Hyaluronic Acid-Conjugated Carbon Nanomaterials for Enhanced Tumour Targeting Ability

Hyaluronic acid (HA) has been implemented for chemo and photothermal therapy to target tumour cells overexpressing the CD44⁺ receptor. HA-targeting hybrid systems allows carbon nanomaterial (CNM) carriers to efficiently deliver anticancer drugs, such as doxorubicin and gemcitabine, to the tumour sites. Carbon nanotubes (CNTs), graphene, graphene oxide (GO), and graphene quantum dots (GQDs) are grouped for a detailed review of the novel nanocomposites for cancer therapy. Some CNMs proved to be more successful than others in terms of stability and effectiveness at removing relative tumour volume. While the literature has been focused primarily on the CNTs and GO, other CNMs such as carbon nano-onions (CNOs) proved quite promising for targeted drug delivery using HA. Near-infrared laser photoablation is also reviewed as a primary method of cancer therapy—it can be used alone or in conjunction with chemotherapy to achieve promising chemo-photothermal therapy protocols. This review aims to give a background into HA and why it is a successful cancer-targeting component of current CNM-based drug delivery systems.     

透明质酸-量子点的制备及应用

基于量子点(QD)独特的光学成像特性, 采用化学合成法制备了透明质酸(HA)修饰的水溶性纳米量子点(HA-QD), 并将其应用于特异性受体CD44的识别研究中. 体外细胞实验结果证实, 在透明质酸受体的介导下, 该纳米复合物可使小鼠肺腺癌细胞LA795显示特异性的荧光成像. 本研究为建立针对透明质酸受体的肿瘤活体检测及研究肿瘤的发生发展提供了重要的纳米靶向荧光探针.     

Hyaluronic Acid/Poly(β‐Amino Ester) Polymer Nanogels for Cancer‐Cell‐Specific NIR Fluorescence Switch

Cancer‐cell‐specific pH‐activatable polymer nanogels consisting of CD44‐receptor‐targeting hyaluronic acid (HA), pH‐sensitive poly(β‐amino ester) (PBAE), and near‐infrared (NIR) fluorescent indocyanine green (ICG) were synthesized and used to detect cancer cells. The HA/PBAE/ICG‐polymer‐nanogel‐based NIR probe was nonfluorescent outside of tumor cells. After internalization by CD44‐receptor‐mediated endocytosis, the probe accumulated in the late endosomes or lysosomes where the acidic pH solubilized the PBAE and caused instant disassembly of the polymer nanogel. During endosomal maturation, the encapsulated ICG was released from its quenched state, inducing strong NIR fluorescence recovery. The nanogels generate a highly tumor‐specific NIR signal with a reduced background signal.     

Bioresponsive Hyaluronic Acid‐Capped Mesoporous Silica Nanoparticles for Targeted Drug Delivery

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell‐targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof‐of‐concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase‐1 (Hyal‐1). Moreover, after receptor‐mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site‐selective, controlled‐release delivery of anticancer drugs.     

The effect of magnetic nanoparticles containing hyaluronic acid and methotrexate on the expression of genes involved in apoptosis and metastasis in A549 lung cancer cell lines

Lung cancer has been shown to be resistant to treatment with some chemotherapy drugs due to epithelial-mesenchymal transmission (EMT). Because the rate of cytotoxicity and induction of apoptosis by methotrexate (MTX) is negligible in A549 lung cancer cells, a CD44 positive cell line, we decided to synthesize magnetic nanoparticles (MNPs) containing hyaluronic acid (HA) and MTX to evaluate the effect of CD44 receptor targeting on the expression of genes involved in apoptosis. The TNF genes can modulate the expression of CD44 and implicate carcinogenesis and metastases. Therefore, inhibition of the TNF gene and study of its interaction with the CD44 receptor can determine the success of a treatment method. The results of the MTT assay confirmed that the MNPs-HA-MTX offered better cellular cytotoxic effects on cell viability than free MTX. The real-time PCR test also showed that the Bak1/Bclx ratio was 52.5 times higher than the control. On the other hand, the expression of the TNF gene was severely reduced, which could be due to the binding of HA-moiety of the MNPs-HA-MTX to the receptor and endocytosis. All the results gave us hope that we could increase the effectiveness of methotrexate in lung cancer by targeting the CD44 receptor.     

Dye adsorbed few-layer thick Ti3C2Tx-MXenes for direct electrochemical detection of CD44 proteins

The direct electrochemical detection of cancer biomarkers using single single-component platforms is challenging. Herein, we propose constructing an efficient screen-printed electrode (SPE) based platform for selective detection of CD44 proteins, a non-kinase transmembrane glycoprotein. A sensing platform, MB-MX/HA/SPE, was developed by incorporating few-layered Ti₃C₂T_x nanosheets pre-loaded with methylene blue (MB) dye. The nanosheets were subsequently immobilized with hyaluronic acid (HA), which served as a ligand for the specific recognition of CD44. The simple electrode configuration and the highly conductive Ti₃C₂T_x facilitated the electrochemical oxidation of MB, generating a reference SWV signal that declined proportionally with the increasing concentration of CD44 owing to ligand (HA)-protein interaction. The sensor could register a sensitive inhibition response in the concentration range of 0.1 to 7.25 ng.mL⁻¹ with a detection limit of 1.2×10⁻² ng.mL⁻¹ for CD44 proteins. Moreover, the synergistic combination of the highly conductive/adsorptive Ti₃C₂T_x nanosheets and hyaluronic acid (HA) led to strong antifouling characteristics even in the presence of other common proteins, such as bovine serum albumin (BSA), haemoglobin (Ig), immunoglobulin G (IgG), prostate-specific antigen (PSA), and neuron-specific enolase (NSE). The proposed strategy eliminates the need for additional components in the electrode modification procedure. In addition, incorporating MXenes as electrode material paves the way for developing sensitive biosensors with prospective applications in cancer diagnosis.     

Tirapazamine encapsulated hyaluronic acid nanomicelles realized targeted and efficient photo-bioreductive cascading cancer therapy

Currently,architecting a ratio nal and efficient nanoplatform combing with multi-therapeutic modalities is highly obligatory for advanced cancer treatment.In order to remedy the self-limiting hypoxic dilemma of photodynamic therapy(PDT),herein,a facile photosensitizer(i.e.,chlorin e6,Ce6) and bioreductive prodrug(i.e.,tirapazamine,TPZ)-coloaded hyaluronic acid(HA) nanomicelles(denoted as TPZ@HA-Ce6)was developed for the cascading mode of photo-bioreductive cancer therapy.Taking the typical advantage of Ce6 coupled HA conjugate,TPZ was easily and successfully accommodated into the hydrophobic core of HA-Ce6 nanomicelles,yielding TPZ@HA-Ce6.It showed good dispersibility and stability with the hydrodynamic size of ca.170 nm.It targeted the CD44 overexpressed cancer cells by receptor-mediated endocytosis way and killed them effectively with singlet oxygen and the subsequent TPZ radicals resulting from the oxygen depletion of PDT.The later was further verified by the hypoxia probe in vivo.Using murine mammary carcinoma 4 T1 model,TPZ@HA-Ce6 nanomicelles exhibited cascading and synergistic anticancer effect of PDT and TPZ bioreductive therapy compared with each monotherapy.This work suggests the promising prospect of the hybrid hyaluronic nanomicelles for highly efficient cancer combination treatment.     

Microfluidic lab-on-chip advances for liquid–liquid extraction process studies

The ever-increasing complexity of industrial product recycling calls for more efficient purification processes such as liquid–liquid (L/L) extraction. Because of the high complexity of L/L extraction, optimizing a large-scale extraction is both time and resource consuming and can only be justified to solve high volume and value purification problems. It is therefore difficult to apply to small scale and highly variable waste material influx. We believe using a fully automated and integrated microfluidic approach will enable fast and cost-effective studies of L/L extraction processes. This review presents an overview of L/L metal extraction performed using microfluidics platforms. We first give an overview of the extraction methods. We then review the most relevant characterization methods integrated with such platforms.     

Polysaccharide films built by simultaneous or alternate spray: a rapid way to engineer biomaterial surfaces

We investigated polysaccharide films obtained by simultaneous and alternate spraying of a chitosan (CHI) solution as polycation and hyaluronic acid (HA), alginate (ALG), and chondroitin sulfate (CS) solutions as polyanions. For simultaneous spraying, the film thickness increases linearly with the cumulative spraying time and passes through a maximum for polyanion/CHI molar charge ratios lying between 0.6 and 1.2. The size of polyanion/CHI complexes formed in solution was compared with the simultaneously sprayed film growth rate as a function of the polyanion/CHI molar charge ratio. A good correlation was found. This suggests the importance of polyanion/polycation complexation in the simultaneous spraying process. Depending on the system, the film topography is either liquid-like or granular. Film biocompatibility was evaluated using human gingival fibroblasts. A small or no difference is observed in cell viability and adhesion between the two deposition processes. The CHI/HA system appears to be the best for cell adhesion inducing the clustering of CD44, a cell surface HA receptor, at the membrane of cells. Simultaneous or alternate spraying of CHI/HA appears thus to be a convenient and fast procedure for biomaterial surface modifications.     

In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates

CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists.     

A pH‐Responsive Hydrogel Based on a Tumor‐Targeting Mesoporous Silica Nanocomposite for Sustained Cancer Labeling and Therapy

A facile strategy is presented to synthesize hyaluronic acid (HA) and a fluorescein isothiocyanate (FITC)‐conjugated mesoporous silica nanocomposite (MSN) with multiple functions of fluorescence, tumor‐cell targeting, pH‐triggered gelation, and enzyme‐responsive drug release. This injectable nanocomposite is able to indicate the entire tumor location and provides a microenvironment with rich anticancer drugs in and around tumor tissue for a long time, to avoid recrudescence. In this design, the mesoporous silica serves as the drug container, the FITC serves as a fluorescent probe, and the anchored HA plays multiple roles as drug‐release cap, tumor‐targeting points, and responsive gel matrix. Owing to the specific affinity between the HA on MSNs and the CD44 antigen over‐expressed on tumor cells, the MSNs can selectively attach to tumor cells. The nanocomposites then exploit the pH‐responsive interactions (hydrogen bonds) among the HA to self‐assemble in situ into a hydrogel around the tumor tissue. The resulting hydrogel gradually releases its payload (doxorubicin, anticancer drugs)‐loaded MSNs upon HA degradation in the presence of hyaluronidase‐1 (Hyal‐1), followed by endocytosis and intracellular drug release. All these properties have distinct benefits for tumor treatment, demonstrating that this device is a promising candidate for oncotherapy applications.

     

Liposome-based anchoring and core-encapsulation for combinatorial cancer therapy

Downregulated pro-apoptotic protein in cancer cells compromises the chemotherapy by a cytotoxic drug. Here, we report co-delivery of a pro-apoptotic protein, caspase 3 (Cas 3), and cytotoxic agent, oridonin (ORD), for synergistic cancer treatment, using a method of liposome-based anchoring and core encapsulation. First, ORD is modified with hyaluronic acid (HA) to improve its solubility. Then, the targeted co-delivery system is prepared by assembling the conjugate HA-ORD onto the Cas 3-loaded liposomes, which the surface HA can target the CD44 receptor on cancer cells. In vitro, the co-loaded liposomes (120 nm) are specifically taken up by 4T1 cells and endow a 1.5-fold increase of Cas 3. After intravenous injection into the tumor-bearing mice, the liposomes accumulate in the tumor with high efficacy and significantly inhibit tumor growth via promoting apoptosis and anti-proliferation of cancer cells. Mechanistically, the co-delivery works synergistically by upregulating the activated Cas form, cleaved-Cas 3.     

Applications of Hyaluronic Acid in Ophthalmology and Contact Lenses

Hyaluronic acid (HA) is a glycosaminoglycan that was first isolated and identified from the vitreous body of a bull’s eye. HA is ubiquitous in the soft connective tissues of animals and therefore has high tissue compatibility for use in medication. Because of HA’s biological safety and water retention properties, it has many ophthalmology-related applications, such as in intravitreal injection, dry eye treatment, and contact lenses. Due to its broad range of applications, the identification and quantification of HA is a critical topic. This review article discusses current methods for analyzing HA. Contact lenses have become a widely used medical device, with HA commonly used as an additive to their production material, surface coating, and multipurpose solution. HA molecules on contact lenses retain moisture and increase the wearer’s comfort. HA absorbed by contact lenses can also gradually release to the anterior segment of the eyes to treat dry eye. This review discusses applications of HA in ophthalmology.     

Theranostic hyaluronic acid prodrug micelles with aggregation-induced emission characteristics for targeted drug delivery

Theranostic hyaluronic acid (HA) prodrug micelles with pH-responsive drug release and aggregation-induced emission (AIE) properties were prepared by chemical graft of biomimetic phosphorylcholine (PC), anticancer drug doxorubicin (DOX) and AIE fluorogen tetraphenylene (TPE) to the HA backbone. DOX was conjugated to the HA backbone by a hydrazone bond which can be hydrolyzed under acidic environment and result in pH-triggered smart release of DOX. The TPE units with typical AIE characteristics were applied for real time drug tracking in cancer cells. The HA-based prodrugs could self-assemble into micelles in aqueous solution as confirmed by the dynamic light scattering (DLS) and transmission electron microscopy (TEM). The intracellular distribution of HA prodrug micelles could be clearly observed by fluorescence microscopy based on the strong fluorescence of TPE. Moreover, after treated with the micelles, stronger fluorescence of TPE in CD44 overexpressed MDA-MB-231 cancer cells was observed, compared to the CD44 negative cell line, NIH3T3 cells, suggesting efficient cell uptake of HA prodrug micelles by receptor-mediated endocytosis. The cell viability results indicated that the prodrug micelles could inhibit the proliferation of the cancer cells effectively. Such pH-triggered theranostic drug delivery system with AIE features can provide a new platform for targeted and image-guided cancer therapy.     

Novel types of carborane-carrier hyaluronan derivatives via "click chemistry"

Two new HA derivatives bearing carborane rings were synthesized by click chemistry. The optimal conditions were assessed for the preparation of biocompatible boron carriers, potentially suitable for application in BNCT and capable of targeting the CD44 antigen. The new polymeric samples were characterized by means of NMR-spectroscopy techniques that gave degrees of 17 and 8% for HAAACB and HapACB, respectively. Both HAAACB and HApACB turned out to be nontoxic for colorectal, ovarian and bladder tumor cell lines, to disclose a specific interaction with the CD44 antigen as the native hyaluronan moiety, and to deliver boron-atom concentrations largely sufficient for BNCT therapy when accumulated in cancer cells.     

Developing fluorescent hyaluronan analogs for hyaluronan studies

Two kinds of fluorescent hyaluronan (HA) analogs, one serving as normal imaging agent and the other used as a biosensitive contrast agent, were developed for the investigation of HA uptake and degradation. Our approach of developing HA imaging agents depends on labeling HA with varying molar percentages of a near-infrared (NIR) dye. At low labeling ratios, the hyaluronan uptake can be directly imaged while at high labeling ratios, the fluorescent signal is quenched and signal generation occurs only after degradation. It is found that the conjugate containing 1%-2% NIR dye can be used as a normal optical imaging agent, while bioactivable imaging agents are formed at 6% to 17% dye loading. It was determined that the conjugation of dye to HA with different loading percentages does not impact HA biodegradation by hyaluronidase (Hyal). The feasibility of using these two NIR fluorescent hyaluronan analogs for HA investigation was evaluated in vivo with optical imaging. The data demonstrates that the 1% dye loaded fluorescent HA can be used to monitor the behavior of HA and its fragments, whereas bioactivatable HA imaging agent (17% dye in HA) is more suitable for detecting HA fragments.     

Current analytical methods for plant auxin quantification – A review

Plant hormones, and especially auxins, are low molecular weight compounds highly involved in the control of plant growth and development. Auxins are also broadly used in horticulture, as part of vegetative plant propagation protocols, allowing the cloning of genotypes of interest. Over the years, large efforts have been put in the development of more sensitive and precise methods of analysis and quantification of plant hormone levels in plant tissues. Although analytical techniques have evolved, and new methods have been implemented, sample preparation is still the limiting step of auxin analysis. In this review, the current methods of auxin analysis are discussed. Sample preparation procedures, including extraction, purification and derivatization, are reviewed and compared. The different analytical techniques, ranging from chromatographic and mass spectrometry methods to immunoassays and electrokinetic methods, as well as other types of detection are also discussed. Considering that auxin analysis mirrors the evolution in analytical chemistry, the number of publications describing new and/or improved methods is always increasing and we considered appropriate to update the available information. For that reason, this article aims to review the current advances in auxin analysis, and thus only reports from the past 15 years will be covered.     

Solid-phase synthesis of heterocyclic aromates: applicability towards combinatorial chemistry; a review

Because of their biological activity, stability in vivo, the rigid spatial positioning of their substituents, and their synthetic challenges, heterocyclic aromates continue to be of interest to both academic and industrial medicinal chemists. Currently, many drug-like heterocyclic aromates are prepared via solid-phase organic chemistry methods. This review examines the applicability of those methods towards combinatorial chemistry with respect to the basic demands of such an approach: 1) synthesis, work-up and subsequent purification should be easily automated enabling the efficient simultaneous synthesis of large numbers of highly pure compounds in a minimum amount of time, 2) large diversity among the ligands to be synthesized, 3) high conversion rates of the individual reaction steps, and 4) the use of commercially available starting materials. Although many methods have been developed for the synthesis of heterocyclic aromates, very few of the available methods enable the synthesis of highly diverse heteroaromatic libraries.