Nanoplexes of ZnS quantum dot-poly-l-lysine/iron oxide nanoparticle-carboxymethylcellulose for photocatalytic degradation of dyes and antibacterial activity in wastewater treatment.

The contamination and pollution of wastewater with a wide diversity of chemical, microbiological, and hazardous substances is a field of raising environmental concern. In this study, we developed, for the first time, new hybrid multifunctional nanoplexes composed of ZnS semiconductor quantum dots (ZnS QDs) chemically biofunctionalized with epsilon-poly-l-lysine (ɛPL) and coupled with magnetic iron oxide nanoparticles (MION, Fe3O4) stabilized by carboxymethylcellulose (CMC) for the photodegradation (ZnS) of organic molecules and antibacterial activity (ɛPL) with a potential of recovery by an external magnetic field (Fe3O4). These nanosystems, which were synthesized entirely through a green aqueous process, were comprehensively characterized regarding their physicochemical properties combined with spectroscopic and morphological features. The results demonstrated that supramolecular colloidal nanoplexes were formed owing to the strong cationic/anionic electrostatic interactions between the biomacromolecule capping ligands of the two nanoconjugates (i.e., polypeptide in ZnS@ɛPL and polysaccharide in Fe3O4@CMC). Moreover, these nanosystems showed photocatalytic degradation of methylene blue (MB) used as a model dye pollutant in water. Besides MB, methyl orange, congo red, and rhodamine dyes were also tested for selectivity investigation of the photodegradation by the nanoplexes. The antibacterial activity ascribed to the ɛPL biomolecule was confirmed against Gram-positive and Gram-negative bacteria, including drug-resistance field strains. Hence, it is envisioned that these novel green nanoplexes offer a new avenue of alternatives to be employed for reducing organic pollutants and inactivating pathogenic bacteria in water and wastewater treatment, benefiting from easy magnetic recovery.

Carboxymethylcellulose biofunctionalized ternary quantum dots for subcellular-targeted brain cancer nanotheranostics.

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.

Soft matter polysaccharide-based hydrogels as versatile bioengineered platforms for brain tissue repair and regeneration.

Acute or chronic brain injuries promote deaths and the life-long debilitating neurological status where, despite advances in therapeutic strategies, clinical outcome hardly achieves total patient recovery. In recent decades, brain tissue engineering emerged as an encouraging area of research for helping in damaged central nervous system (CNS) recovery. Polysaccharides are abundant naturally occurring biomacromolecules with a great potential enhancement of advanced technologies in brain tissue repair and regeneration (BTRR). Besides carrying rich biological information, polysaccharides can interact and communicate with biomolecules, including glycosaminoglycans present in cell membranes and many signaling moieties, growth factors, chemokines, and axon guidance molecules. This review includes a comprehensive investigation of the current progress on designing and developing polysaccharide-based soft matter biomaterials for BTRR. Although few interesting reviews concerning BTRR have been reported, this is the first report specifically focusing on covering multiple polysaccharides and polysaccharide-based functionalized biomacromolecules in this emerging and intriguing field of multidisciplinary knowledge. This review aims to cover the state of art challenges and prospects of this fascinating field while presenting the richness of possibilities of using these natural biomacromolecules for advanced biomaterials in prospective neural tissue engineering applications.

Nanotheranostics through Mitochondria-targeted Delivery with Fluorescent Peptidomimetic Nanohybrids for Apoptosis Induction of Brain Cancer Cells.

Overview: Malignant brain tumors remain one of the greatest challenges faced by health professionals and scientists among the utmost lethal forms of cancer. Nanotheranostics can play a pivotal role in developing revolutionary nanoarchitectures with multifunctional and multimodal capabilities to fight cancer. Mitochondria are vital organelles to eukaryotic cells, which have been recognized as a significant target in cancer therapy where, by damaging the mitochondria, it will cause irreparable cell death or apoptosis. Methods: We designed and produced novel hybrid nanostructures comprising a fluorescent semiconductor core (AgInS2, AIS) and cysteine-modified carboxymethylcellulose (termed thiomer, CMC_Cys) conjugated with mitochondria-targeting peptides (KLA) forming a macromolecular shell for combining bioimaging and for inducing brain cancer cell (U-87 MG) death. Results: The optical and physicochemical properties of the nanoconjugates demonstrated suitability as photoluminescent nanostructures for cell bioimaging and intracellular tracking. Additionally, the results proved a remarkable killing activity towards glioblastoma cells of cysteine-bearing CMC conjugates coupled with KLA peptides through the half-maximal effective concentration values, approximately 70-fold higher compared to the conjugate analogs without Cys residues. Moreover, these thiomer-based pro-apoptotic drug nanoconjugates displayed higher lethality against U-87 MG cancer cells than doxorubicin, a model drug in chemotherapy, although extremely toxic. Remarkably, these peptidomimetic nanohybrids demonstrated a relative "protective effect" regarding healthy cells while maintaining high killing activity towards malignant brain cells. Conclusion: These findings pave the way for developing hybrid nanoarchitectures applied as targeted multifunctional platforms for simultaneous imaging and therapy against cancer while minimizing the high systemic toxicity and side-effects of conventional drugs in anticancer chemotherapy.

3D sponges of chemically functionalized chitosan for potential environmental pollution remediation: biosorbents for anionic dye adsorption and 'antibiotic-free' antibacterial activity.

In this work, it was developed three-dimensional (3D) porous hydrogel sponges produced by the freeze-dried process using chitosan polymer functionalized by 11-mercaptoundecanoic acid (MUA). These chitosan-based sponges were used as cationic adsorbents for the removal of anionic methyl orange (MO) dye, simulating a model organic pollutant in aqueous medium. Moreover, these porous 3D constructs were also evaluated as 'antibiotic-free' antibacterial materials against gram-negative and gram-positive bacteria, Pseudomonas aeruginosa and Staphylococcus aureus, respectively, which were used as model pathogens possibly found in contaminated hospital discharges. These 3D hydrogels were comprehensively characterized through morphological methods such as scanning electron microscopy and X-ray micro-computed tomography techniques, combined with FTIR, Raman, and UV-visible spectroscopy analyses. Additionally, the surface area, the degree of swelling, and the adsorption profiles and kinetics of these scaffolds were systematically investigated. The chemically thiolated chitosan (CHI-MUA) hydrogels were successfully produced with a supramolecular polymeric network based on hydrogen bonds, disulfide bonds, and hydrophobic interactions that resulted in higher stability in aqueous medium than hydrogels of pristine chitosan. CHI-MUA exhibited sponge-like three-dimensional structures, with highly interconnected and hierarchical pore size distribution with high porosity and surface area. These architectural aspects of the 3D sponges favoured the high adsorption capacity for MO dye (∼388 mg.g-1) in water with removal efficiency greater than 90% for MO solutions (from 20 mg.L-1-1200 mg.L-1). The adsorption data followed a pseudo-second-order kinetic model and adsorption isotherm analysis and spectroscopy studies suggested a multilayer behaviour with coexistence of adsorbent-adsorbate and adsorbate-adsorbate interactions. Additionally, the in vitro evaluation of toxicity (MTT and LIVE-DEAD® assays) of 3D-sponges revealed a non-toxic response and preliminary suitability for bio-related applications. Importantly, the 3D-sponges composed of chitosan-thiolated derivative proved high antibacterial activity, specificity against P. aeruginosa (model hazardous pathogen), equivalent to conventional antibiotic drugs, while no lethality against S. aureus (reference commensal bacteria) was observed.

Cu-In-S/ZnS@carboxymethylcellulose supramolecular structures: Fluorescent nanoarchitectures for targeted-theranostics of cancer cells.

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.

Fluorescent quantum dots-zika virus hybrid nanoconjugates for biolabeling, bioimaging, and tracking host-cell interactions.

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.

Supramolecular magnetonanohybrids for multimodal targeted therapy of triple-negative breast cancer cells.

Despite the undeniable advances in recent decades, cancer remains one of the deadliest diseases of the current millennium, where the triple-negative breast cancer (TNBC) is very aggressive, extremely metastatic, and resistant to conventional chemotherapy. The nanotheranostic approach focusing on targeting membrane receptors often expressed at abnormal levels by cancer cells can be a strategic weapon for fighting malignant tumors. Herein, we introduced a novel "all-in-one nanosoldier" made of colloidal hybrid nanostructures, which were designed for simultaneously targeting, imaging, and killing TNBC cells. These nanohybrids comprised four distinct components: (a) superparamagnetic iron oxide nanoparticles, as bi-functional nanomaterials for inducing ferroptosis via inorganic nanozyme-mediated catalysis and magnetotherapy by hyperthermia treatment; (b) carboxymethyl cellulose biopolymer, as a water-soluble capping macromolecule; (c) folic acid, as the membranotopic vector for targeting folate receptors; (d) and doxorubicin (DOX) drug for chemotherapy. The results demonstrated that this novel strategy was highly effective for targeting and killing TNBC cells in vitro, expressing high levels of folate membrane-receptors. The results evidenced that three integrated mechanisms triggered the deaths of the cancer cells in vitro: (a) ferroptosis, by magnetite nanoparticles inducing a Fenton-like reaction; (b) magneto-hyperthermia effect by generating heat under an alternate magnetic field; and (c) chemotherapy, through the DOX intracellular release causing DNA dysfunction. This "all-in-one nanosoldier" strategy offers a vast realm of prospective alternatives for attacking cancer cells, combining multimodal therapy and the delivery of therapeutic agents to diseased sites and preserving healthy cells, which is one of the most critical clinical challenges faced in fighting drug-resistant breast cancers.

Dual-functional supramolecular nanohybrids of quantum dot/biopolymer/chemotherapeutic drug for bioimaging and killing brain cancer cells in vitro.

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.

L-cysteine and poly-L-arginine grafted carboxymethyl cellulose/Ag-In-S quantum dot fluorescent nanohybrids for in vitro bioimaging of brain cancer cells.

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 AgInS2 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.

Bifunctional magnetopolymersomes of iron oxide nanoparticles and carboxymethylcellulose conjugated with doxorubicin for hyperthermo-chemotherapy of brain cancer cells.

Glioblastoma is the most aggressive primary brain cancer, which has no cure yet. Emerging nanotheranostic alternatives such as magnetic iron oxide nanoparticles (MIONs) have great potential as multimodal cancer therapy mediators. They can act as nanocarriers of anticancer drugs and generate localized heat when exposed to an alternating magnetic field (AMF), resulting in combined effects of chemotherapy and magnetic hyperthermia therapy. Thus, we designed and synthesized novel MIONs directly through a co-precipitation method by a single step one-pot aqueous green process using carboxymethylcellulose (CMC) as a multifunctional, biocompatible and water-soluble biopolymer ligand (iron oxide nanoparticle-CMC, MION@CMC). They were bioconjugated via amide bonds with doxorubicin (DOX, an anticancer drug) forming nanohybrids (MION@CMC-DOX). The CMC, MION@CMC and MION@CMC-DOX nanoconjugates were comprehensively characterized by 1HNMR, FTIR, TEM/SAED/EDX, UV-visible, XRD, zeta potential (ZP) and DLS analyses. Moreover, cytotoxicity and cell killing activities of these nanoconjugates were assessed by in vitro biological assays. The nanoconjugates were incubated with glioma cells (U87), a magnetic hyperthermia (MHT) assay was performed for evaluating the activity against brain cancer cells and confocal laser scanning laser microscopy was used for bioimaging their cellular uptake pathways. The results showed that fairly monodisperse and water-soluble ultra-small iron oxide nanoparticles (Fe3O4) were synthesized (core size = 7 ± 2 nm) and stabilized by CMC producing negatively charged nanocolloids (-38 ± 3 mV, MION@CMC; hydrodynamic radius, HD = 38 ± 2 nm). The results confirmed the conjugation of MION@CMC with DOX by amide bonds, leading to the development of magnetopolymersome nanostructures (MION@CMC-DOX). The cell viability bioassays evidenced low toxicity of MION@CMC compared to the severe cytotoxicity of MION@CMC-DOX nanosystems mainly caused by the release of DOX. Under an alternating magnetic field, MION@CMC and MION@CMC-DOX systems demonstrated activity for killing U87 cancer cells due to the heat generated by hyperthermia. In addition, the MION@CMC-DOX bioconjugates showed significantly higher cell killing response when exposed to an AMF due to the combined chemotherapy effect of DOX release inside the cancer cells triggering apoptotic pathways.

Bioengineered carboxymethyl cellulose-doxorubicin prodrug hydrogels for topical chemotherapy of melanoma skin cancer.

Melanoma is the most aggressive type of skin cancer with high rates of mortality. Despite encouraging advances demonstrated by anticancer drug carriers in recent years, developing ideal drug delivery systems to target tumor microenvironment by overcoming physiological barriers and chemotherapy side effects still remain intimidating challenges. Herein, we designed and developed a novel carbohydrate-based prodrug composed of carboxymethylcellulose (CMC) polymer bioconjugated with anticancer drug doxorubicin hydrochloride (DOX) by covalent amide bonds and crosslinked with citric acid for producing advanced hydrogels. The results demonstrated the effect of CMC hydrogel network structure with distinct degree of substitution of carboxymethyl groups of the cellulose backbone regarding to the process of bioconjugation and on tailoring the DOX release kinetics in vitro and the cytotoxicity towards melanoma cancer cells in vitro. To this end, an innovative platform was developed based on polysaccharide-drug hydrogels offering promising perspectives for skin disease applications associated with topical chemotherapy of melanoma.

Engineered 3D-scaffolds of photocrosslinked chitosan-gelatin hydrogel hybrids for chronic wound dressings and regeneration.

Wound repair is one of the most complex biological processes in human life. To date, no ideal biomaterial solution has been identified, which that encompasses all functions and properties of real skin tissue. Thus, this study focused on the synthesis of new biocompatible hybrid hydrogel scaffolds based on methacrylate-functionalized high molecular mass chitosan with gelatin-A photocrosslinked with UV radiation to tailor matrix network properties. These hybrid hydrogels were produced via freeze-drying and were extensively characterized by swelling and degradation measurements, Fourier transform infrared spectroscopy (FTIR), UV-visible spectroscopy (UV-Vis), scanning electron microscopy (SEM-EDS), and micro-computed tomography (micro-CT). The results demonstrated that hydrogels were produced with broadly designed swelling degrees typically ranging from 500% to 2000%, which were significantly dependent on the relative concentration of polymers and irradiation time for crosslinking. Analogously, degradation was reduced with increased photocrosslinking of the network. Moreover, insights into the mechanism of photochemical crosslinking were suggested based on FTIR and UV-Vis analyses of the characteristic functional groups involved in the reactions. SEM analysis associated with micro-CT imaging of the hybrid scaffolds showed uniformly interconnected 3D porous structures, with architectural features affected by the crosslinking of the network. These hydrogels were biocompatible, with live cell viability responses of human embryonic kidney (HEK293T) cells being above 95%. Hence, novel hybrid hydrogels were designed and produced with tunable properties through photocrosslinking and with a biocompatible response suitable for use in wound dressing and skin tissue repair applications.