Acidic Microenvironment Research Articles

Revealing tumor cells and tissues with high selectivity through folic acid-targeted nanofluorescence probes responsive to acidic microenvironments.

Tumor-specific fluorescent probes must fulfill the dual requirements of targeted accumulation within tumors and high-resolution imaging capabilities. To achieve both tumor-targeted accumulation and high-resolution imaging performance, we developed a composite comprising an acid-responsive bodipy conjugated to amphiphilic PEG-b-PLA polymer, along with folic acid (FA)-modified PEG-b-PLA as a targeting moiety for active tumor-specific accumulation. Finally, a novel assembly of hybrid fluorescent nanoparticles was successfully synthesized by integrating these two components, demonstrating exceptional responsiveness to acidic conditions for fluorescence excitation and remarkable tumor-targeted accumulation capabilities. We conducted comprehensive in vitro and in vivo investigations employing techniques such as analysis of physicochemical properties, fluorescence-based probes detection at varying pH levels, assessment of in vitro cytotoxicity, evaluation of cellular uptake capacity, analysis of lysosomal co-localization imaging, examination of tumor fluorescence images in vivo, and investigation of biological distribution patterns. The results demonstrated that the acid-responsive nanofluorescence probe we designed and synthesized possesses desirable physical and chemical characteristics, including a small particle size and low cytotoxicity. Moreover, it exhibits rapid real-time response to acidic environments and displays enhanced fluorescence intensity, enabling the real-time tracking of probe entry into tumor cells as well as intracellular lysozyme accumulation. We achieved highly specific in vivo tumor visualization by combining nanoprobes targeting folate receptor. Through imaging cervical tumor mice, we demonstrated the precise imaging performance and high targeted accumulation of FA-targeted nanofluorescence probes in tumor tissue. Furthermore, we confirmed the in vivo safety of the FA-targeted nanofluorescence probe through biological distribution analysis. These findings highlight the potential widespread application of FA-targeted acid-responsive nanofluorescence probes for selective imaging of tumor cells and tissues.

Chemodynamic therapy combined with endogenous ferroptosis based on “sea urchin-like” copper sulfide hydrogel for enhancing anti-tumor efficacy

Chemodynamic therapy (CDT) is a promising strategy for cancer treatment, however, its application is restricted by low hydrogen peroxide (H2O2) concentration, insufficient reactive oxygen species (ROS) generation, and high glutathione (GSH) levels. Here, we developed an injectable thermosensitive hydrogel (DSUC-Gel) based on “sea urchin-like” copper sulfide nanoparticles (UCuS) loaded with dihydroartemisinin (DHA) and sulfasalazine (SAS) to overcome these limitations of CDT. DSUC was cleaved to release DHA, SAS and Cu2+ under acidic tumor microenvironment to enhance CDT. DHA with peroxide bridge responded to intracellular Fe2+ to alleviate H2O2 deficiency. SAS prevented GSH synthesis by targeting SLC7A11 and inhibited glutathione peroxidase (GPX4) activity to induce endogenous ferroptosis. ROS produced by Fenton-like reaction of Cu2+ promoted lipid peroxidation (LPO) accumulation to promote ferroptosis. Enhanced CDT and ferroptosis induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) infiltration. As a result, DSUC-Gel significantly inhibited tumor growth both in vitro and in vivo. Our study provides a novel approach for enhancing anti-tumor efficacy by combining CDT, endogenous ferroptosis and ICD.

Exploring the Potential Use of Natural Products Together with Alkalization in Cancer Therapy

Cancer treatment is a significant focus in medicine, owing to the increasing global incidence of cancers. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with supplementation with natural products may confer benefits to cancer patients, by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

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BackgroundMetastasis is one of the main factors leading to the high mortality rate of gastric cancer. The current monitoring methods are not able to accurately monitor gastric cancer metastasis.MethodsIn this paper, we constructed a new type of hollow Mn3O4\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ ext {Mn}_{3}\ ext {O}_{4}$$\\end{document} nanocomposites, Mn3O4\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ ext {Mn}_{3}\ ext {O}_{4}$$\\end{document}@HMSN-Cy7.5-FA, which had a size distribution of approximately 100 nm and showed good stability in different liquid environments. The in vitro magnetic resonance imaging (MRI) results show that the nanocomposite has good response effects to the acidic microenvironment of tumors. The acidic environment can significantly enhance the contrast of T1\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext {T}_{1}}$$\\end{document}-weighted MRI. The cellular uptake and endocytosis results show that the nanocomposite has good targeting capabilities and exhibits good biosafety, both in vivo and in vitro. In a gastric cancer nude mouse orthotopic metastatic tumor model, with bioluminescence imaging’s tumor location information, we realized in vivo MRI/fluorescence imaging (FLI) guided precise monitoring of the gastric cancer orthotopic and metastatic tumors with this nanocomposite.ResultsThis report demonstrates that Mn3O4\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ ext {Mn}_{3}\ ext {O}_{4}$$\\end{document}@HMSN-Cy7.5-FA nanocomposites is a promising nano-diagnostic platform for the precision diagnosis and therapy of gastric cancer metastasis in the future.ConclusionsIn vivo MRI/FLI imaging results show that the nanocomposites can achieve accurate monitoring of gastric cancer tumors in situ and metastases. BLI’s tumor location information further supports the good accuracy of MRI/FLI dual-modality imaging. The above results show that the MHCF NPs can serve as a good nano-diagnostic platform for precise in vivo monitoring of tumor metastasis. This nanocomposite provides more possibilities for the diagnosis and therapy of gastric cancer metastases.

Sorafenib Encapsulated Poly(ester amide) Nanoparticles for Efficient and Biosafe Prostate Cancer Therapy.

Prostate cancer (PCa) with a high incidence worldwide is a serious threat to men's health. Despite the continuous development of treatment strategies for PCa in recent years, the long-term prognosis of patients is still poor. Hence, the discovery and development of novel, secure, and efficient therapeutic approaches hold significant clinical significance. Although sorafenib (SOR) displays potential as a therapeutic option for PCa, its clinical efficacy is hindered by drug resistance, limited water solubility, and rapid metabolism. Therefore, we proposed to prepare nanoparticles (named SOR@8P4 NPs) utilizing the phenylalanine-based poly(ester amide) polymer (8P4) as the drug carrier to enhance the solubility and drug stability of SOR and improve the therapeutic targeting and bioavailability. SOR@8P4 NPs had high stability and showed acid-responsive drug release at the acidic tumor microenvironment. Additionally, SOR@8P4 NPs demonstrated more remarkable anticancer, antimetastatic, and antiproliferative abilities in vitro, compared with those of free drugs. SOR@8P4 NPs showed high tumor targeting and significantly inhibited tumor growth in vivo. In summary, the drug delivery system of SOR@8P4 NPs provides new ideas for the clinical treatment of PCa.

Fabrication of verrucarin-a-loaded zinc oxide nanocomposite for inducing apoptosis in triple-negative breast cancer cells

Due to its low bioavailability and insolubility in water, little is known about the biological effects of Verrucarin-A. Chitosan-coated zinc oxide (ZnO) nanoparticles were employed as a potential nanocarrier to transport Verrucarin-A to its target cells to enhance its bioavailability. Results showed improved water solubility, entrapment, drug release, and loading efficiencies for the fabricated Verrucarin-A clocked ZnO- nanocomposite (Ver-A@ZnNCs). Comparing Ver-A@ZnNCs to both non-cancerous epithelial (MCF-10A) cells and triple-negative breast cancer (MDA-MB-231) cells in an in vitro cell viability test (MTT), the latter showed greater biocompatibility. According to observations, verrucarin-A release from Ver-A@ZnNCs at cancer cell sites may be caused by the acidic tumor microenvironment. Apoptosis occurred in the cancer cells after increased nanoparticle uptake, which may have stimulated ROS generation. Further evidence of Ver-A@ZnNCs' in vitro anticancer activity was obtained through apoptosis investigations. After performing significant in vitro studies, it has been shown that Ver-A@ZnNCs is compatible with humanity and shows promise as an anticancer drug for triple-negative breast cancer patients.

Colloidal Hydrogel for Sensitizing Microwave Ablation‐Induced in Situ Tumor Vaccination and Modulating Innate and Adaptive Immunotherapy

AbstractDrawing inspiration from recent advances in microwave ablation (MWA) induced in situ tumor vaccination, a colloidal hydrogel comprising amphoteric gelatin nanoparticles and poly (acrylic acid) (PAA)‐calcium carbonate nanorods (PAA‐CaCO3 NRs) is developed to deliver the microwave‐sensitive agent sodium fluoride (NaF) which can also act as a glycolysis inhibitor in conjunction with the blockade of the T‐cell Ig and ITIM domain (TIGIT), a coinhibitory receptor expressed by both natural killer (NK) cells and T cells. The combination of NaF with microwave (MW) thermal‐dynamic sensitization effectively reversed the acidic and immunosuppressive tumor microenvironment (TME). Moreover, the incorporation of anti‐TIGIT monoclonal antibody (aTIGIT) molecules amplified both the innate and adaptive immune responses by counteracting the exhaustion of NK and effective CD8+ T cells. This augmentation resulted in enhanced tumor elimination and suppression of tumor metastasis and recurrence. Thus, this study underscores the potential of colloidal hydrogel‐sensitized MWA therapy, in conjunction with aTIGIT treatments, as a promising clinical strategy for in situ cancer vaccination.

Inflammatory microenvironment regulation and osteogenesis promotion by bone-targeting calcium and magnesium repletion nanoplatform for osteoporosis therapy

Osteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people, which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment. Magnesium and calcium are pivotal matrix components that participate in the bone formation process, especially in the immune microenvironment regulation and bone remodeling stages. Nevertheless, how to potently deliver magnesium and calcium to bone tissue remains a challenge. Here, we have constructed a multifunctional nanoplatform composed of calcium-based upconversion nanoparticles and magnesium organic frameworks (CM-NH2-PAA-Ald, denoted as CMPA), which features bone-targeting and pH-responsive properties, effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis. The nanoplatform can efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions. This study validates that CMPA possessing favorable biocompatibility can suppress inflammation and facilitate osteogenesis to treat osteoporosis. Importantly, high-throughput sequencing results demonstrate that the nanoplatform exerts a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway, thereby normalizing the osteoporotic microenvironment. This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.

An acidic pH environment converts necroptosis to apoptosis

Cardiac ischemia results in anaerobic metabolism and lactic acid accumulation and with time, intracellular and extracellular acidosis. Ischemia and subsequent reperfusion injury (IRI) lead to various forms of programmed cell death. Necroptosis is a major form of programmed necrosis that worsens cardiac function directly and also promotes inflammation by the release of cellular contents. Potential effects of increasing acidosis on programmed cell death and their specific components have not been well studied. While apoptosis is caspase-dependent, in contrast, necroptosis is mediated by the receptor-interacting protein kinases 1 and 3 (RIPK1/3). In our study, we observed that at physiological pH = 7.4, caspase-8 inhibition did not prevent TNFα-induced cell death in mouse cardiac vascular endothelial cells (MVECs) but promoted necroptotic cell death. As expected, necroptosis was blocked by RIPK1 inhibition. However, at pH = 6.5, TNFα induced an apoptosis-like pattern which was inhibited by caspase-8 inhibition. Interestingly phosphorylation of necroptotic molecules RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) was enhanced in an acidic pH environment. However, RIPK3 and MLKL phosphorylation was self-limited which may have limited their participation in necroptosis. In addition, an acidic pH promoted apoptosis-inducing factor (AIF) cleavage and nuclear translocation. AIF RNA silencing inhibited cell death, supporting the role of AIF in this cell death. In summary, our study demonstrated that the pH of the micro-environment during inflammation can bias cell death pathways by altering the function of necroptosis-related molecules and promoting AIF-mediated cell death. Further insights into the mechanisms by which an acidic cellular micro-environment influences these and perhaps other forms of regulated cell death, may lead to therapeutic strategies to attenuate IRI.

A phase 1 dose-escalation and expansion study of an intratumorally administered dual STING agonist (ONM-501) alone and in combination with cemiplimab in patients with advanced solid tumors and lymphomas.

TPS2693 Background: The Stimulator of Interferon Genes (STING) pathway has garnered significant interest as a target for anticancer interventions due to its role in driving the production of pro-inflammatory cytokines and activating tumor-specific cell killing. Cyclic dinucleotides (CDNs) such as cGAMP, the endogenous STING agonist, are not ideal clinical candidates for exogenous routes of delivery. Early trials showed limited efficacy with CDNs due to rapid clearance, degradation and/or off-target toxicity. ONM-501 is comprised of a STING-activating pH-sensitive PC7A polymer conjugated with cGAMP. At physiologic pH, ONM-501 forms a micelle, preventing degradation of cGAMP. In the acidic tumor microenvironment, ONM-501 effects STING agonism through a multi-faceted mode of action: 1) endocytosis of nanoparticles and pH-activated micelle dissociation and payload release in endolysosomes enhances intracellular delivery of cGAMP 2) the combination of cGAMP canonical binding, and PC7A polymer noncanonical binding on STING yields synergistic STING activation and 3) stabilization of STING by PC7A polymers delays its degradation and prolongs STING activation. In pre-clinical models, these factors combine to help generate a stronger and more prolonged innate immune response that more effectively translates to a robust adaptive immune response. ONM-501 is being investigated in this first-in-human Phase 1 trial as monotherapy and combination therapy with the anti-PD1 antibody, cemiplimab, for patients with solid tumors and lymphomas. Methods: ONM5001 (NCT06022029) is a first-in-human, open-label, multi-center clinical trial. Adult patients with solid tumors or lymphomas for which no standard therapy exists or for which patients decline palliative standard therapy who have at least one injectable lesion are eligible for this study. This Phase 1 study consists of three parts: monotherapy dose escalation; combination therapy dose finding; and combination therapy dose expansion in specific tumor indication(s) that will be selected based on data from mono- and combination therapy dose finding. Each dosing cycle of ONM-501 is 21 days: patients receive an intratumoral injection of ONM-501 weekly for three weeks, followed by three weeks without injection. Cemiplimab is administered intravenously during combination therapy arms according to standard administration protocol, once every three weeks. The primary endpoint is to evaluate safety of ONM-501 monotherapy as evidenced by the number of dose limiting toxicities and treatment-emergent adverse events, and to determine the recommended dose for expansion. Secondary endpoints include characterization of pharmacokinetics and pharmacodynamics, as well as initial efficacy based on RECIST evaluation criteria. Enrollment began in November 2023. Clinical trial information: NCT06022029 .

Construction of a three-dimensional culture system based on Gelatin methacryloyl hydrogel for lung cancer cells

Abstract Hypoxia and acidity are key characteristics of the tumor microenvironment (TME). Gelatin methacryloyl (GelMA) is a versatile biomaterial extensively utilized in various biomedical fields. Studies have shown that during the photocrosslinking process of GelMA hydrogel, the commonly used photoinitiator Irgacure 2959 consumes oxygen and induces an acidic and hypoxia environment. However, there is currently limited research on its involvement in the three-dimensional (3D) culture of tumor cells. Therefore, we constructed a 3D culture system utilizing GelMA hydrogel and investigated its influence on the growth and drug response of lung cancer cells (A549). The results demonstrated that the GelMA hydrogel-based 3D culture system exhibited excellent biocompatibility and robust mechanical properties and provided an acidic microenvironment conducive to tumor cell proliferation. Furthermore, the cancer cells exhibited heightened sensitivity to chemotherapeutics in this 3D culture model. These results suggest that the GelMA hydrogel-based 3D culture system can serve as a perfect model for in vitro study of tumor cells.

Caffeic Acid Enhances Anticancer Drug-induced Apoptosis in Acid-adapted HCT116 Colon Cancer Cells.

Apoptosis resistance in cancer cells adapted to acidic microenvironments poses a challenge for effective treatment. This study investigated the potential use of caffeic acid as an adjunct therapy to overcome drug resistance in colorectal cancer cells under acidic conditions. Long-term exposure to low-pH conditions induced resistance in HCT116 colorectal cancer cells. The effects of caffeic acid on proliferation, clonogenicity, and apoptosis induction were assessed alone and in combination with oxaliplatin and 5-Fluorouracil. The signaling pathways involved in drug resistance were examined by assessing the activities of PI3K/Akt and ERK1/2. Caffeic acid inhibited the proliferation and clonogenicity of acid-adapted cancer cells, and enhanced apoptosis when combined with anticancer drugs. Mechanistically, caffeic acid attenuated the hyperactivation of the PI3K/Akt and ERK1/2 signaling pathways associated with drug resistance. Caffeic acid is a promising therapeutic agent for targeting resistant cancer cells in acidic microenvironments. Its ability to inhibit proliferation, sensitize cells to apoptosis, and modulate signaling pathways highlights its potential for overcoming drug resistance in cancer therapy.

A hydrogen generator composed of poly (lactic-co-glycolic acid) nanofibre membrane loaded iron nanoparticles for infectious diabetic wound repair

Diabetic wound, which is chronic skin disease, poses a significant challenge in clinical practice because of persistent inflammation and impaired angiogenesis. Recently, hydrogen has emerged as a novel therapeutic agent due to its superior antioxidant and anti-inflammatory properties. In this study, we engineered a poly (lactic-co-glycolic acid) (PLGA) electrospun nanofibre membrane loaded with citric acid (CA) and iron (Fe) nanoparticles, referred to as Fe@PLGA + CA. Our in vitro assays demonstrated that the Fe@PLGA + CA membrane continuously generated and released hydrogen molecules via a chemical reaction between Fe and CA in an acidic microenvironment created by CA. We also discovered that hydrogen can ameliorate fibroblast migration disorders by reducing the levels of matrix metalloproteinase 9 (MMP9). Furthermore, we confirmed that hydrogen can scavenge or biochemically neutralise accumulated reactive oxygen species (ROS), inhibit pro-inflammatory responses, and induce anti-inflammatory reactions. This, in turn, promotes vessel formation, wound-healing and accelerates skin regeneration. These findings open new possibilities for using elemental iron in skin dressings and bring us one step closer to implementing hydrogen-releasing biomedical materials in clinical practice.

Development and characterization of antacid microcapsules to buffer the acidic intervertebral disc microenvironment.

During intervertebral disc (IVD) degeneration, microenvironmental challenges such as decreasing levels of glucose, oxygen, and pH play crucial roles in cell survival and matrix turnover. Antacids, such as Mg(OH)2 and CaCO3, entrapped in microcapsules are capable of neutralizing acidic microenvironments in a controlled fashion and therefore may offer the potential to improve the acidic niche of the degenerated IVD and enhance cell-based regeneration strategies. The objectives of this work were, first, to develop and characterize antacid microcapsules and assess their neutralization capacity in an acidic microenvironment and, second, to combine antacid microcapsules with cellular microcapsules in a hybrid gel system to investigate their neutralization effect as a potential therapeutic in a disc explant model. To achieve this, we screened five different pH- neutralizing agents (Al(OH)3, Mg(OH)2, CaCO3, and HEPES) in terms of their pH neutralization capacities, with Mg(OH)2 or CaCO3 being carried forward for further investigation. Antacid-alginate microcapsules were formed at different concentrations using the electrohydrodynamic spraying process and assessed in terms of size, buffering kinetics, cell compatibility, and cytotoxicity. Finally, the combination of cellular microcapsules and antacid capsules was examined in a bovine disc explant model under physiological degenerative conditions. Overall, CaCO3 was found to be superior in terms of neutralization capacities, release kinetics, and cellular response. Specifically, CaCO3 elevated the acidic pH to neutral levels and is estimated to be maintained for several weeks based on Ca2+ release. Using a disc explant model, it was demonstrated that CaCO3 microcapsules were capable of increasing the local pH within the core of a hybrid cellular gel system. This work highlights the potential of antacid microcapsules to positively alter the challenging acidic microenvironment conditions typically observed in degenerative disc disease, which may be used in conjunction with cell therapies to augment regeneration.

Targeting nanoplatform synergistic glutathione depletion-enhanced chemodynamic, microwave dynamic, and selective-microwave thermal to treat lung cancer bone metastasis

Once bone metastasis occurs in lung cancer, the efficiency of treatment can be greatly reduced. Current mainstream treatments are focused on inhibiting cancer cell growth and preventing bone destruction. Microwave ablation (MWA) has been used to treat bone tumors. However, MWA may damage the surrounding normal tissues. Therefore, it could be beneficial to develop a nanocarrier combined with microwave to treat bone metastasis. Herein, a microwave-responsive nanoplatform (MgFe2O4@ZOL) was constructed. MgFe2O4@ZOL NPs release the cargos of Fe3+, Mg2+ and zoledronic acid (ZOL) in the acidic tumor microenvironment (TME). Fe3+ can deplete intracellular glutathione (GSH) and catalyze H2O2 to generate •OH, resulting in chemodynamic therapy (CDT). In addition, the microwave can significantly enhance the production of reactive oxygen species (ROS), thereby enabling the effective implementation of microwave dynamic therapy (MDT). Moreover, Mg2+ and ZOL promote osteoblast differentiation. In addition, MgFe2O4@ZOL NPs could target and selectively heat tumor tissue and enhance the effect of microwave thermal therapy (MTT). Both in vitro and in vivo experiments revealed that synergistic targeting, GSH depletion-enhanced CDT, MDT, and selective MTT exhibited significant antitumor efficacy and bone repair. This multimodal combination therapy provides a promising strategy for the treatment of bone metastasis in lung cancer patients.

Synthesis, characterization, and evaluation of the anticancer properties of pH-responsive carvacrol-zinc oxide quantum dots on breast cancer cell line (MDA-MB-231).

Since most solid tumors have a low pH value, a pH-responsive drug delivery system may offer a broad method for tumor-targeting treatment. The present study is used to analyze the anticancer activity of carvacrol-zinc oxide quantum dots (CVC-ZnO QDs) against breast cancer cells (MDA-MB-231). CVC-ZnO QDs demonstrate pH responsive and are specifically released within the acidic pH tumor microenvironment. This property enables targeted drug delivery exclusively to cancer cells while minimizing the impact on normal cells. To the synthesized ZnO QDs, the CVC was loaded and then examined by X-ray diffraction, ultraviolet-visible, Fourier transform infrared spectrophotometer, scanning electron microscopy-energy dispersive X-ray, and transmission electron microscopy. For up to 20 h, CVC release was examined in different pH-buffered solutions. The results showed that carvacrol release was stable in an acidic pH solution. Further, cytotoxicity assay, antioxidant, and lipid peroxidation activity, reactive oxygen species, mitochondrial membrane potential, nuclear damage, and the ability of CVC-ZnO QDs to cause apoptosis were all examined. Apoptosis markers such as Bcl2, Bax, caspase-3, and caspase-9, were also studied. In conclusion, the CVC-ZnO QDs destabilized the MDA-MB-231cells under its acidic tumor microenvironment and regulated apoptosis.

Optimization of metal–organic framework nanozyme activity via histidine modification for simultaneous pesticide detection

Biosensors provide simple, rapid and sensitive detection of a wide range of analytes. Recently, they have been widely used for the rapid detection of pesticides, which makes up for the shortcomings of traditional detection methods. However, the catalytic activity of some nanozymes is not satisfactory in practical applications, limiting the performance of biosensors. Further development of highly active and stable nanozymes is conducive to improving the sensitivity of the sensors and expanding their application in practical detection. Herein we simulated the amino acid microenvironment of natural enzymes and synthesized His-MIL-101(Fe)-X with different histidine (His) modification amounts (X = 0, 25%, 50%, 75%) by regulating the ratio of histidine and terephthalic acid ligands using a one-step solvothermal method. With increasing histidine doping, the peroxidase-like activity of His-MIL-101(Fe)-X was gradually enhanced, and the sensing performance of the sensor arrays constructed by combining His-MIL-101(Fe)-X with three peroxidase substrates was also gradually improved, with a 25-fold increase in detection limit. The His-MIL-101(Fe)-75% sensor array was not only able to accurately discriminate five pesticides in the range of 2-100 μM, but also to quantitatively identify different concentrations of pesticides. Moreover, the His-MIL-101(Fe)-75% sensor array showed good anti-interference capability and was able to discriminate five pesticides at only 2 μM in soil, lake water, seawater, and apple samples, as well as quantitatively detecting diafenthiuron, which has great potential for practical application.

Enhanced antibacterial and osteogenic properties of titanium by sputtering a nanostructured fluoride-doped tantalum oxide coating

Infections and poor osseointegration are the main challenges for titanium implants in clinical practice. Herein, we proposed fabricating a novel fluoride-doped tantalum oxide (F-TaOx) coating on titanium by one-step reactive sputtering deposition to endow implants with superior antibacterial and osteogenic ability. By altering the fluorine and oxygen loading amount, the coating’s physicochemical properties, corrosion resistance, antibacterial and osteogenic activities are tuned simultaneously. All coatings exhibit nano-morphology, superhydrophilicity and improved surface hardness. Despite containing fluoride, the F-TaOx coating produced with fluorine and oxygen dual-deposition still shows enhanced corrosion resistance due to the protection of existing metal oxidizes. The antibacterial test reveals that the F-TaOx coating exhibits long-lasting and superior antibacterial properties. The microenvironment acidification by F-, the excessive ROS generation and the disruption of ATP by F-, TiF3 and Ta2O5, and the repulsive force by superhydrophilic surface synergistically result in bacterial death. The cell experiments indicate that the F-TaOx coating shows good cytocompatibility, promote cell spread and osteogenic differentiation by enhancing ALP activities and ECM mineralization. This work provides a promising strategy for the surface functionalization of metallic implants to produce dual anti-infection and osteogenesis effects for orthopedic and dental applications.

Size-switchable and dual-targeting nanomedicine for cancer chemoimmunotherapy by potentiating deep tumor penetration and antitumor immunity

The effectiveness of commonly adopted therapeutic regimen is low for treating triple-negative breast cancer (TNBC), especially for inoperable patients at advanced stage. Herein, we reported a nano-based recipe for orthotopic and metastatic TNBC management by potentiating the deep penetration of antitumor agents in solid tumors and remodeling the tumor immune microenvironment through combinational chemoimmunotherapy. Specifically, doxorubicin (DOX) was loaded in DSPE-PEG2000-modified poly(amidoamine) (PAMAM) dendrimer to obtain small-sized DOX@P nanoparticles, which were further inserted into the phospholipid monolayer of imiquimod (R837)-encapsulated reconstituted high-density lipoprotein (rHDL) to acquire R@rHDP. Finally, M2 macrophage-targeting peptide (M2pep) was modified on the surface of R@rHDP to obtain R@rHDP-M2pep nanoparticles with special targeting ability towards M2-like tumor-associated macrophages (TAMs). Upon intravenous injection, R@rHDP-M2pep actively anchored TNBC sites owing to the natural tumor targeting potential of rHDL. Once reaching tumor sites, small-sized DOX@P was released from large-sized R@rHDP-M2pep due to the breakdown of imine bond in acidic tumor microenvironment (TME), further carrying DOX into the deep tumor core to exert chemotherapeutic effect. On the other hand, the remaining R@rH-M2pep continued to target M2-like TAMs to deliver R837 for effective polarization of TAM phenotype from protumoral M2-like into antitumoral M1-like type. Consequently, the immunosuppressive TME was remodeled to facilitate improved immunotherapeutic performance. Hence, the designed R@rHDP-M2pep nanoparticles displayed potent antitumor efficacy against TNBC, which not only remarkably suppressed orthotopic tumor growth, but also prevented the lethal lung metastasis of TNBC, largely prolonging the survival time of mice suffered from TNBC. Altogether, the proposed strategy exhibited promising research value in advancing the therapeutic protocols for TNBC.

Microenvironment‐Adaptive Metallo‐Polymeric Nanodecoys via Subcomponent Coordination for Bacterial Biofilm Eradication and Immunomodulation

AbstractBiofilm‐associated infections pose complex challenges that require addressing the multifaceted requirements of biofilm disruption, bacterial killing, and immunomodulation. In this study, microenvironment‐adaptive metallo‐polymeric nanodecoys (MPNs) are synthesized through one‐pot subcomponent coordination in aqueous solution, effectively eradicating bacterial biofilms and modulating immune response. Within the acidic microenvironment of biofilms, the positively charged MPNs demonstrated the ability to interact with and eliminate bacteria while facilitating a Fenton‐like reaction for efficient eradication of bacterial biofilms. As the local microenvironment shifted from a neutral to a basic state during subsequent tissue healing processes, the MPNs adaptively harness the multiple properties to bind pathogen‐associated molecular patterns, scavenge reactive oxygen species, thereby modulating the immune response, alleviating inflammation, and promoting tissue healing. This study presents an efficient strategy for preparing enzyme‐mimicking materials that closely resemble natural metalloenzymes, and the MPNs offer an efficient alternative to current antibiotic treatments for biofilm‐associated infections.