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Among the most lethal forms of cancer, malignant brain tumors persist as one of the greatest challenges faced by oncologists, where nanotechnology-driven theranostics can play a critical role in developing novel polymer-based supramolecular nanoarchitectures with multifunctional and multi-modal characteristics to fight cancer. However, it is virtually a consensus that, besides the complexity of active delivering anticancer drugs by the nanocarriers to the tumor site, the current evaluation methods primarily relying on in vitro assays and in vivo animal models have been accounted for the low translational effectiveness to clinical applications. In this view, the chick chorioallantoic membrane (CAM) assay has been increasingly recognized as one of the best preclinical models to study the effects of anticancer drugs on the tumor microenvironment (TME). Thus, in this study, we designed, characterized, and developed novel hybrid nanostructures encompassing chemically functionalized carboxymethylcellulose (CMC) with mitochondria-targeting pro-apoptotic peptide (KLA) and cell-penetrating moiety (cysteine, CYS) with fluorescent inorganic semiconductor (Ag-In-S, AIS) for simultaneously bioimaging and inducing glioblastoma cancer cell (U-87 MG, GBM) death. The results demonstrated that the CMC-peptide macromolecules produced supramolecular vesicle-like nanostructures with aqueous colloidal stability suitable as nanocarriers for passive and active targeting of cancer tumors. The optical properties and physicochemical features of the nanoconjugates confirmed their suitability as photoluminescent nanoprobes for cell bioimaging and intracellular tracking. Moreover, the results in vitro demonstrated a notable killing activity towards GBM cells of cysteine-bearing CMC conjugates coupled with pro-apoptotic KLA peptides. More importantly, compared to doxorubicin (DOX), a model anticancer drug in chemotherapy that is highly toxic, these innovative nanohybrids nanoconjugates displayed higher lethality against U-87 MG cancer cells. In vivo CAM assays validated these findings where the nanohybrids demonstrated a significant reduction of GBM tumor progression (41% area) and evidenced an antiangiogenic activity. These results pave the way for developing polymer-based hybrid nanoarchitectonics applied as targeted multifunctional theranostics for simultaneous imaging and therapy against glioblastoma while possibly reducing the systemic toxicity and side-effects of conventional anticancer chemotherapeutic agents., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Although the field of oncology nanomedicine has shown indisputable progress in recent years, cancer remains one of the most lethal diseases, where the early diagnosis plays a pivotal role in the patient's prognosis and therapy. Herein, we report for the first time, the synthesis of biocompatible nanostructures composed of Cu-In-S and Cu-In-S/ZnS nanoparticles functionalized with carboxymethylcellulose biopolymer produced by a green aqueous process. These inorganic-organic colloidal nanohybrids developed supramolecular architectures stabilized by chemical functional groups of the polysaccharide shell with the fluorescent semiconductor nanocrystal core, which were extensively characterized by several morphological and spectroscopical techniques. Moreover, these nanoconjugates were covalently bonded with folic acid via amide bonds and electrostatically conjugated with the anticancer drug, producing functionalized supramolecular nanostructures. They demonstrated nanotheranostics properties for bioimaging and drug delivery vectorization effective for killing breast cancer cells in vitro. These hybrids offer a new nanoplatform using fluorescent polysaccharide-drug conjugates for cancer theranostics applications., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is the utmost aggressive and lethal primary brain cancer, which has a poor prognosis and remains virtually incurable. Nanomedicine with emerging disruptive nanotechnology alternatives, including designed supramolecular nanohybrids has excellent potential as multimodal tools against cancer by combining nanomaterials, biomacromolecules, and drugs. Thus, we developed and constructed for the first time quantum dot-biopolymer-drug nanohybrids based on host-guest chemistry for simultaneous bioimaging, targeting, and anti-cancer drug delivery against GBM cells in vitro. ZnS fluorescent quantum dots (ZnS-QDs) were produced using chemically modified polysaccharide, carboxymethylcellulose (CMC), as water-soluble capping ligand and biofunctional layer via a facile one-step eco-friendly aqueous colloidal process at room temperature and physiological pH. These hybrid inorganic-organic nanocolloids (ZnS@CMC) were electrostatically conjugated with doxorubicin (DOX) anti-cancer drug forming innovative supramolecular complexes (ZnS@CMC-DOX) for amalgamating bioimaging and killing cancer cells. These nanoconjugates were characterized regarding their optical and physicochemical properties combined with morphological and structural features. The cytocompatibility was evaluated by MTT assay using healthy and GBM cells. The results showed that ultra-small ZnS-QDs were expertly produced uniform nanocolloids (average size = 3.6 nm). They demonstrated photoluminescence emission within the visible range of spectra. The cell viability results in vitro showed no cytotoxicity of ZnS@CMC nanohybrids towards both cell types. In summary, the novelty of this research relies on using a nanotheranostic strategy for developing ZnS@CMC-DOX nanohybrids with supramolecular vesicle-like structures. They behaved simultaneously as active fluorescent nanoprobes and nanocarriers with modulated drug release for bioimaging and killing malignant glioma cells proving the high potential for applications in cancer nanomedicine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Although noticeable scientific and technological progress, cancer remains one of the deadliest diseases worldwide and advancements in diagnosis, targeting and treating cancer cells are an urgency. In this study, we designed and synthesized novel amino acid and polypeptide modified polysaccharide derivatives associated with fluorescent nanomaterials for producing nanohybrids with functionalities for bioimaging and cell penetrating. Carboxymethylcellulose (CMCel) was chemically biofunctionalized with L-cysteine (CMCelCys) or poly-L-arginine (CMCelPolyArg) and the conjugates were used as capping ligands for synthesizing fluorescent AgInS 2 quantum dots (AIS-QDs) in aqueous colloidal media. These systems were characterized by FTIR, NMR, UV-Vis, TEM-EDX, DLS, zeta potential and PL for assessing physicochemical properties, structural and morphological features. Mitochondrial activity assay (MTT) was used for evaluating preliminary cytotoxicity and confocal laser microscopy for investigating cellular uptake of the nanohybrids. Results confirmed the biofunctionalization of CMCel through amide bonds formation and indicated the formation of water-dispersed fluorescent nanocolloids with core-shell nanostructures composed by semiconductor cores stabilized by shell layers of CMCelCys or CMCelPolyArg. The nanohybrids' optical properties were affected by the grafting of functionalities into CMCel. All nanohybrids demonstrated no in vitro cytotoxicity based on MTT results and were successfully internalized by glioma cells, behaving as fluorescent nanoprobes for bioimaging and biolabeling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Colloidal semiconductor quantum dots (QDs) are light-emitting ultra-small nanoparticles, which have emerged as a new class of nanoprobes with unique optical properties for bioimaging and biomedical diagnostic. However, to be used for most biomedical applications the biocompatibility and water-solubility are mandatory that can achieved through surface modification forming QD-nanoconjugates. In this study, semiconductor II-VI quantum dots of type MX (M=Cd, Pb, Zn, X=S) were directly synthesized in aqueous media and at room temperature using carboxymethylcellulose sodium salt (CMC) behaving simultaneously as stabilizing and surface biofunctional ligand. These nanoconjugates were extensively characterized using UV-visible spectroscopy, photoluminescence spectroscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, dynamic light scattering and zeta potential. The results demonstrated that the biopolymer was effective on nucleating and stabilizing the colloidal nanocrystals of CdS, ZnS, and PbS with the average diameter ranging from 2.0 to 5.0nm depending on the composition of the semiconductor core, which showed quantum-size confinement effect. These QD/polysaccharide conjugates showed luminescent activity from UV-visible to near-infrared range of the spectra under violet laser excitation. Moreover, the bioassays performed proved that these novel nanoconjugates were biocompatible and behaved as composition-dependent fluorescent nanoprobes for in vitro live cell bioimaging with very promising perspectives to be used in numerous biomedical applications and nanomedicine., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cancer research has experienced astonishing advances recently, but cancer remains a major threat because it is one of the leading causes of death worldwide. Glioblastoma (GBM) is the most malignant brain tumor, where the early diagnosis is vital for longer survival. Thus, this study reports the synthesis of novel water-dispersible ternary AgInS 2 (AIS) and quaternary AgInS 2 -ZnS (ZAIS) fluorescent quantum dots using carboxymethylcellulose (CMC) as ligand for multiplexed bioimaging of malignant glioma cells (U-87 MG). Firstly, AgInS 2 core was prepared using a one-pot aqueous synthesis stabilized by CMC at room temperature and physiological pH. Then, an outer layer of ZnS was grown and thermally annealed to improve their optical properties and split the emission range, leading to core-shell alloyed nanostructures. Their physicochemical and optical properties were characterized, demonstrating that luminescent monodispersed AIS and ZAIS QDs were produced with average sizes of 2.2 nm and 4.3 nm, respectively. Moreover, the results evidenced that they were cytocompatible using in vitro cell viability assays towards human embryonic kidney cell line (HEK 293T) and U-87 MG cells. These AIS and ZAIS successfully behaved as fluorescent nanoprobes (red and green, resp.) allowing multiplexed bioimaging and biolabeling of costained glioma cells using confocal microscopy.

In this study, it is reported the use of sodium carboxymethyl cellulose (CMCel) as a multifunctional biocompatible polysaccharide for the direct synthesis of fluorescent alloyed-ZnCdS quantum dot (QD) nanoconjugates via aqueous "green" process at room temperature. The nanoconjugates were extensively characterized by spectroscopical (NMR, FTIR, UV-vis, PL) and morphological techniques (DLS, TEM) for accessing their structural and physicochemical properties associated with X-ray photoelectron spectroscopy (XPS) for surface and interface analysis. The results proved the hypothesis of formation of core-shell nanostructures composed by the semiconductor ZnCdS QD core and the organic biocompatible ligand CMCel shell. Moreover, CMCel chemical functional groups played a pivotal role for controlling the size of water-soluble colloidal nanocrystals (2r=4-5nm) and hydrodynamic diameters (<15nm) evidenced by metal complexation and interactions at the nanointerfaces. Additionally, these nanoconjugates were cytocompatible and luminescent for bioimaging human osteosarcoma cancer cells. Thus, these novel polysaccharide-based fluorescent bioconjugates offer promising perspectives as nanoplatforms for cancer cell bioimaging and diagnosis purposes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Herein, for the first time, we demonstrated that novel biofunctionalized semiconductor nanomaterials made of Cd-containing fluorescent quantum dot nanoconjugates with the surface capped by an aminopolysaccharide are not biologically safe for clinical applications. Conversely, the ZnS-based nanoconjugates proved to be noncytotoxic, considering all the parameters investigated. The results of in vitro cytotoxicity were remarkably dependent on the chemical composition of quantum dot (CdS or ZnS), the nature of the cell (human cancerous and embryonic types), and the concentration and time period of exposure to these nanomaterials, caused by the effects of Cd 2+ on the complex nanotoxicity pathways involved in cellular uptake. Unexpectedly, no decisive evidence of nanotoxicity of CdS and ZnS conjugates was observed in vivo using intravenous injections in BALB/c mice for 30 days, with minor localized fluorescence detected in liver tissue specimens. Therefore, these results proved that CdS nanoconjugates could pose an excessive threat for clinical applications due to unpredicted and uncorrelated in vitro and in vivo responses caused by highly toxic cadmium ions at biointerfaces. On the contrary, ZnS nanoconjugates proved that the "safe by design" concept used in this research (ie, biocompatible core-shell nanostructures) could benefit a plethora of applications in nanomedicine and oncology.

Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular level for diagnostic and therapeutic purposes. In this work, we report the synthesis of novel multifunctional nanoconjugates composed of fluorescent inorganic semiconductor quantum dot (QD) cores and tripeptide-modified polysaccharide organic shells. These structures were designed for targeting and imaging the αvβ3 integrin receptors of cancer cells. Initially, chitosan was covalently bound with the RGD peptide using a crosslinker to form bioconjugates (RGD-chitosan), which were later utilized as capping ligands for the production of surface-functionalized CdS QDs via a single-step process in aqueous media at room temperature. These core-shell nanostructures were extensively characterized by UV-vis spectroscopy, photoluminescence (PL) spectroscopy, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), zeta potential (ZP) and dynamic light scattering (DLS). The TEM images and the UV-vis absorption results indicated the formation of ultra-small CdS QD nanocrystals with average diameters between 2.0 and 3.0 nm. In addition, the PL results demonstrated that the nanobioconjugates exhibited intense green fluorescence under excitation. The CdS-RGD-chitosan systems were effective at specific targeting integrin when assayed in vitro using two model cell cultures, HEK 293 (non-cancerous human embryonic kidney cell) and SAOS (cancerous sarcoma osteogenic-derived cells) imaged using fluorescence microscopy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cancer remains one of the world's most devastating diseases with millions of fatalities and new cases every year. In this work, we attempted to develop a facile "enzyme-free" fluoroimmunoassay based on the novel nanoconjugates composed of CdS quantum dots (QDs) as the fluorescent inorganic core and an antibody-modified polysaccharide as the organic shell, modeling their possible application for the in vitro diagnosis of non-Hodgkin lymphoma (NHL) cancer. Chitosan was conjugated with an anti-CD20 polyclonal antibody (pAbCD20) by the formation of covalent amide bonds. In the sequence, these chitosan-antibody conjugates were utilized as direct ligands for the surface biofunctionalization of CdS QDs (CdS/chitosan-pAbCD20) using a single-step colloidal process in aqueous medium at room temperature. The most relevant physico-chemical properties of these nanoconjugates were assessed by morphological and spectroscopic techniques. The results indicated that CdS nanocrystals were produced with an average diameter of 2.5 nm and with cubic zinc blende crystalline nanostructure. The CdS-immunoconjugates (CdS/chitosan-pAbCD20) presented colloidal hydrodynamic diameter (HD) of 15.0 ± 1.2n m. In addition, the results evidenced that the "enzyme-free" QD-linked immunosorbent assay (QLISA) was effective for the in vitro detection against the antigen CD20 (aCD20) based on fluorescent behavior of the CdS nanoconjugates. Moreover, the CdS-immunoconjugates were successfully used for fluorescence bioimaging of NHL cancer cells. Finally, the cell viability results using different cell cultures based on LDH, MTT and Resazurin bio-assays have demonstrated no cytotoxicity of the new CdS-chitosan bioconjugates relative to the standard controls. Thus, CdS conjugates may offer a promising platform for the future development of in vitro and in vivo applications for the detection and diagnosis of NHL cancer cells., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Bioengineered hybrids are emerging as a new class of nanomaterials consisting of a biopolymer and inorganic semiconductors used in biomedical and environmental applications. The aim of the present work was to determine the cytocompatibility of novel water-soluble Bi2S3 quantum dots (QDs) functionalized with chitosan and O-carboxymethyl chitosan (CMC) as capping ligands using an eco-friendly aqueous process at room temperature. These hybrid nanocomposites were tested for cytocompatibility using a 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyl tetrazolium bromide (MTT) cell proliferation assay with cultured human osteosarcoma cells (SAOS), human embryonic kidney cells (HEK293T cells) and a LIVE/DEAD® viability-cytotoxicity assay. The results of the in vitro assays demonstrated that the CMC and chitosan-based nanohybrids were not cytotoxic and exhibited suitable cell viability responses. However, despite the "safe by design" approach used in this research, we have proved that the impact of the size, surface charge and biofunctionalization of the nanohybrids on cytotoxicity was cell type-dependent due to complex mechanisms. Thus, these novel bionanocomposites offer promising prospects for potential biomedical and pharmaceutical applications as fluorescent nanoprobes. [ABSTRACT FROM AUTHOR]

In this study, novel nanobioconjugates based on quantum dots and a PEGylated chitosan derivative (PEG-CHI) have been designed and synthesised by a single-step aqueous route at room temperature. Chitosan was chemically modified by PEGylation aiming to significantly improve its water solubility and used as the capping ligand in the preparation of CdS quantum dot (QD) colloidal systems. UV/Vis and photoluminescence spectroscopy, transmission electron microscopy, dynamic light scattering, and the zeta potential were used to characterise the biopolymer-capped semi-conductor nanocrystals and their relative stability. The results clearly demonstrated that the PEG-CHI derivative is remarkably effective in nucleating and stabilising ultra-small colloidal CdS QDs in aqueous suspensions under acidic, neutral and alkaline media with an average size of approximately 2.0-3.0 nm and simultaneously showing luminescent activity in the visible range. In addition, the results of cell viability analysis in vitro using two cell cultures based on MTT bioassays demonstrated no cytotoxicity of the CdS QD/PEG-chitosan bioconjugates. Thus, based on these findings, it can be envisioned that these bioconjugates have potential use as biocompatible fluorescent biomarkers for nanomedicine applications. [ABSTRACT FROM AUTHOR]

• New functional quantum dot/polysaccharide/Zika-virus nanoconjugates were produced. (81) • Fluorescent Ag-In-S/ZnS-CMC nanocolloids produced via facile green aqueous process. (82) • Ag-In-S/ZnS-CMC nanocolloids biofunctionalized by Zika-virus targeted VERO cells. (80) • ZAIS-CMC bioconjugates acted as fluorescent nanoprobes for cell imaging and tracking. (84) • ZAIS-CMC fluorescent conjugates showed insights of ZIKA virus-host cell interactions. (84) The earliest possible diagnosis and understanding of the infection mechanisms play a crucial role in the outcome of fighting viral diseases. Thus, we designed and developed for the first time, novel bioconjugates made of Ag-In-S@ZnS (ZAIS) fluorescent quantum dots coupled with ZIKA virus via covalent amide bond with carboxymethylcellulose (CMC) biopolymer for labeling and bioimaging the virus-host cell interactions mechanisms through confocal laser scanning microscopy. This work offers relevant insights regarding the profile of the ZIKA virus-nanoparticle conjugates interactions with VERO cells, which can be applied as a nanoplatform to elucidate the infection mechanisms caused by this viral disease. [ABSTRACT FROM AUTHOR]

A novel versatile and clean colloidal processing route was developed for synthesizing CdX (X = Te, Se or S) quantum dots (QDs) based on the simultaneous production of the respective precursors via cadmium sacrificial anode electrochemical methodology. The CdX QDs stabilized by 3-mercaptopropionic acid (MPA) were synthesized in one-pot electrochemical process using aqueous medium at room temperature with full reaction time of approximately 16 min. The CdX quantum dots conjugates were extensively characterized by UV–vis, PL, FTIR, TEM-EDS, XRD, DLS, XPS, and Zeta potential, evidencing that very stable colloidal quantum dots were produced with uniform narrow-size distributions and average nanoparticle diameter of approximately 3.0 nm and quantum yield (QY) of approximately 10%. The cell viability response of HeLa cells toward the CdX-MPA conjugates clearly demonstrated that they are non-toxic based on the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) mitochondrial metabolic activity assay for 24 h of incubation with HeLa cervical cancer cells. Moreover, they showed effective fluorescent activity with time-dependent intensities for evaluating continuous endocytosis of cancer cells, thus, offering innumerous possibilities to be used as fluorescent nanoprobes for bioimaging and biosensing of cancer cells. [ABSTRACT FROM AUTHOR]

Semiconductor quantum dots (QDs) are one of the most interesting photoluminescent nanomaterials with very promising applications in cancer nanomedicine. In this work, ZnS fluorescent quantum dots (ZnS-QDs) were synthesized and stabilized by carboxymethylcellulose (CMC) as a pH-sensitive biopolymer using a facile one-step green aqueous colloidal process at distinct pH conditions (acidic, neutral and alkaline) and chemical proportions of precursors (Zn2+, S2−). The optical properties of these nanoconjugates (ZnS@CMC) were characterized by UV–visible and photoluminescence spectroscopy. The morphological features and physicochemical properties were evaluated by TEM, FTIR spectroscopy, zeta potential, and dynamic light scattering (DLS) analyses. The cytocompatibility in vitro of ZnS@CMC was assessed by MTT assay using normal and malignant glioma cells. The UV–Vis results indicated that ZnS-QDs were effectively produced with different bandgap energies (from 4.5 to 3.8 eV) blue-shifted from bulk (E bulk = 3.61 eV), and sizes (typically from 3.3 to 4.5 nm), dependent on the pH and concentration ratio of precursors during the synthesis. Analogously, the changes of synthesis parameters significantly altered the photoluminescence emission energies and intensities within the visible range of spectra (PL maxima from λ = 400–430 nm, at pH = 3.5, [Zn:S] ratio = 1:2). The cell viability results in vitro (>90%) demonstrated no cytotoxicity of ZnS@CMC nanohybrids towards both cell types. Importantly, these ZnS@CMC nanoconjugates behaved as active fluorescent nanoprobes for bioimaging malignant glioma cells proving the high potential for applications in cancer nanomedicine. Image 1004 • Facile green synthesis of ZnS quantum dot-carboxymethylcellulose nanoconjugates. (79). • CMC pH-sensitive ligand tailored nucleation/growth processes of ZnS nanocrystals. (80). • Colloidal process parameters regulated the optical properties of ZnS@CMC nanohybrids. (84). • ZnS@CMC colloids behaved as active photoluminescent biological nanoprobes. (73). • Fluorescent nanoconjugates were effective for bioimaging brain cancer cells in vitro. (84). [ABSTRACT FROM AUTHOR]