To develop the next-generation Pt drug with remarkable activity and low toxicity to maximally inhibit tumor growth, we optimized a Pt(II) thiosemicarbazone compound (C4) with remarkable cytotoxicity to SK-N-MC cells and then constructed a new human serum albumin-C4 (HSA-C4) complex delivery system. The in vivo results showed that C4 and the HSA-C4 complex have remarkable therapeutic efficiency and almost no toxicity; they induced apoptosis and inhibited tumor angiogenesis. This system showed potential as a practical Pt drug. This study could pave the way for developing next-generation dual-targeted Pt drugs and achieving their targeting therapy for cancer.

Developing an Anticancer Platinum(II) Compound Based on the Uniqueness of Human Serum Albumin.

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.

Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin.

To integrate targeted diagnosis and treatment of cancer, we proposed to develop a gadolinium (Gd) agent based on the properties of apoferritin (AFt). To this end, we not only optimized a series of Gd(III) 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazone compounds to obtain a Gd(III) compound (C4) with remarkable T1-weighted magnetic resonance imaging (MRI) performance and cytotoxicity to cancer cells in vitro but also constructed an AFt-C4 nanoparticle (NP) delivery system. Importantly, AFt-C4 NPs improved the targeting ability of C4 in vivo and showed enhanced MRI performance and tumor growth inhibition ratio relative to C4 alone. Furthermore, we confirmed that C4 and AFt-C4 NPs inhibited tumor growth through apoptosis, ferroptosis, and ferroptosis-induced immune response.

Developing a Gadolinium(III) Compound Based on Apoferritin for Targeted Magnetic Resonance Imaging and Dual-Modal Therapy of Cancer.

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and β-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease β-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated. 

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response.

Designing a Mitochondria-Targeted Theranostic Cyclometalated Iridium(III) Complex: Overcoming Cisplatin Resistance and Inhibiting Tumor Metastasis through Necroptosis and Immune Response.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

Metal-based drugs have been used for decades to treat solid cancers; however, these drugs have no significant therapeutic effect on glioma because they cannot effectively cross the blood-brain barrier (BBB). To develop a novel metal-based agent that can cross the BBB to target glioma, we synthesized an Au complex (C2) with remarkable glioma cytotoxicity and fabricated lactoferrin (LF)-C2 nanoparticles (LF-C2 NPs) as a novel therapy. We confirmed that C2 kills glioma cells by inducing apoptosis and autophagic death. The LF-C2 NPs cross the BBB, inhibit glioma growth, and selectively accumulate in the tumor tissue, significantly decreasing the side effects of C2. This study provides a novel strategy for applying metal-based agents to targeted therapy for glioma.

Encapsulation of Au(III) Complex Using Lactoferrin Nanoparticles to Combat Glioma.

Designing novel anticancer non-platinum metal agents is fully challenging. Herein, a series of little-known indium (In) 2-acetylpyridine thiosemicarbazone compounds as potential anticancer agents were designed, synthesized, and characterized. The hydrogen atoms at the N-4 position with the alkyl of the In compounds significantly increased cellular uptake and cytotoxicity. In(III) compounds showed significantly higher cytotoxicity toward cisplatin-resistant cell lines than cisplatin. More importantly, C4 greatly inhibited A549DDP tumor growth in a vaccinated mouse model. C4 exerted cytotoxic effects via a multitarget mechanism. First, it activated p53 and blocked the cell cycle at the S phase, which then led to weak expression levels of cyclin and related kinases and upregulation of the expression levels of cyclin-dependent kinase inhibitors. C4 also depolarized the mitochondrial membrane potential and regulated the expression of the Bcl-2 family, which then released cyt-c and activated caspase-3/8/9 to execute apoptotic pathways. Then, it inhibited telomerase through the inhibition of the expression of the c-Myc regulator gene and expression of the human telomerase reverse transcriptase. Furthermore, C4 showed excellent antimetastatic activity.

Designing a multitarget In(III) compound to overcome the resistance of lung cancer cells to cisplatin.

This study aimed to elucidate the mechanism of Wenzheng Jiedu Powder Modified Formula (WJPMF) in treating neuropathic pain (NP). Network pharmacology and experimental verification were integrated to explore the therapeutic effects and key targets of WJPMF. Active components, corresponding target genes, and absorption, distribution, metabolism, and excretion (ADME) genes of WJPMF against NP were screened from public databases. Network analysis and molecular docking were conducted to identify key targets and verify binding abilities. In vivo experiments were performed on spared nerve injury (SNI) rats to assess the analgesic effects and regulatory mechanisms of WJPMF. WJPMF significantly improved pain behaviors in SNI rats by regulating ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor alpha (PPARA), peroxisome proliferator-activated receptor gamma (PPARG), and superoxide dismutase 2 (SOD2) expression, which were key targets involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. WJPMF shows promising therapeutic potential for NP through the modulation of specific targets, offering a novel therapeutic strategy for managing NP.

Network pharmacology and pharmacological evaluation of Wenzheng Jiedu Powder Modified Formula for neuropathic pain relief.

Objectives The Traditional Chinese Medicine (TCM) formula Yi-Fei-Jian-Pi-Tang (YFJPT) has been demonstrated effective against Corona Virus Disease 2019 (Covid-19). The aim of this article is to make a thorough inquiry about its active constituent as well as mechanisms against Covid-19 via TCM network pharmacology. Methods All the ingredients of YFJPT are obtained from the pharmacology database of the TCM system. The genes which are associated with the targets are obtained by utilizing UniProt. The herb-target network is built up by utilizing Cytoscape. The target protein-protein interaction network is built by utilizing the STRING database and Cytoscape. The critical targets of YFJPT are explored by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results The outcomes show that YFJPT might has 33 therapeutic targets on Covid-19, namely, interleukin 2 (IL2), heme oxygenase 1 (HMOX1), interleukin 4 (IL4), interferon gamma (FNG), α nuclear factor of kappa light polypeptide gene enhancer in Bcells inhibitor, alpha (NFKBIA), nuclear factor-k-gene binding (NFKB), nitric oxide synthase 3 (NOS3), intercellular adhesion molecule 1 (ICAM1), hypoxia inducible factor 1 subunit alpha (HIF1A), mitogen-activated protein kinase 3 (MAPK3), epidermal growth factor receptor (EGFR), interleukin 10 (IL10), jun proto-oncogene (JUN), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8 (CXCL8), tumor protein p53 (TP53), interleukin 1 beta (IL1B), AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor (TNF), interleukin 6 (IL6), erb-b2 receptor tyrosine kinase 2 (ERBB2), RELA proto-oncogene (RELA), NF-κB subunit, caspase 8 (CASP8), peroxisome proliferator activated receptor alpha (PPARA), TIMP metallopeptidase inhibitor 1 (TIMP1), transforming growth factor beta 1 (TGFB1), interleukin 1 alpha (IL1A), signal transducer and activator of transcription 1 (STAT1), mitogen-activated protein kinase 8 (MAPK8), myeloperoxidase (MPO), matrix metallopeptidase 3 (MMP3), matrix metallopeptidase 1 (MMP1), and NFE2 like bZIP transcription factor 2 (NFE2L2). The gene enrichment analysis prompts that YFJPT most likely contributes to patients related to Covid-19 by regulating the pathways of cancers. Conclusions That will lay a foundation for the clinical rational application and further experimental research of YFJPT.

Reveal the Mechanisms of Yi-Fei-Jian-Pi-Tang on Covid-19 through Network Pharmacology Approach

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