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- Zwitterion-functionalized dendrimer-entrapped gold nanoparticles for serum-enhanced gene delivery to inhibit cancer cell metastasisPublication . Xiong, Zhijuan; Alves, Carla S.; Wang, Jianhua; Li, Aijun; Liu, Jinyuan; Shen, Mingwu; Rodrigues, João; Tomás, Helena; Shi, XiangyangWe demonstrate a novel serum-enhanced gene delivery approach using zwitterion-functionalized dendrimer-entrapped gold nanoparticles (Au DENPs) as a non-viral vector for inhibition of cancer cell metastasis in vitro. Poly(amidoamine) dendrimers of generation 5 decorated with zwitterion carboxybe taine acrylamide (CBAA) and lysosome-targeting agent morpholine (Mor) were utilized to entrap gold NPs. We show that both Mor-modified and Mor-free Au DENPs are cytocompatible and can effectively deliver plasmid DNA encoding different reporter genes to cancer cells in medium with or without serum. Strikingly, due to the antifouling property exerted by the attached zwitterion CBAA, the gene delivery efficiency of Mor-modified Au DENPs and the Mor-free Au DENPs in the serum-containing medium are 1.4 and 1.7 times higher than the corresponding vector in serum-free medium, respectively. In addition, the Mor-free vector has a better gene expression efficiency than the Mor-modified one although the Mor modification enables the polyplexes to have enhanced cancer cell uptake. Wound healing and hyperme thylated in cancer 1 (HIC1) protein expression assay data reveal that the expression of HIC1 gene in cancer cells enables effective inhibition of cell migration. Our findings suggest that the created zwitterion-functionalized Au DENPs may be employed as a powerful vector for serum-enhanced gene therapy of different diseases.
- Multifunctional dendrimer-entrapped gold nanoparticles conjugated with Doxorubicin for pH-responsive drug delivery and targeted computed tomography imagingPublication . Zhu, Jingyi; Wang, Guoying; Alves, Carla S.; Tomás, Helena; Xiong, Zhijuan; Shen, Mingwu; Rodrigues, João; Shi, XiangyangNovel theranostic nanocarriers exhibit a desirable potential to treat diseases based on their ability to achieve targeted therapy while allowing for real-time imaging of the disease site. Development of such theranostic platforms is still quite challenging. Herein, we present the construction of multifunctional dendrimer-based theranostic nanosystem to achieve cancer cell chemotherapy and computed tomography (CT) imaging with targeting specificity. Doxorubicin (DOX), a model anticancer drug, was first covalently linked onto the partially acetylated poly(amidoamine) dendrimers of generation 5 (G5) prefunctionalized with folic acid (FA) through acid-sensitive cis-aconityl linkage to form G5·NHAc-FA-DOX conjugates, which were then entrapped with gold (Au) nanoparticles (NPs) to create dendrimer-entrapped Au NPs (Au DENPs). We demonstrate that the prepared DOX-Au DENPs possess an Au core size of 2.8 nm, have 9.0 DOX moieties conjugated onto each dendrimer, and are colloid stable under different conditions. The formed DOX-Au DENPs exhibit a pH-responsive release profile of DOX because of the cis-aconityl linkage, having a faster DOX release rate under a slightly acidic pH condition than under a physiological pH. Importantly, because of the coexistence of targeting ligand FA and Au core NPs as a CT imaging agent, the multifunctional DOX-loaded Au DENPs afford specific chemotherapy and CT imaging of FA receptor-overexpressing cancer cells. The constructed DOX-conjugated Au DENPs hold a promising potential to be utilized for simultaneous chemotherapy and CT imaging of various types of cancer cells.
- 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.
- RGD peptide-modified multifunctional dendrimer platform for drug encapsulation and targeted inhibition of cancer cellsPublication . He, Xuedan; Alves, Carla S.; Oliveira, Nilsa; Rodrigues, João; Zhu, Jingyi; Bányai, István; Tomás, Helena; Shi, XiangyangDevelopment of multifunctional nanoscale drug-delivery systems for targeted cancer therapy still remains a great challenge. Here, we report the synthesis of cyclic arginine-glycine-aspartic acid (RGD) peptide-conjugated generation 5 (G5) poly(amidoamine) dendrimers for anticancer drug encapsulation and targeted therapy of cancer cells overexpressing αvβ3 integrins. In this study, amine-terminated G5 dendrimers were used as a platform to be sequentially modified with fluorescein isothiocyanate (FI) via a thiourea linkage and RGD peptide via a polyethylene glycol (PEG) spacer, followed by acetylation of the remaining dendrimer terminal amines. The developed multifunctional dendrimer platform (G5.NHAc-FI-PEG-RGD) was then used to encapsulate an anticancer drug doxorubicin (DOX). We show that approximately six DOX molecules are able to be encapsulated within each dendrimer platform. The formed complexes are water-soluble, stable, and able to release DOX in a sustained manner. One- and two-dimensional NMR techniques were applied to investigate the interaction between dendrimers and DOX, and the impact of the environmental pH on the release rate of DOX from the dendrimer/DOX complexes was also explored. Furthermore, cell biological studies demonstrate that the encapsulation of DOX within the G5.NHAc-FI-PEG-RGD dendrimers does not compromise the anticancer activity of DOX and that the therapeutic efficacy of the dendrimer/DOX complexes is solely related to the encapsulated DOX drug. Importantly, thanks to the role played by RGD-mediated targeting, the developed dendrimer/drug complexes are able to specifically target αvβ3 integrin-overexpressing cancer cells and display specific therapeutic efficacy to the target cells. The developed RGD peptide-targeted multifunctional dendrimers may thus be used as a versatile platform for targeted therapy of different types of αvβ3 integrin-overexpressing cancer cells.
- Laponite®: a key nanoplatform for biomedical applications?Publication . Tomás, Helena; Alves, Carla S.; Rodrigues, JoãoLaponite® is a synthetic smectite clay that already has many important technological applications, which go beyond the conventional uses of clays in pharmaceutics and cosmetics. In biomedical applications, particularly in nanomedicine, this material holds great potential. Laponite® is a 2-dimensional (2D) nanomaterial composed of disk-shaped nanoscale crystals that have a high aspect ratio. These disks can strongly interact with many types of chemical entities (from small molecules or ions, to natural or synthetic polymers, to different inorganic nanoparticles) and are also easily functionalized and readily degraded in the physiological environment giving rise to non-toxic and even bioactive products. This review will highlight the potential of Laponite® as a nanomaterial in the fields of drug delivery, bioimaging, tissue engineering and regenerative medicine. New concepts, as well as novel innovative materials that stand out from the usual ones due to the unique properties of Laponite®, will also be presented and discussed.