Receptor CD44 Research Articles

Benchmarking Water Models in Molecular Dynamics of Protein-Glycosaminoglycan Complexes.

Glycosaminoglycans (GAGs) made of repeating disaccharide units intricately engage with proteins, playing a crucial role in the spatial organization of the extracellular matrix (ECM) and the transduction of biological signals in cells to modulate a number of biochemical processes. Exploring protein-GAG interactions reveals several challenges for their analysis, namely, the highly charged and periodic nature of GAGs, their multipose binding, and the abundance of the interfacial water molecules in the protein-GAG complexes. Most of the studies on protein-GAG interactions are conducted using the TIP3P water model, and there are no data on the effect of various water models on the results obtained in molecular dynamics (MD) simulations of protein-GAG complexes. Hence, it is essential to perform a systematic analysis of different water models in MD simulations for these systems. In this work, we aim to evaluate the properties of the protein-GAG complexes in MD simulations using different explicit: TIP3P, SPC/E, TIP4P, TIP4PEw, OPC, and TIP5P and implicit: IGB = 1, 2, 5, 7, and 8 water models to find out which of them are best suited to study the dynamics of protein-GAG complexes. The FF14SB and GLYCAM06 force fields were used for the proteins and GAGs, respectively. The interactions of several GAG types, such as heparin, chondroitin sulfate, and hyaluronic acid with basic fibroblast growth factor, cathepsin K, and CD44 receptor, respectively, are investigated. The observed variations in different descriptors used to study the binding in these complexes emphasize the relevance of the choice of water models for the MD simulation of these complexes.

Melatonin inhibits the stemness of head and neck squamous cell carcinoma by modulating HA synthesis via the FOSL1/HAS3 axis.

Hyaluronic acid (HA) is a glycosaminoglycan and the main component of the extracellular matrix (ECM), which has been reported to interact with its receptor CD44 to play critical roles in the self-renewal and maintenance of cancer stem cells (CSCs) of multiple malignancies. Melatonin is a neuroendocrine hormone with pleiotropic antitumor properties. However, whether melatonin could regulate HA accumulation in the ECM to modulate the stemness of head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, we found that melatonin suppressed CSC-related markers, such as CD44, of HNSCC cells and decreased the tumor-initiating frequency of CSCs in vivo. In addition, melatonin modulated HA synthesis of HNSCC cells by downregulating the expression of hyaluronan synthase 3 (HAS3). Further study showed that the Fos-like 1 (FOSL1)/HAS3 axis mediated the inhibitory effects of melatonin on HA accumulation and stemness of HNSCC in a receptor-independent manner. Taken together, melatonin modulated HA synthesis through the FOSL1/HAS3 axis to inhibit the stemness of HNSCC cells, which elucidates the effect of melatonin on the ECM and provides a novel perspective on melatonin in HNSCC treatment.

Dual-Targeting Macrophages and Hepatic Stellate Cells by Modified Albumin Nanoparticles for Liver Cirrhosis Treatment.

Hepatic cirrhosis has become a global public health concern with high mortality and currently lacks effective clinical treatment methods. Activation of hepatic stellate cells (HSCs) and the large number of macrophages infiltrating into the liver play a critical role in the development of liver cirrhosis. This study developed a novel modified nanoparticle system (SRF-CS-PSA NPs) in which Sorafenib (SRF) was encapsulated by palmitic acid-modified albumin (PSA) and further modified with chondroitin sulfate (CS). These modifications enabled the SRF-CS-PSA NPs to effectively target hepatic stellate cells (HSCs) and macrophages. SRF-CS-PSA NPs showed uniform particle size distribution of approximately 120 nm and high loading efficiency of up to 99.5% and can be taken up by HSCs and macrophages via CD44 and SR-A receptors, respectively. In a mouse model of liver cirrhosis, SRF-CS-PSA NPs demonstrated superior targeting and inhibition of HSCs and macrophages, effectively reversing the process of liver cirrhosis. Overall, our study demonstrates the potential of SRF-CS-PSA NPs as a targeted therapy for liver cirrhosis, with promising clinical applications.

Robust Synthesis of Targeting Glyco-nanoparticles for Surface Enhanced Resonance Raman Based Image-Guided Tumor Surgery.

Surface Enhanced Resonance Raman (SERS) is a powerful optical technique, which can help enhance the sensitivity of Raman spectroscopy aided by noble metal nanoparticles (NPs). However, current SERS-NPs are often suboptimal, which can aggregate under physiological conditions with much reduced SERS enhancement. Herein, a robust one-pot method has been developed to synthesize SERS-NPs with more uniform core diameters of 50 nm, which is applicable to both non-resonant and resonant Raman dyes. The resulting SERS-NPs are colloidally stable and bright, enabling NP detection with low-femtomolar sensitivity. An algorithm has been established, which can accurately unmix multiple types of SERS-NPs enabling potential multiplex detection. Furthermore, a new liposome-based approach has been developed to install a targeting carbohydrate ligand, i.e., hyaluronan, onto the SERS-NPs bestowing significantly enhanced binding affinity to its biological receptor CD44 overexpressed on tumor cell surface. The liposomal HA-SERS-NPs enabled visualization of spontaneously developed breast cancer in mice in real time guiding complete surgical removal of the tumor, highlighting the translational potential of these new glyco-SERS-NPs.

Study of Iron Complex Photosensitizer with Hollow Double-Shell Nano Structure Used to Enhance Ferroptosis and Photodynamic Therapy.

Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2-HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+, which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2O2 and enhances the production of singlet oxygen (1O2) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2-HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.

Singlet oxygen‐responsive hyaluronate dot clusters for tumor therapy

AbstractIn this study, we developed nanoclusters that respond to singlet oxygen and can be adjusted in size to enhance the efficacy of tumor therapy. Specifically, we engineered nanoclusters, denoted as dHAc‐PSDA‐Ce6, through the covalent conjugation of hyaluronate dots (dHA) with 3,3‐(propane‐2,2‐diylbis(sulfanediyl))dipropionic acid (PSDA) as a cleavable crosslinker mediated by singlet oxygen, and chlorin e6 (Ce6) as a representative model drug for photodynamic therapy. The hyaluronic acid (HA) component within dHAc‐PSDA‐Ce6 was harnessed for the specific targeting of CD44 receptors that are overexpressed on tumor cells. Upon subjecting the vicinity of tumor cells to light irradiation, the PSDA crosslinker within dHAc‐PSDA‐Ce6 undergoes cleavage, likely facilitated by the singlet oxygen generated by Ce6. This cleavage process leads to the formation of dHA‐Ce6 molecules. We hypothesized that a nanocluster, circulating safely within the bloodstream, would undergo a transformation into individual dHA‐Ce6 molecules upon light irradiation at the localized tumor site. This transformation, in turn, enhances the photodynamic antitumor effect. Our in vitro investigations have demonstrated the remarkable efficacy of dHAc‐PSDA‐Ce6 in inducing tumor cell death upon light irradiation. Furthermore, our in vivo biodistribution studies have revealed the substantial accumulation of these nanoclusters within the tumor site. We anticipate that this singlet oxygen‐responsive nanocluster harbors substantial promise for enhancing tumor accumulation and fortifying the effectiveness of tumor eradication.

Engineering Dual-Responsive Prodrug-MOFs as Immunogenic Cell Death Initiator for Enhancing Cancer Immunotherapy.

In recent years, the anticancer effects of disulfiram, a clinical drug for anti-alcoholism, are confirmed. However, several defects limit the clinical translation of disulfiram obviously, such as Cu(II)-dependent anticancer activity, instability, and non-selectivity for cancer cells. Herein, a phosphate and hydrogen peroxide dual-responsive nanoplatform (PCu-HA-DQ) is reported, which is constructed by encapsulating disulfiram prodrug (DQ) and modifying hyaluronic acid (HA) on copper doping metal-organic frameworks (PCu MOFs). PCu-HA-DQ is expected to accumulate in tumor by targeting CD-44 receptors and enable guidance with magnetic resonance imaging. Inside the tumor, Cu(DTC)2 will be generated in situ based on a dual-responsive reaction. In detail, the high concentration of phosphate can induce the release of DQ, after that, the intracellular hydrogen peroxide will further mediate the generation of Cu(DTC)2 . In vitro and in vivo results indicate PCu-HA-DQ can induce the apoptosis as well as immunogenic cell death (ICD) of tumor cells distinctly, leading to enhanced immune checkpoint inhibitor (ICI) efficacy by combining the anti-programmed death-1 antibody. This work provides a portable strategy to construct a dual-responsive nanoplatform integrating tumor-targeted ability and multi-therapy, and the designed nanoplatform is also an ICD inducer, which presents a prospect for boosting systemic antitumor immunity and ICI efficacy.

SRGN amplifies microglia-mediated neuroinflammation and exacerbates ischemic brain injury

BackgroundMicroglia is the major contributor of post-stroke neuroinflammation cascade and the crucial cellular target for the treatment of ischemic stroke. Currently, the endogenous mechanism underlying microglial activation following ischemic stroke remains elusive. Serglycin (SRGN) is a proteoglycan expressed in immune cells. Up to now, the role of SRGN on microglial activation and ischemic stroke is largely unexplored.MethodsSrgn knockout (KO), Cd44-KO and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO) to mimic ischemic stroke. Exogenous SRGN supplementation was achieved by stereotactic injection of recombinant mouse SRGN (rSRGN). Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological functions were evaluated by the modified neurological severity score (mNSS) and grip strength. Microglial activation was detected by Iba1 immunostaining, morphological analysis and cytokines’ production. Neuronal death was examined by MAP2 immunostaining and FJB staining.ResultsThe expression of SRGN and its receptor CD44 was significantly elevated in the ischemic mouse brains, especially in microglia. In addition, lipopolysaccharide (LPS) induced SRGN upregulation in microglia in vitro. rSRGN worsened ischemic brain injury in mice and amplified post-stroke neuroinflammation, while gene knockout of Srgn exerted reverse impacts. rSRGN promoted microglial proinflammatory activation both in vivo and in vitro, whereas Srgn-deficiency alleviated microglia-mediated inflammatory response. Moreover, the genetic deletion of Cd44 partially rescued rSRGN-induced excessed neuroinflammation and ischemic brain injury in mice. Mechanistically, SRGN boosted the activation of NF-κB signal, and increased glycolysis in microglia.ConclusionSRGN acts as a novel therapeutic target in microglia-boosted proinflammatory response following ischemic stroke.

Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis

BackgroundThe complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs.MethodsBy exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and β-glycerophosphate disodium salt (β-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel).ResultsCellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity.ConclusionThis triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.Graphical

Fabrication of hyaluronic acid with graphene quantum dot as a dual drug delivery system for cancer therapy

With recent advancements in nanomedicine, there has been growing interest in developing drug delivery systems with multifunctional capabilities. In this study, we developed a novel dual drug delivery system by combining two drug carriers via positive and negative electrostatic interactions. First, we modified polyethyleneimine (PEI) with graphene quantum dots (GQDs) to create a positively charged particle (GPI) with high drug loading efficiency and good dispersibility. Second, we embedded the pyrenebutyric acid structure in hyaluronic acid (HA) through EDC/NHS cross-linking and used TAK-632 as the hydrophobic drug to create negatively charged particles (HANPs) with hydrogel-like properties and the CD44 receptor. After the two components were constructed, the increase in the particle charge and simultaneous delivery of both drugs synergistically enhanced the therapeutic effect of this strategy. Qualitative tests confirmed the successful synthesis of the drug carrier, while the potential of this system as a cancer treatment strategy was evaluated in HCT116 cancer cells (through MTT cell viability assays) and in vivo mice xenograft experiments. Our results demonstrated that the dual drug delivery system, HANPs(TAK)/GPI(DOX), had a significant inhibitory effect on the growth of cancer cells both in vitro and in vivo, suggesting that this system is a promising candidate for a new type of treatment.

Potentiating Gilteritinib Efficacy Using Nanocomplexation with a Hyaluronic Acid-Epigallocatechin Gallate Conjugate.

Acute myeloid leukemia carrying FMS-like tyrosine kinase receptor-3 (FLT3) mutations is a fatal blood cancer with a poor prognosis. Although the FLT3 inhibitor gilteritinib has recently been approved, it still suffers from limited efficacy and relatively high nonresponse rates. In this study, we report the potentiation of gilteritinib efficacy using nanocomplexation with a hyaluronic acid-epigallocatechin gallate conjugate. The self-assembly, colloidal stability, and gilteritinib loading capacity of the nanocomplex were characterized by reversed-phase high-performance liquid chromatography and dynamic light scattering technique. Flow cytometric analysis revealed that the nanocomplex efficiently internalized into FLT3-mutated leukemic cells via specific interactions between the surface-exposed hyaluronic acid and CD44 receptor overexpressed on the cells. Moreover, this nanocomplex was found to induce an eradication of the leukemic cells in a synergistic manner by elevating the levels of reactive oxygen species and caspase-3/7 activities more effectively than free gilteritinib. This study may provide a useful strategy to design nanomedicines capable of augmenting the therapeutic efficacy of FLT3 inhibitors for effective leukemia therapy.

PH-responsive degradable mesoporous organosilica nanoparticle for tumor targeting and phototherapy combined with chemotherapy

In the context of the tumor microenvironment, the design of a high concentration glutathione (GSH) driven degradation drug delivery system (ID@MON-HA) is according to a different quantity of GSH to normal tissues. This system involves loading doxorubicin (DOX) and new indocyanine green (IR820) onto mesoporous organosilica nanoparticles (MON). The disulfide linkages in MON are broken in response to high amounts of GSH in tumor cells, resulting in the degradation of the overall structure and preventing carrier accumulation. To connect the hyaluronic acid (HA) and the carrier with encapsulated drugs, a pH-sensitive Schiff based bond is utilized. Furthermore, MON specifically target to tumor sites due to the selective binding of HA to tumor cells that overexpress the CD44 receptor. Experiments have shown that increased GSH concentrations and pH levels below physiological can accelerate drug release. Additionally, in vitro cellular experiments have demonstrated that combining chemotherapy and phototherapy enhances the suppression of tumor cells (median inhibition concentration IC50 = 1.53 μg mL_1). These findings indicate that the study offers an acceptable approach for developing degradable nanoplatforms for tumor combination therapy.

The Matrix Receptor CD44 Is Present in Astrocytes throughout the Human Central Nervous System and Accumulates in Hypoxia and Seizures.

In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial "interlaminar" astrocytes, sending long processes into the cortex. The hippocampus also contains similar astrocytes. We have examined all levels of the human central nervous system and found CD44+ astrocytes in every region. Astrocytes in white matter and astrocytes that interact with large blood vessels but not with capillaries in gray matter are CD44+, the latter extending long processes into the parenchyma. Motor neurons in the brainstem and spinal cord, such as oculomotor, facial, hypoglossal, and in the anterior horn of the spinal cord, are surrounded by CD44+ processes, contrasting with neurons in the cortex, basal ganglia, and thalamus. We found CD44+ processes that intercalate between ependymal cells to reach the ventricle. We also found CD44+ astrocytes in the molecular layer of the cerebellar cortex. Protoplasmic astrocytes, which do not normally contain CD44, acquire it in pathologies like hypoxia and seizures. The pervasive and inducible expression of CD44 in astrocytes is a novel finding that lays the foundations for functional studies into the significance of CD44 in health and disease.

Fabrication of hyaluronic acid-inulin coated Enterococcus faecium for colon-targeted delivery to fight Fusobacterium nucleatum

The abundance of Fusobacterium nucleatum (F. nucleatum) is highly associated with the development and poor prognosis of colorectal cancer (CRC), which is regarded as a promising target for CRC. However, until now, the novel strategy to clear F. nucleatum in the colon and CRC has not been well proposed. Herein, a probiotic strain Enterococcus faecium (E. faecium, EF47) is verified to secrete various organic acids and bacteriocins to exert superior antimicrobial activity towards F. nucleatum. However, the oral delivery of EF47 is affected by the complex digestive tract environment, so we design the hyaluronic acid-inulin (HA-IN) coated EF47 for colon-targeted delivery to fight F. nucleatum. IN can protect EF47 from the harsh gastrointestinal tract environment and is degraded specifically in the colon, acting as prebiotics to further promote the proliferation of EF47. The exposed HA can also enhance the targeting effect to the tumor area via the interaction with the CD44 receptor on the tumor cells, which is confirmed to increase the adhesive ability in tumor tissues and inhibit the growth of F. nucleatum. Therefore, this colon-targeted delivery system provides a novel platform to realize high-activity and adhesive delivery of probiotics to assist the therapeutic efficiency of CRC.

Role of the mechanical microenvironment on CD-44 expression of breast adenocarcinoma in response to radiotherapy

The biological effects of ionizing radiation are exploited in the clinical practice of radiotherapy to destroy tumour cells while sparing the surrounding normal tissue. While most of the radiotherapy research focused on DNA damage and repair, recently a great attention is going to cells' interactions with the mechanical microenvironment of both malignant and healthy tissues after exposure. In fact, the stiffness of the extracellular matrix can modify cells' motility and spreading through the modulation of transmembrane proteins and surface receptors' expression, such as CD-44. CD-44 receptor has held much interest also in targeted-therapy due to its affinity with hyaluronic acid, which can be used to functionalize biodegradable nanoparticles loaded with chemotherapy drugs for targeted therapy. We evaluated changes in CD-44 expression in two mammary carcinoma cell lines (MCF10A and MDA-MB-231) after exposure to X-ray (2 or 10 Gy). To explore the role of the mechanical microenvironment, we mimicked tissues' stiffness with polyacrylamide's substrates producing two different elastic modulus values (0.5 and 15 kPa). We measured a dose dependent increase in CD-44 relative expression in tumour cells cultured in a stiffer microenvironment. These findings highlight a crucial connection between the mechanical properties of the cell's surroundings and the post-radiotherapy expression of surface receptors.

Exploring the Role of Nanotherapeutics for Diagnosis and Treatment of Solid Tumor

Background: Tumors are increasingly heterogeneous throughout the process of their growth, producing a mixed-cell community with a range of molecular features and susceptibility to therapies. Nanotechnology has shown tremendous potential in diagnosing and treating solid tumors. Objective: Most cancer-related deaths are attributed to the lack of early detection and effective treatment. Its early diagnosis helps overall survival and health-related quality of life in patients identified with cancer. Nanosystems are favorable for endocytic intracellular retention, high drug loading, enhanced therapeutic efficacy, greater drug-circulation time, superior dose scheduling for patient compliance, and site-specific targeting. Integrating nanosystems into biomedical applications will also reintroduce medicines that are no longer used in clinical practice because of certain drawbacks and help the identification of new active medicines with their sub-optimal kinetic profiles. This review provides insights about the targeted cancer treatment based on active targeting (folate receptor-α, heat shock protein, receptor 2 for epidermal human growth factor, and CD44 receptor) and various nano device-based systems. Methodology: The highly relevant articles were retrieved using various search engines, including Web of Sciences, Science Direct, Scihub, PubMed, Scopus, PubChem, Google Scholar, and others. The keywords and phrases used for the search are “liposomes,” “quantum dots,” “nanoparticles,” “nanocrystals,” “photodynamic therapy,” “passive targeting,” “active targeting,” “nanomaterials,” “nanotechnology,” “cancer,” “nanotheranostics” and several others. In this review, we briefly introduced the concept of the contribution of nanotheranostics to cancer therapy with their recent findings. We also discuss the role of biosensor-based nanosystems in cancer. Conclusion: This review addresses nanotechnology’s exciting role in identifying, imaging, and managing solid tumors and their immense potential.

ДИФФЕРЕНЦИАЛЬНАЯ ЭКСПРЕССИЯ ГЕНОВ МОЛЕКУЛ АДГЕЗИИ И МЕЖКЛЕТОЧНОГО ВЗАИМОДЕЙСТВИЯ В МИКРОЭКСПЛАНТАХ КОСТНОГО МОЗГА ПРИ МОДЕЛИРОВАНИИ МИКРОГРАВИТАЦИИ

Functional activity of the bone marrow cells is dependent on external signals received from a local microenvironment. In addition to the soluble growth factors and hormones, contacts with neighbor cells and signals from the extracellular matrix are also the most important homeostasis regulators in the bone marrow niche. Purpose of the work is to explore the effects of simulated microgravity on the transcription activity of genes the products of which define the cell-to-cell and cell-to-matrix interactions in bone marrow micro-explants. Femoral marrow cells from male mice BalbC 19-20 wks of age were used in the investigation. After isolation, bone marrow cells were pooled and exposed to simulated microgravity in vitro over 14 days. Following the exposure, bone marrow micro-explants were found to increase expression of genes of the cell adhesion molecules responsible for cell-to-cell interaction (Ncam1, Icam1, Vcam1), and integrins α-М (Itgam) and β-1 (Itgb1). Also, there was a reliable decrease in expression of genes involved in the cell-to-matrix interaction, including integrins β-3 (Itgb3), β-2 (Itgb2), α-Х (Itgax), α-l (Itga1), α-5 (Itga5), receptor CD44 (Cd44), and molecules of the adhesion complexes, such as α- and β-katenins (Ctnna1, Ctnnb1). These changes in the pattern of cells-to-environment interaction may induce disorders in self-renewal, proliferation and differentiation of stromal and hemopoietic precursors which may end up with distortion of hemopoiesis, change in bone homeostasis leading to osteopenia observed after space missions.

Dual drug-loaded metal-phenolic networks for targeted magnetic resonance imaging and synergistic chemo-chemodynamic therapy of breast cancer.

The development of nanomedicines with simplified compositions and synergistic theranostic functionalities remains a great challenge. Herein, we develop a simple method to integrate both atovaquone (ATO, a mitochondrial inhibitor) and cisplatin within tannic acid (TA)-iron (Fe) networks coated with hyaluronic acid (HA) for targeted magnetic resonance (MR) imaging-guided chemo-chemodynamic synergistic therapy. The formed TFP@ATO-HA displayed good colloidal stability with a mean size of 95.5 nm, which could accumulate at tumor sites after circulation and be specifically taken up by metastatic 4T1 cells overexpressing CD44 receptors. In the tumor microenvironment, TFP@ATO-HA could release ATO/cisplatin and Fe3+ in a pH-responsive manner, deplete glutathione, and generate reactive oxygen species with endogenous H2O2 for chemodynamic therapy (CDT). Additionally, ATO could enhance chemotherapeutic efficacy by inhibiting mitochondrial respiration, relieving hypoxia, and amplifying the CDT effect by decreasing intracellular pH and elevating Fenton reaction efficiency. In vivo experiments demonstrated that TFP@ATO-HA could effectively inhibit tumor growth and suppress lung metastases without obvious systemic toxicity. Furthermore, TFP@ATO-HA exhibited a r1 relaxivity of 2.6 mM-1 s-1 and targeted MR imaging of 4T1 tumors. Dual drug-loaded metal-phenolic networks can be easily prepared and act as effective theranostic nanoplatforms for targeted MR imaging and synergistic chemo-chemodynamic therapy.

A copper-platinum nanoplatform for synergistic photothermal and chemodynamic tumor therapy via ROS outburst and GSH exhaustion.

A multifunctional nanoplatform is obtained by modifying copper hexacyanoferrate (Cu-HCF) nanozyme with hyaluronic acid (HA) and further loading platinum (Pt) nanoparticles. This Cu-HCF-HA@Pt platform shows peroxidase-like and glutathione oxidase-like dual-enzyme catalytic activities and photothermal properties, enabling synergistic chemodynamic and photothermal tumor therapy. HA binds to the CD44 receptor, which is highly expressed on the exterior surface of tumor cells, endowing the nanoplatform with tumor specificity. Cu-HCF-HA@Pt catalyzes the decomposition of H2O2 to produce abundant hydroxyl radicals within tumor cells, increasing intracellular oxidative stress levels and inducing tumor cell apoptosis. Meanwhile, Cu-HCF-HA@Pt catalyzes the conversion of intracellular reduced glutathione (GSH) to oxidized glutathione, resulting in GSH exhaustion. The conversion of CuII to CuI in Cu-HCF via a Fenton-like reaction can improve the peroxidase-like property of Cu-HCF-HA@Pt. After the probe is targeted to the tumor site, irradiation by an 808 nm near-infrared laser causes local heating and brings about photothermal tumor apoptosis when reaching 45 °C. The prepared Cu-HCF-HA@Pt combines nanozyme-catalyzed therapy with photothermal therapy to induce apoptosis in tumor cells.

Hyaluronic acid-modified liposomes Potentiated in-vivo anti-hepatocellular carcinoma of icaritin.

Introduction: Icaritin (ICT), a promising anti-hepatocellular carcinoma (HCC) prenylated flavonoid, is hindered from being applied due to its low water solubility and high lipophilicity in poorly differentiated HCC which is associated with upregulation of CD44 isoforms. Thus, hyaluronic acid (HA), a natural polysaccharide with high binding ability to CD44 receptors, was used to formulate a modified liposome as a novel targeted ICT-delivery system for HCC treatment. Methods: The ICT-Liposomes (Lip-ICT) with and without HA were prepared by a combined method of thin-film dispersion and post-insertion. The particle size, polydispersity (PDI), zeta potential, encapsulation efficacy (%EE), drug loading content (%DLC), and in vitro drug release profiles were investigated for physicochemical properties, whereas MTT assay was used to assess cytotoxic effects on HCC cells, HepG2, and Huh7 cells. Tumor bearing nude mice were used to evaluate the inhibitory effect of HA-Lip-ICT and Lip-ICT in vivo. Results: Lip-ICT and HA-Lip-ICT had an average particle size of 171.2 ± 1.2nm and 208.0 ± 3.2 nm, with a zeta potential of -13.9 ± 0.83 and -24.8 ± 0.36, respectively. The PDI resulted from Lip-ICT and HA-Lip-ICT was 0.28 ± 0.02 and 0.26 ± 0.02, respectively. HA-Lip-ICT demonstrated higher in vitro drug release when pH was dropped from 7.4 to 5.5, The 12-h release rate of ICT from liposomes increased from 30% at pH7.4 to more than 60% at pH5.5. HA-Lip-ICT displayed higher toxicity than Lip-ICT in both HCC cells, especially Huh7with an IC50 of 34.15 ± 2.11μM. The in vivo tissue distribution and anti-tumor experiments carried on tumor bearing nude mice indicated that HA-Lip- ICT exhibited higher tumor accumulation and achieved a tumor growth inhibition rate of 63.4%. Discussion: The nano-sized Lip-ICT was able to prolong the drug release time and showed long-term killing HCC cells ability. Following conjugation with HA, HA-Lip-ICT exhibited higher cytotoxicity, stronger tumor targeting, and tumor suppression abilities than Lip-ICT attributed to HA-CD44 ligand-receptor interaction, increasing the potential of ICT to treat HCC.