Napabucasin deactivates STAT3 and promotes mitoxantrone-mediated cGAS-STING activation for hepatocellular carcinoma chemo-immunotherapy.

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

Advanced nano delivery system for stem cell therapy for Alzheimer's disease.

Alzheimer's Disease (AD) represents one of the most significant neurodegenerative challenges of our time, with its increasing prevalence and the lack of curative treatments underscoring an urgent need for innovative therapeutic strategies. Stem cells (SCs) therapy emerges as a promising frontier, offering potential mechanisms for neuroregeneration, neuroprotection, and disease modification in AD. This article provides a comprehensive overview of the current landscape and future directions of stem cell therapy in AD treatment, addressing key aspects such as stem cell migration, differentiation, paracrine effects, and mitochondrial translocation. Despite the promising therapeutic mechanisms of SCs, translating these findings into clinical applications faces substantial hurdles, including production scalability, quality control, ethical concerns, immunogenicity, and regulatory challenges. Furthermore, we delve into emerging trends in stem cell modification and application, highlighting the roles of genetic engineering, biomaterials, and advanced delivery systems. Potential solutions to overcome translational barriers are discussed, emphasizing the importance of interdisciplinary collaboration, regulatory harmonization, and adaptive clinical trial designs. The article concludes with reflections on the future of stem cell therapy in AD, balancing optimism with a pragmatic recognition of the challenges ahead. As we navigate these complexities, the ultimate goal remains to translate stem cell research into safe, effective, and accessible treatments for AD, heralding a new era in the fight against this devastating disease.

Mapping the evolution and research landscape of ferroptosis-targeted nanomedicine: insights from a scientometric analysis.

Objective: Notable progress has been made in "ferroptosis-based nano drug delivery systems (NDDSs)" over the past 11 years. Despite the ongoing absence of a comprehensive scientometric overview and up-to-date scientific mapping research, especially regarding the evolution, critical research pathways, current research landscape, central investigative themes, and future directions. Methods: Data ranging from 1 January 2012, to 30 November 2023, were obtained from the Web of Science database. A variety of advanced analytical tools were employed for detailed scientometric and visual analyses. Results: The results show that China significantly led the field, contributing 82.09% of the total publications, thereby largely shaping the research domain. Chen Yu emerged as the most productive author in this field. Notably, the journal ACS Nano had the greatest number of relevant publications. The study identified liver neoplasms, pancreatic neoplasms, gliomas, neoplasm metastases, and melanomas as the top five crucial disorders in this research area. Conclusion: This research provides a comprehensive scientometric assessment, enhancing our understanding of NDDSs focused on ferroptosis. Consequently, it enables rapid access to essential information and facilitates the extraction of novel ideas in the field of ferroptotic nanomedicine for both experienced and emerging researchers.

Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications.

The charge-reversal nano-drug delivery system (CRNDDS) is a promising system for delivering chemotherapy drugs and has gained widespread application in cancer treatment. In this review, we summarize the recent advancements in CRNDDSs in terms of cancer treatment. We also delve into the charge-reversal mechanism of the CRNDDSs, focusing on the acid-responsive, redox-responsive, and enzyme-responsive mechanisms. This study elucidates how these systems undergo charge transitions in response to specific microenvironmental stimuli commonly found in tumor tissues. Furthermore, this review explores the pivotal role of CRNDDSs in tumor diagnosis and treatment, and their potential limitations. By leveraging the unique physiological characteristics of tumors, such as the acidic pH, specific redox potential, and specific enzyme activity, these systems demonstrate enhanced accumulation and penetration at tumor sites, resulting in improved therapeutic efficacy and diagnostic accuracy. The implications of this review highlight the potential of charge-reversal drug delivery systems as a novel and targeted strategy for cancer therapy and diagnosis.

Green synthesis of polyethylene glycol coated, ciprofloxacin loaded CuO nanoparticles and its antibacterial activity against Staphylococcus aureus.

Antibacterial resistance requires an advanced strategy to increase the efficacy of current therapeutics in addition to the synthesis of new generations of antibiotics. In this study, copper oxide nanoparticles (CuO-NPs) were green synthesized using Moringa oleifera root extract. CuO-NPs fabricated into a form of aspartic acid-ciprofloxacin-polyethylene glycol coated copper oxide-nanotherapeutics (CIP-PEG-CuO) to improve the antibacterial activity of NPs and the efficacy of the drug with controlled cytotoxicity. These NPs were charachterized by Fourier transform infrared spectroscopy (FTIR), x-rays diffraction spectroscopy (XRD), scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). Antibacterial screening and bacterial chemotaxis investigations demonstrated that CIP-PEG-CuO NPs show enhanced antibacterial potential against Gram-positive and Gram-negative clinically isolated pathogenic bacterial strains as compared to CuO-NPs. In ex-vivo cytotoxicity CIP-PEG-CuO-nano-formulates revealed 88% viability of Baby Hamster Kidney 21 cell lines and 90% RBCs remained intact with nano-formulations during hemolysis assay. An in-vivo studies on animal models show that Staphylococcus aureus were eradicated by this newly developed formulate from the infected skin and showed wound-healing properties. By using specially designed nanoparticles that are engineered to precisely transport antimicrobial agents, these efficient nano-drug delivery systems can target localized infections, ensure targeted delivery, enhance efficacy through increased drug penetration through physical barriers, and reduce systemic side effects for more effective treatment.

Natural product-loaded lipid-based nanocarriers for skin cancer treatment: An overview.

The skin is essential for body protection and regulating physiological processes. It is the largest organ and serves as the first-line barrier against UV radiation, harmful substances, and infections. Skin cancer is considered the most prevalent type of cancer worldwide, while melanoma skin cancer is having high mortality rates. Skin cancer, including melanoma and non-melanoma forms, is primarily caused by prolonged exposure to UV sunlight and pollution. Currently, treatments for skin cancer include surgery, chemotherapy, and radiotherapy. However, several factors hinder the effectiveness of these treatments, such as low efficacy, the necessity for high concentrations of active components to achieve a therapeutic effect, and poor drug permeation into the stratum corneum or lesions. Additionally, low bioavailability at the target site necessitates high doses, leading to skin irritation and further obstructing drug absorption through the stratum corneum. To overcome these challenges, recent research focuses on developing a medication delivery system based on nanotechnology as an alternative to this traditional approach. Nano-drug delivery systems have demonstrated great promise in treating skin cancer by providing a more effective means of delivering drugs with better stability and drug absorption. An overview of various lipid-based nanocarriers is given in this review article that are utilized to carry natural compounds to treat skin cancer.

Transforming Cancer Treatment with Nanotechnology: The Role of Berberine as a Star Natural Compound.

Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. This review introduced the expansive spectrum of BBR's anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery. Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. Nano-delivery systems increase drug concentration at the tumor site by improving pharmacological activity and tissue distribution, enhancing drug bioavailability. Organic nanocarriers have advantages for berberine delivery including biocompatibility, encapsulation, and controlled release of the drug. While the advantages of inorganic nanocarriers for berberine delivery mainly lie in their efficient loading ability of the drug and their slow release ability of the drug. This review introduced the expansive spectrum of BBR's anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery.

Design and Characterization of Fast-Dissolving Oral Film of Apixaban.

BACKGROUND: Following the COVID-19 pandemic, microvascular and macrovascular thrombotic problems emerged that required anticoagulants. Apixaban (RN) is a factor Xa inhibitor that treats deep vein thrombosis and the two forms of artery diseases (coronary artery disease and peripheral artery disease). MATERIALS AND METHODS: The study objective was to create fast-disintegrating Apixaban Oral Thin Films (OTF) with the help of various super disintegrants to shorten disintegration time and enhance drug release in order to assist patients who have difficulty in swallowing conventional dosage forms and increase bioavailability. OTF was created using the solvent casting method. A 22 factorial design was employed in Design-Expert® software to develop an ideal formula. RESULTS: The optimized film formula pH, drug content, disintegration time, folding endurance, and dissolution rate were estimated, and the film was subjected to a short-term stability study. The optimized formula exhibited a cumulative drug release of 93.47% in 60 sec. CONCLUSION: The drug's in vitro release pattern shows first-order kinetics and fickian diffusion was the mechanism of drug release. These findings supported that Apixaban OTFs offer a quick release of the medication from the administration site into the systemic circulation.

Nano-drug delivery system for the treatment of multidrug-resistant breast cancer: Current status and future perspectives.

Breast cancer (BC) is one of the most frequently diagnosed cancers in women. Chemotherapy continues to be the treatment of choice for clinically combating it. Nevertheless, the chemotherapy process is frequently hindered by multidrug resistance, thereby impacting the effectiveness of the treatment. Multidrug resistance (MDR) refers to the phenomenon in which malignant tumour cells develop resistance to anticancer drugs after one single exposure. It can occur with a broad range of chemotherapeutic drugs with distinct chemical structures and mechanisms of action, and it is one of the major causes of treatment failure and disease relapse. Research has long been focused on overcoming MDR by using multiple drug combinations, but this approach is often associated with serious side effects. Therefore, there is a pressing need for in-depth research into the mechanisms of MDR, as well as the development of new drugs to reverse MDR and improve the efficacy of breast cancer chemotherapy. This article reviews the mechanisms of multidrug resistance and explores the application of nano-drug delivery system (NDDS) to overcome MDR in breast cancer. The aim is to offer a valuable reference for further research endeavours.

Statistical Design Approach for the Formulation And Optimization of Nanosponges Using Poorly Water-soluble Candidate.

BACKGROUND AND OBJECTIVES: Nanosponges are one of the most innovative ways to use the newest developments in nanodrugs delivery. Nanosponges can catch drugs that dissolve in water or ones that don't. This work uses statistical design to find the best nanosponges for drugs that don't dissolve easily and make them. MATERIAL AND METHODS: It was looked into how to statistically make the most of the effects of independent factors. The ethyl cellulose ratio and stirring rate were chosen based on how they affected the dependent variables, such as particle size and how well they were trapped. FTIR, SEM, zeta potential, entrapment efficiency, and particle size data were used to test the nanosponges that were made. Using carbopol, the best lot of nanosponges was added to the gel. RESULTS: Using ethyl cellulose and polyvinyl alcohol as stabilizers in the emulsion liquid diffusion method, it was possible to make drug-loaded nanosponges. It was possible to make the nanosponges composition work better by using Central Composite Design. It has been seen that making drug-filled nanosponges improves stability. CONCLUSION: The study showcased the enhanced capacity of a formulation with decreased particle size and high entrapment efficiency to disseminate effectively.

Nano-drug delivery systems (NDDS) in metabolic dysfunction-associated steatotic liver disease (MASLD): current status, prospects and challenges.

About one-third of the global population suffers from metabolic dysfunction-associated steatotic liver disease (MASLD), but specific treatments for MASLD have long been lacking, primarily due to the unclear etiology of the disease. In addition to lifestyle modifications and weight loss surgery, pharmacotherapy is the most common treatment among MASLD patients, and these drugs typically target the pathogenic factors of MASLD. However, bioavailability, efficacy, and side effects all limit the maximum therapeutic potential of the drugs. With the development of nanomedicine, recent years have seen attempts to combine MASLD pharmacotherapy with nanomaterials, such as liposomes, polymer nanoparticles, micelles, and cocrystals, which effectively improves the water solubility and targeting of the drugs, thereby enhancing therapeutic efficacy and reducing toxic side effects, offering new perspectives and futures for the treatment of MASLD.

Advancements in nanomedicine delivery systems: unraveling immune regulation strategies for tumor immunotherapy.

This review highlights the significant role of nanodrug delivery systems (NDDS) in enhancing the efficacy of tumor immunotherapy. Focusing on the integration of NDDS with immune regulation strategies, it explores their transformative impacts on the tumor microenvironment and immune response dynamics. Key advancements include the optimization of drug delivery through NDDS, targeting mechanisms like immune checkpoint blockade and modulating the immunosuppressive tumor environment. Despite the progress, challenges such as limited clinical efficacy and complex manufacturing processes persist. The review emphasizes the need for further research to optimize these systems, potentially revolutionizing cancer treatment by improving delivery efficiency, reducing toxicity and overcoming immune resistance.

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Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma.

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.

pH-Responsive Mesoporous Silica Nanoparticles Loaded with Naringin for Targeted Osteoclast Inhibition and Bone Regeneration.

Background: It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research. Methods: First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo. Results: CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 µg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent. Conclusion: Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.

Therapeutic potentials of allicin in cardiovascular disease: advances and future directions.

Cardiovascular disease (CVD) remains the predominant cause of mortality and disability worldwide. Against this backdrop, finding effective drugs for the pharmacological treatment of CVD has become one of the most urgent and challenging issues in medical research. Garlic (Allium sativum L.) is one of the oldest plants and is world-renowned for its dietary and medicinal values. Allicin (diallyl thiosulfinate) is one of the primary natural active ingredients in garlic, which has been proven to have powerful cardioprotective effects and mediate various pathological processes related to CVD, such as inflammatory factor secretion, myocardial cell apoptosis, oxidative stress, and more. Therefore, allicin holds a promising application prospect in the treatment of CVD. This review summarized the biological functions of allicin and its potential mechanisms in CVD, including antioxidation, anti-inflammation, and anti-apoptosis effects. Reckoning with these, we delved into recent studies on allicin's cardioprotective effects concerning various CVDs, such as atherosclerosis, hypertension, myocardial infarction, arrhythmia, cardiac hypertrophy, heart failure, and cardiotoxicity. Further, considering the tremendous advancement in nanomedicine, nanotechnology-based drug delivery systems show promise in addressing limitations of allicin's clinical applications, including improving its solubility, stability, and bioavailability. Through this review, we hope to provide a reference for further research on allicin in cardioprotection and drug development.

Nano-based drug delivery systems in hepatocellular carcinoma.

The high recurrence rate of hepatocellular carcinoma (HCC) and poor prognosis after medical treatment reflects the necessity to improve the current chemotherapy protocols, particularly drug delivery methods. Development of targeted and efficient drug delivery systems (DDSs), in all active, passive and stimuli-responsive forms for selective delivery of therapeutic drugs to the tumour site has been extended to improve efficacy and reduce the severe side effects. Recent advances in nanotechnology offer promising breakthroughs in the diagnosis, treatment and monitoring of cancer cells. In this review, the specific design of DDSs based on the different nano-particles and their surface engineering is discussed. In addition, the innovative clinical studies in which nano-based DDS was used in the treatment of HCC were highlighted.

Phytoactive Molecules and Nanodelivery Approaches for Breast Cancer Treatment: Current and Future Perspectives.

One of the most common malignancies in women, breast cancer accounts for nearly 25% of all cancer cases. Breast cancer is a diverse cancer form that exhibits variability in both morphology and molecular characteristics, and is linked to numerous risk factors. Although various approaches and research are ongoing in the treatment and prevention of breast cancer, medication resistance in the current breast cancer treatment contributes to the disease's relapse and recurrence. Phytoactive molecules are the subject of growing research in both breast cancer prevention and treatment but currently used conventional medicines and techniques limit their application. Recent years have seen significant advancements in the field of nanotechnology, which has proven to be essential in the fight against drug resistance. The transport of synthetic and natural anticancer molecules via nanocarriers has recently been added to breast cancer therapy, greatly alleviating the constraints of the current approach. In light of these developments, interest in nano-delivery studies of phytoactive molecules has also increased. In this review, research of phytoactive molecules for breast cancers along with their clinical studies and nanoformulations, was presented from current and future perspectives.

Progress and application of lung-on-a-chip for lung cancer.

Lung cancer is a malignant tumour with the highest incidence and mortality worldwide. Clinically effective therapy strategies are underutilized owing to the lack of efficient models for evaluating drug response. One of the main reasons for failure of anticancer drug therapy is development of drug resistance. Anticancer drugs face severe challenges such as poor biodistribution, restricted solubility, inadequate absorption, and drug accumulation. In recent years, "organ-on-a-chip" platforms, which can directly regulate the microenvironment of biomechanics, biochemistry and pathophysiology, have been developed rapidly and have shown great potential in clinical drug research. Lung-on-a-chip (LOC) is a new 3D model of bionic lungs with physiological functions created by micromachining technology on microfluidic chips. This approach may be able to partially replace animal and 2D cell culture models. To overcome drug resistance, LOC realizes personalized prediction of drug response by simulating the lung-related microenvironment in vitro, significantly enhancing therapeutic effectiveness, bioavailability, and pharmacokinetics while minimizing side effects. In this review, we present an overview of recent advances in the preparation of LOC and contrast it with earlier in vitro models. Finally, we describe recent advances in LOC. The combination of this technology with nanomedicine will provide an accurate and reliable treatment for preclinical evaluation.

Gonadotropin-Releasing Hormone (GnRH) and Its Agonists in Bovine Reproduction II: Diverse Applications during Insemination, Post-Insemination, Pregnancy, and Postpartum Periods.

The administration of GnRH and its agonists benefits various aspects of bovine reproductive programs, encompassing physiological stages such as estrous synchronization, post-insemination, pregnancy, and the postpartum period. The positive impact of GnRH administration in overcoming challenges like repeat breeder cows, early embryonic loss prevention, and the management of cystic ovarian disease (COD) is thoroughly surveyed. Furthermore, this review focuses on the significance of GnRH administration during the postpartum period, its role in ovulation induction, and how it enhances the productivity of embryo transfer (ET) programs. An emerging feature of this field is introduced, focusing on nano-drug delivery systems for GnRH agonists, and the potential benefits that may arise from such advancements are highlighted. While this review offers valuable insights into various applications of GnRH in bovine reproduction, it emphasizes the crucial need for further research and development in this field to advance reproductive efficiency and health management in dairy cattle.

Strategies and Recent Advances on Improving Efficient Antitumor of Lenvatinib Based on Nanoparticle Delivery System.

Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future.