solubility, its use as a chemotherapeutic drug is limited. Here, DACHPtCl2 was conjugated, in a bidentate form, with half-generation PAMAM dendrimers (G0.5–G3.5) with carboxylate end-groups, and the resulting conjugates were evaluated against various types of cancer cell lines. In this way, we aimed at increasing the solubility and availability at the target site of DACHPt while potentially reducing the adverse side effects. DNA binding assays showed a hyperchromic effect compatible with DNA helix’s disruption upon the interaction of the metallodendrimers and/or the released active metallic fragments with DNA. Furthermore, the prepared DACHPt metallodendrimers presented cytotoxicity in a wide set of cancer cell lines used (the relative potency regarding oxaliplatin was in general high) and were not hemotoxic. Importantly, their selectivity for A2780 and CACO-2 cancer cells with respect to non-cancer cells was particularly high. Subsequently, the anticancer drug 5-FU was loaded in a selected metallodendrimer (the G2.5COO(DACHPt)16) to investigate a possible synergistic effect between the two drugs carried by the same dendrimer scaffold and tested for cytotoxicity in A2780cisR and CACO-2 cancer cell lines. This combination resulted in IC50 values much lower than the IC50 for 5-FU but higher than those found for the metallodendrimers without 5-FU. It seems, thus, that the metallic fragment-induced cytotoxicity dominates over the cytotoxicity of 5-FU in the set of considered cell lines.
- Engineered fluorescent carbon dots and G4-G6 PAMAM dendrimer nanohybrids for bioimaging and gene deliveryPublication . Martins, Ivo; Tomás, Helena; Lahoz, Fernando; Rodrigues, JoãoABSTRACT: Carbon dots (CDs) and G4-G6 (polyamidoamine)- PAMAM-NH2 dendrimers were self-assembled to produce CDs@ PAMAM nanohybrids for transfection and bioimaging purposes. CDs were synthesized by the hydrothermal method, using ascorbic acid as a starting precursor and characterized by transmission electron microscopy, UV−Vis, and fluorescence (in solution and solid-state) techniques. CDs were electrostatically combined with PAMAM dendrimers at room temperature, and the UV−Vis, fluorescence, and NMR spectroscopies were used to confirm the self-assembly. When compared to pristine CDs, nanohybrids were more photostable, resisting high acidic and basic pH. Moreover, they were considerably internalized by cells, as assessed by flow cytometry and fluorescence microscopy, and, when excited, displayed multi color emission easily quantified and visualized. These nanoscale hybrids, coined hybridplexes, can condense pDNA and transfecting cells successfully, particularly the G5 CDs@PAMAM nanohybrids. In summary, CDs prepared in mild and smooth lab conditions, showing good optical properties, were used to prepare elegantly CDs@PAMAM nanohybrids with promising biomedical applications.
- New insights into the blue intrinsic fluorescence of oxidized PAMAM dendrimers considering their use as bionanomaterialsPublication . Camacho, Cláudia S.; Urgellés, Marta; Tomás, Helena; Lahoz, Fernando; Rodrigues, JoãoLike other bionanomaterials, dendrimers are usually labelled with fluorescent compounds in order to be optically detected within cells. However, this process can interfere with their biological properties, so it is crucial to find other solutions for their traceability. Here, the blue intrinsic fluorescence of amine terminated poly(amidoamine) (PAMAM) dendrimers was enhanced using oxidative treatment with ammonium persulfate (APS). The effects of dendrimer generation (G3, G4, and G5) and pH on the spectroscopic behavior of both pristine and APS-treated PAMAM dendrimers were studied in aqueous solution. Overall, the results pointed out that there are at least two types of emitting electron-rich hetero-atomic sub-luminophores (HASLs) confined within the dendrimer scaffold that have very close maximum emission wavelengths and whose emission properties strongly depend on pH. The APS treatment significantly enhanced the fluorescence intensity by leading to the protonation of the interior of the dendrimer. However, fluorescence intensity was not only dependent on the number of HASLs in the dendrimer scaffold (i.e., on dendrimer generation), but also on the rigidification suffered by the dendrimer due to the acidic environment (at low pH values, APS-treated G4 was indeed the most emissive species). Moreover, photoluminescence studies with lyophilized samples were also conducted, which confirmed the coexistence of more than one type of HASLs emitting in the dendrimer structure. The APS treatment affected these HASLs to a different extent. Time-resolved fluorescence experiments always showed higher average lifetimes of HASLs for APS-treated dendrimers than for pristine ones, in accordance with the fluorescence intensity results. On the other hand, the fraction and lifetimes of HASLs in APS-treated dendrimers were similar in solution and the lyophilized form. This behaviour was different for the pristine dendrimers that presented increased luminescence upon aggregation. Finally, the highly emissive oxidized dendrimers were shown not only to be much less cytotoxic and hemotoxic than pristine dendrimers but also to be detectable inside cells upon excitation with UV light.
- Prodrug Systems (II): a perspective of Polymer-based Doxorubicin Prodrug systems towards chemotherapyPublication . Wang, Zhao; Olim, Filipe; Sun, Jingjing; Neves, Ana Rute; Mendes, Fátima; Tomás, Helena; Sheng, RuilongUtilizing biocompatible polymers as platforms to covalently conjugate with chemotherapeutics to construct polymer-based prodrugs and their nano drug delivery systems has attracted great attention in recent years. This perspective reviewed state-of-the-arts for polymer-based doxorubicin prodrugs and the related nanodelivery systems, including: (1) pH-responsive polymer-doxorubicin prodrugs/conjugates; (2) pH/redox dual responsive prodrugs/conjugates; (3) reactive oxygen species/hypoxia-responsive polymer-doxorubicin prodrugs; (4) tumor receptor targeting polymer prodrugs; (5) enzyme-responsive polymer-doxorubicin prodrugs. Finally, possible future perspectives were also stated and discussed.
- Physicochemical properties and cell viability of shrimp chitosan films as affected by film casting solvents. I-potential use as wound dressingPublication . Eulálio, Hugo Yves C.; Vieira, Mariana; Fideles, Thiago B.; Tomás, Helena; Silva, Suédina M. L.; Peniche, Carlos A.; Fook, Marcus Vinícius L.: Chitosan solubility in aqueous organic acids has been widely investigated. However, most of the previous works have been done with plasticized chitosan films and using acetic acid as the film casting solvent. In addition, the properties of these films varied among studies, since they are influenced by different factors such as the chitin source used to produce chitosan, the processing variables involved in the conversion of chitin into chitosan, chitosan properties, types of acids used to dissolve chitosan, types and amounts of plasticizers and the film preparation method. Therefore, this work aimed to prepare chitosan films by the solvent casting method, using chitosan derived from Litopenaeus vannamei shrimp shell waste, and five different organic acids (acetic, lactic, maleic, tartaric, and citric acids) without plasticizer, in order to evaluate the effect of organic acid type and chitosan source on physicochemical properties, degradation and cytotoxicity of these chitosan films. The goal was to select the best suited casting solvent to develop wound dressing from shrimp chitosan films. Shrimp chitosan films were analyzed in terms of their qualitative assessment, thickness, water vapor permeability (WVP), water vapor transmission rate (WVTR), wettability, tensile properties, degradation in phosphate buffered saline (PBS) and cytotoxicity towards human fibroblasts using the resazurin reduction method. Regardless of the acid type employed in film preparation, all films were transparent and slightly yellowish, presented homogeneous surfaces, and the thickness was compatible with the epidermis thickness. However, only the ones prepared with maleic acid presented adequate characteristics of WVP, WVTR, wettability, degradability, cytotoxicity and good tensile properties for future application as a wound dressing material. The findings of this study contributed not only to select the best suited casting solvent to develop chitosan films for wound dressing but also to normalize a solubilization protocol for chitosan, derived from Litopenaeus vannamei shrimp shell waste, which can be used in the pharmaceutical industry.
- Cytocompatible cellulose nanofibers from invasive plant species Agave americana L. and Ricinus communis L.: a renewable green source of highly crystalline nanocellulosePublication . Evdokimova, Olga L.; Alves, Carla S.; Krsmanović Whiffen, Radenka M.; Ortega, Zaida; Tomás, Helena; Rodrigues, João: In this study, the fibers of invasive species Agave americana L. and Ricinus communis L. were successfully used for the first time as new sources to produce cytocompatible and highly crystalline cellulose nanofibers. Cellulose nanofibers were obtained by two methods, based on either alkaline or acid hydrolysis. The morphology, chemical composition, and crystallinity of the obtained materials were characterized by scanning electron microscopy (SEM) together with energy-dispersive X-ray spectroscopy (EDX), dynamic light scattering (DLS), X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. The crystallinity indexes (CIs) of the cellulose nanofibers extracted from A. americana and R. communis were very high (94.1% and 92.7%, respectively). Biological studies evaluating the cytotoxic effects of the prepared cellulose nanofibers on human embryonic kidney 293T (HEK293T) cells were also performed. The nanofibers obtained using the two different extraction methods were all shown to be cytocompatible in the concentration range assayed (i.e., 0‒500 µg/mL). Our results showed that the nanocellulose extracted from A. americana and R. communis fibers has high potential as a new renewable green source of highly crystalline cellulose-based cytocompatible nanomaterials for biomedical applications.
- Prodrug Systems (I): Lipid-based Doxorubicin Prodrugs and their nanodelivery systemsPublication . Olim, Filipe; Neves, Ana Rute; Wang, Zhao; Sun, Jingjing; Tomás, Helena; Sheng, RuilongUsing natural lipids to covalently connect with antitumor agents to construct lipid-based molecular prodrugs and their nanosystems is a promising research frontier for sustainable medicinal chemistry, nanobiotechnology and tumor chemotherapy. This paper reviewed recent progress of lipid-based doxorubicin (molecular) prodrugs and their nanodelivery systems, including lipid-doxorubicin prodrugs, stimuli-responsive lipid-doxorubicin prodrugs, and lipid-doxorubicin prodrug-based drug co-delivery nanosystems. Additionally, possible future research outlooks in this field were also discussed.