Browsing by Author "Shi, Xiangyang"
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- 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.
- An exploratory study to evaluate the potential of nanohydroxyapatite as a powerful sorbent for efficient extraction of volatile organic metabolites, potential biomarkers of cancerPublication . Qiao, Zheng; Perestrelo, Rosa; Shi, Xiangyang; Rodrigues, João; Câmara, José S.Developing early-stage diagnostic methods which are specific, highly sensitive and non-invasive for cancer has received much attention. In this paper, nanohydroxyapatite (NHA) was for the first time used as a sorbent to extract volatile organic metabolites (VOMs) which are considered as potential biomarkers of cancer, such as hexanal, heptanal, decanal, benzaldehyde, 4-heptanone, phenol, undecane, and 5-methyl-2-furfural. The extraction process was performed by simply dispersing nanohydroxyapatite into working solution containing targeted VOMs and then eluting the centrifuged sorbent with an organic solvent. Batch techniques were performed to optimize the experimental variables affecting the extraction of targeted VOMs such as the sorbent amount, adsorption time, elution time and types of elution solvent. The eluent was collected, concentrated and analyzed by gas chromatography-mass spectrometry (GC-qMS). Under optimized conditions, the results obtained demonstrated a good linearity (r2 ≥ 0.993), over the linear dynamic range, for all urinary volatile metabolites investigated. The proposed strategy provided limits of detection (LODs) ranging from 9.8 ng L−1 to 69.5 ng L−1 and limits of quantification (LOQs) from 32.5 ng L−1 to 231.6 ng L−1. The method also afforded satisfactory results in terms of the matrix effect (72.8–96.1%) and recoveries (accuracy) higher than 70% for most of the studied VOMs. The intra-day and inter-day precision was lower than 3% and 13%, respectively. The established method has been successfully applied to the determination of the target urinary VOMs, from cancer patients, described as potential cancer biomarkers.
- Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimersPublication . Liao, Huihui; Liu, Hui; Li, Yulin; Zhang, Mengen; Tomás, Helena; Shen, Mingwu; Shi, XiangyangWe report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG-COOH) onto the surface of generation 5 amine-terminated PAMAM dendrimer (G5.NH2), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG-COOH/G5.NH2, G5.NHAc-mPEGn (n55, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc-mPEGn/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications.
- 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.
- Attapulgite-doped electrospun poly(lactic-co-glycolic acid) nanofibers enable enhanced osteogenic differentiation of human mesenchymal stem cellsPublication . Wang, Zhe; Zhao, Yili; Luo, Yu; Wang, Shige; Shen, Mingwu; Tomás, Helena; Zhu, Meifang; Shi, XiangyangThe extracellular matrix mimicking property of electrospun polymer nanofibers affords their uses as an ideal scaffold material for differentiation of human mesenchymal stem cells (hMSCs), which is important for various tissue engineering applications. Here, we report the fabrication of electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers incorporated with attapulgite (ATT) nanorods, a clay material for osteogenic differentiation of hMSCs. We show that the incorporation of ATT nanorods does not significantly change the uniform morphology and the hemocompatibility of the PLGA nanofibers; instead the surface hydrophilicity and cytocompatibility of the hybrid nanofibers are slightly improved after doping with ATT. Alkaline phosphatase activity, osteocalcin secretion, calcium content, and von Kossa staining assays reveal that hMSCs are able to be differentiated to form osteoblast-like cells onto both PLGA and PLGA–ATT composite nanofibers in osteogenic medium. Most strikingly, the doped ATT within the PLGA nanofibers is able to induce the osteoblastic differentiation of hMSCs in growth medium without the inducing factor of dexamethasone. The fabricated organic/inorganic hybrid ATT-doped PLGA nanofibers may find many applications in the field of tissue engineering and regenerative medicine.
- Bench-to-bedside translation of dendrimers: reality or utopia? A concise analysisPublication . Mignani, Serge; Rodrigues, João; Tomás, Helena; Roy, René; Shi, Xiangyang; Majoral, Jean-PierreNanomedicine, which is an application of nanotechnologies in healthcare is developed to improve the treatments and lives of patients suffering from a range of disorders and to increase the successes of drug candidates. Within the nanotechnology universe, the remarkable unique and tunable properties of dendrimers have made them promising tools for diverse biomedical applications such as drug delivery, gene therapy and diagnostic. Up-to-date, very few dendrimers has yet gained regulatory approval for systemic administration, why? In this critical review, we briefly focus on the list of desired basic dendrimer requirements for decision-making purpose by the scientists (go/no-go decision), in early development stages, to become clinical candidates, and to move towards Investigational New Drugs (IND) application submission. In addition, the successful translation between research and clinic should be performed by the implementation of a simple roadmap to jump the 'valley of death' successfully.
- Biodegradable polymer nanogels for drug/nucleic acid deliveryPublication . Li, Yulin; Maciel, Dina; Rodrigues, João; Shi, Xiangyang; Tomás, Helena
- Carbon nanotube-incorporated multilayered cellulose acetate nanofibers for tissue engineering applicationsPublication . Luo, Yu; Wang, Shige; Shen, Mingwu; Qi, Ruiling; Fang, Yi; Guo, Rui; Cai, Hongdong; Cao, Xueyan; Tomás, Helena; Zhu, Meifang; Shi, XiangyangWe report the fabrication of a novel carbon nanotube-containing nanofibrous polysaccharide scaffolding material via the combination of electrospinning and layer-by-layer (LbL) self-assembly techniques for tissue engineering applications. In this approach, electrospun cellulose acetate (CA) nanofibers were assembled with positively charged chitosan (CS) and negatively charged multiwalled carbon nanotubes (MWCNTs) or sodium alginate (ALG) via a LbL technique. We show that the 3-dimensional fibrous structures of the CA nanofibers do not appreciably change after the multilayered assembly process except that the surface of the fibers became much rougher than that before assembly. The incorporation of MWCNTs in the multilayered CA fibrous scaffolds tends to endow the fibers with improved mechanical property and promote fibroblast attachment, spreading, and proliferation when compared with CS/ALG multilayer-assembled fibrous scaffolds. The approach to engineering the nanofiber surfaces via LbL assembly likely provides many opportunities for new scaffolding materials design in various tissue engineering applications.
- Dendrimer-assisted formation of fluorescent nanogels for drug delivery and intracellular imagingPublication . Gonçalves, Mara; Maciel, Dina; Capelo, Débora; Xiao, Shili; Sun, Wenjie; Shi, Xiangyang; Rodrigues, João; Tomás, Helena; Li, YulinAlthough, in general, nanogels present a good biocompatibility and are able to mimic biological tissues, their unstability and uncontrollable release properties still limit their biomedical applications. In this study, a simple approach was used to develop dual-cross-linked dendrimer/alginate nanogels (AG/G5), using CaCl2 as cross-linker and amine-terminated generation 5 dendrimer (G5) as a cocrosslinker, through an emulsion method. Via their strong electrostatic interactions with anionic AG, together with cross-linker Ca(2+), G5 dendrimers can be used to mediate the formation of more compact structural nanogels with smaller size (433 ± 17 nm) than that (873 ± 116 nm) of the Ca(2+)-cross-linked AG nanogels in the absence of G5. Under physiological (pH 7.4) and acidic (pH 5.5) conditions, the sizes of Ca(2+)-cross-linked AG nanogels gradually decrease probably because of their degradation, while dual-cross-linked AG/G5 nanogels maintain a relatively more stable structure. Furthermore, the AG/G5 nanogels effectively encapsulate the anticancer drug doxorubicin (Dox) with a loading capacity 3 times higher than that of AG nanogels. The AG/G5 nanogels were able to release Dox in a sustained way, avoiding the burst release observed for AG nanogels. In vitro studies show that the AG/G5-Dox NGs were effectively taken up by CAL-72 cells (a human osteosarcoma cell line) and maintain the anticancer cytotoxicity levels of free Dox. Interestingly, G5 labeled with a fluorescent marker can be integrated into the nanogels and be used to track the nanogels inside cells by fluorescence microscopy. These findings demonstrate that AG/G5 nanogels may serve as a general platform for therapeutic delivery and/or cell imaging.
- Dendrimers in combination with natural products and analogues as anti-cancer agentsPublication . Mignani, Serge; Rodrigues, João; Tomás, Helena; Zablocka, Maria; Shi, Xiangyang; Caminade, Anne-marie; Majoral, Jean-PierreFor the first time, an overview of dendrimers in combination with natural products and analogues as anti-cancer agents is presented. This reflects the development of drug delivery systems, such as dendrimers, to tackle cancers. The most significant advantages of using dendrimers in nanomedicine are their high biocompatibility, good water solubility, and their entry - with or without encapsulated, complexed or conjugated drugs - through an endocytosis process. This strategy has accelerated over the years in order to develop nanosystems as nanocarriers, to decrease the intrinsic toxicity of anti-cancer agents, to decrease the drug side effects, to increase the efficacy of the treatment, and consequently to improve patient compliance.