Cancer Chemotherapy Drugs Research Articles

Upfront DPYD Genotype-Guided Treatment for Fluoropyrimidine-Based Chemotherapy in Advanced and Metastatic Colorectal Cancer: A Cost-Effectiveness Analysis

ObjectivesFluoropyrimidines are the most widely used chemotherapy drugs for advanced and metastatic colorectal cancer (CRC). Individuals with certain DPYD gene variants are exposed to an increased risk of severe fluoropyrimidine-related toxicities. This study aimed to evaluate the cost-effectiveness of preemptive DPYD genotyping to guide fluoropyrimidine therapy in patients with advanced or metastatic CRC. MethodsOverall survival of DPYD wild-type patients who received a standard dose and variant carriers treated with a reduced dose were analyzed by parametric survival models. A decision tree and a partitioned survival analysis model with a lifetime horizon were designed, taking the Iranian healthcare perspective. Input parameters were extracted from the literature or expert opinion. To address parameter uncertainty, scenario and sensitivity analyses were also performed. ResultsCompared with no screening, the genotype-guided treatment strategy was cost-saving ($41.7). Nevertheless, due to a possible reduction in the survival of patients receiving reduced-dose regimens, it was associated with fewer quality-adjusted life-years (9.45 vs 9.28). In sensitivity analyses, the prevalence of DPYD variants had the most significant impact on the incremental cost-effectiveness ratio. The genotyping strategy would remain cost-saving, as long as the genotyping cost is < $49 per test. In a scenario in which we assumed equal efficacy for the 2 strategies, genotyping was the dominant strategy, associated with less costs (∼$1) and more quality-adjusted life-years (0.1292). ConclusionsDPYD genotyping to guide fluoropyrimidine treatment in patients with advanced or metastatic CRC is cost-saving from the perspective of the Iranian health system.

A Short Review on the Use of Chemotherapy Drugs in Uterine Cancer

A Short Review on the Use of Chemotherapy Drugs in Uterine Cancer

Baicalin enhances the efficacy of 5-Fluorouracil in gastric cancer by promoting ROS-mediated ferroptosis

Background5-Fluorouracil (5-Fu) is one of the most commonly used chemotherapy drugs for gastric cancer (GC). But the increase of drug resistance makes the prognosis of patients worse. Studies have shown that Baicalin can not only inhibit various cancers but also increase the sensitivity of cancers to chemotherapy. However, how Baicalin works in chemotherapeutic resistance of GC are unclear. MethodsCCK8 (Cell Counting Kit 8) was used to detect the IC50 (half maximal inhibitory concentration) of Baicalin and 5-Fu. Proliferation, migration, and invasion of GC were tested through colony formation assay and transwell assay. Fluorescent probes detected intracellular reactive oxygen species (ROS). RNA-seq (RNA sequencing) detected differentially expressed genes and pathways, and qPCR (Quantitative Real-time PCR) tested the expression of ferroptosis-related genes. ResultsThe combination of Baicalin and 5-Fu inhibited GC progression and increased intracellular ROS levels. Both the inhibition of malignant phenotype of gastric cancer cells and the generation of intracellular ROS caused by Baicalin could be saved by the inhibitor of ferroptosis–Ferrostatin-1 (Fer-1). Heat map of enriched differentially expressed genes identified by RNA-seq included four ferroptosis-related genes, and subsequent GO (Gene Ontology) analysis suggested an association between the ferroptosis pathway and Baicalin treatment. The changes in expression of ferroptosis-related genes were validated by qPCR, and the result confirmed that the combination of Baicalin and 5-Fu promoted ferroptosis in GC. ConclusionsBaicalin inhibits GC and enhances 5-Fu by promoting ROS-related ferroptosis in GC.

Optimization of drug scheduling for cancer chemotherapy with considering reducing cumulative drug toxicity

An improved optimal drug scheduling model with considering two control drugs is proposed and the Gauss pseudospectral-based optimization method is studied to decrease the tumor size and drug toxicity in this work. Firstly, the Dexrazoxane drug, which has significant clinical effect to reduce the toxicity of the anticancer drug, is introduced. By analyzing the growth kinetics model of cancer chemotherapy, the toxicity reduction drug is regarded as the second input in the cancer dynamic equations. Correspondingly, the drug scheduling optimization problem with particular optimization goal and necessary constraints is established. Next, a model transformation technique is proposed to reduce the complexity of dynamic equations. With deriving the Gaussian time grid discretization detailly, the Gauss pseudospectral method (GPM)-based cancer chemotherapy drug scheduling algorithm is presented to test the performance of the proposed model within different rates. Finally, the implementation structure of drug scheduling optimization is given in detail. To test and validate the performance of proposed chemotherapy model, extensive simulation results and comparative evaluation are carried out on a specific mathematical model. Simulation results show that the improved optimization model is superior to other literature studies, resulting in the average improvement of performance index by 66.54% and revealing the significant guiding property for cancer chemotherapy.

Recent Advances in Doxorubicin Formulation to Enhance Pharmacokinetics and Tumor Targeting.

Doxorubicin (DOX), a widely used drug in cancer chemotherapy, induces cell death via multiple intracellular interactions, generating reactive oxygen species and DNA-adducted configurations that induce apoptosis, topoisomerase II inhibition, and histone eviction. Despite its wide therapeutic efficacy in solid tumors, DOX often induces drug resistance and cardiotoxicity. It shows limited intestinal absorption because of low paracellular permeability and P-glycoprotein (P-gp)-mediated efflux. We reviewed various parenteral DOX formulations, such as liposomes, polymeric micelles, polymeric nanoparticles, and polymer-drug conjugates, under clinical use or trials to increase its therapeutic efficacy. To improve the bioavailability of DOX in intravenous and oral cancer treatment, studies have proposed a pH- or redox-sensitive and receptor-targeted system for overcoming DOX resistance and increasing therapeutic efficacy without causing DOX-induced toxicity. Multifunctional formulations of DOX with mucoadhesiveness and increased intestinal permeability through tight-junction modulation and P-gp inhibition have also been used as orally bioavailable DOX in the preclinical stage. The increasing trends of developing oral formulations from intravenous formulations, the application of mucoadhesive technology, permeation-enhancing technology, and pharmacokinetic modulation with functional excipients might facilitate the further development of oral DOX.

Polysaccharide based supramolecular injectable hydrogels for in situ treatment of bladder cancer

Implantable system maximizes drug concentration and continuously releases drugs near the tumor, which is an effective tool to solve the difficult retention of chemotherapy drugs in bladder cancer. In this work, a novel polysaccharide supramolecular injectable hydrogel (CCA hydrogels for short) is rapidly constructed by simply mixing cationic chitosan, anionic sulfobutyl ether β-cyclodextrin (SBE-β-CD) and a trace amount of silver ions. The injected hydrogel reconstituted and regained its shape in less than 1 h, and it can still maintain the elasticity suitable for the human body. By packaging the drug directly, the gel achieves a high concentration of doxorubicin, an anticancer drug. Using MB49-luc cells as the model of bladder tumor for anti-tumor in vivo, the CCA-DOX gel has obvious inhibitory effect on bladder tumor, and its inhibitory effect is much greater than that of free DOX. Therefore, this self-healing injectable hydrogel has great potential for in situ treatment of bladder cancer.

GABA Administration Ameliorates the Toxicity of Doxorubicin on CSF and the Brain of Albino Rats.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and is a non-proteinogenic amino acid. Doxorubcin (DOX) or adriamycin is one of the most potent chemotherapy drugs for breast cancer. This study focused on diminishing the brain injury and neurotoxicity of doxorubicin (DOX) by GABA administration. Rats were randomly divided into four groups (8 rats each), which were the control group, DOX group (3 mg/kg for 4 weeks, then 2 mg/kg for 2 weeks), GABA group (2 mg/kg for 21 days), and DOX + GABA group (treated as the second and third groups). Neurotoxicity and brain injury were assessed by determining CSF biomarkers, serum inflammatory markers, and histopathological evaluation of the cerebral cortex. DOX treatment significantly increased the levels of all CSF biomarkers (S100B, IL-1β, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), spectrin breakdown products (SBDP145), and C-C motif chemokine ligand 2 (CCL2) and all inflammatory markers (IL-6, TNF-α, and IFN-γ), causing extensive neutrophilic infiltration and great alteration in the cerebral cortex architecture as evidence of neurotoxicity. The oral administration of GABA significantly reduced the levels of all CSF biomarkers and inflammatory markers and restored the normal architecture of the cerebral cortex, with observed ameliorations in neutrophilic infiltration. GABA administration can ameliorate neurotoxicity and protect the brain against the negative effects of DOX treatment.

Transforming a Toxic Non-Ionizable Drug into an Efficacious Liposome via Ionizable Prodrug and Remote Loading Strategies against Malignant Breast Tumors.

Liposomes (lipos), one of the most successful nanotherapeutics in the clinic, have made a rapid advance over the past few years. However, still, several challenges exist for lipos for clinical practice, such as low drug loading and premature drug leakage during in vivo circulation. Paclitaxel (PTX), a commonly used first-line drug for cancer chemotherapy, was chosen as the model drug. Due to its non-ionizable and water-insoluble characteristics, the drug-loading efficiency of the marketable PTX lipos, Lipusu, is only 6.76%. Herein, we designed an ionizable PTX prodrug (PTXP) by modifying phenylboronic acid on the C2' hydroxyl group of PTX for the remote loading of liposomal formulations through the pH gradient method. Compared with Lipusu, PTXP lipos displayed a 34% higher loading efficiency and an encapsulation efficiency of approximately 95%. A series of in vitro/vivo experiments indicated that PTXP lipos possess colloidal stability, prolonged blood circulation, high tumor site accumulation, potent anti-tumor effects, and safety. A combination of ionizable prodrugs and remote loading has proved to be an effective and simple strategy to achieve high liposomal encapsulation efficiency of poorly soluble non-ionizable drugs for clinical application.

A sensing platform for on-site detection of glutathione S-transferase using oxidized Pi@Ce-doped Zr-based metal-organic frameworks(MOFs)

The development of point-of-care testing (POCT) for glutathione S-transferase (GST) is an effective way to establish the mechanism of targeted monitoring of cancer chemotherapy drug metabolism. Assays for GST with high sensitivity as well as on-site screening have been urgently required to monitor this process. Herein, we synthesized oxidized Pi@Ce-doped Zr-based metal–organic frameworks (MOFs) by electrostatic self-assembly between phosphate and oxidized Ce-doped Zr-based MOFs. It was found that the oxidase-like activity of oxidized Pi@Ce-doped Zr-based MOFs was substantially increased after phosphate ion (Pi) assembly. And a stimulus-responsive hydrogel-based kit was constructed by embedding oxidized Pi@Ce-doped Zr-based MOFs into a PVA (polyvinyl alcohol) hydrogel system, we integrated a portable hydrogel kit with a smartphone for real-time monitoring of GST for quantitative and accurate analysis. The color reaction was triggered based on oxidized Pi@Ce-doped Zr-based MOFs with 3,3′,5,5′-tetramethylbenzidine (TMB). However, in the presence of glutathione (GSH), the above color reaction was hindered due to the reducibility of GSH. Catalyzed by GST, GSH can react with 1-chloro-2,4-dinitrobenzo (CDNB) to form an adduct, which caused the color reaction to occur again, resulting in the color response of the kit. In combination with ImageJ software, the kit image information acquired by smartphone could be converted into hue intensity, providing a direct quantitative tool for the detection of GST with a detection limit of 0.19mU·L−1. Based on the advantages of simple operation and cost-effectiveness, the introduction of the POCT miniaturized biosensor platform will meet the requirements of on-site quantitative analysis of GST.

Cancer Therapeutics: Structure-Based Drug Design of Inhibitors for a Novel Angiogenic Growth Factor

Angiogenesis, the formation of new blood vessels, is a critical and rate-limiting tumor growth step controlled by pro-angiogenic factors and specific inhibitors. Tumor angiogenesis is essential for cancer progression and metastasis. Platelet growth factors (PDGF) and their receptors (PDGFR) are associated with tumor angiogenesis through overexpression of PDGF. Inhibition of PDGF and its signaling pathway is a new approach to the discovery of anticancer therapeutic agents. The present study focuses on the PDGF-C protein in the identification of novel anti-angiogenic compounds. MODELLER 9.10 software allows users to create and refine a 3D homology model of the PDGF-C protein (345 a.a. length). Secondary structure analysis of the 3D energy model reveals 16 β sheets held together by four cation–π and one π–σ interactions, and three salt bridges. The quality of the model is assessed using the Ramachandran plot (90 percent amino acids in the favorable region) and the ProSA server (Z-score = –2.28). Active site residues are identified using Castp, QSite search engine, site map, and protein docking of the protein to its receptor. In addition, virtual screening is performed at the active site using the Glide module of the Schrodinger Suite. Glide score, glide energy and ADME are being measured to discover new benefits of pyrazolone and pyrrolidine-2,3-dione scaffolds as potent PDGF-C antagonists for anti-angiogenic cancer chemotherapy drugs.

In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer

Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein–protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.

KIF14 mediates cabazitaxel-docetaxel cross-resistance in advanced prostate cancer by promoting AKT phosphorylation

Docetaxel is a first-line chemotherapy drug for castration-resistant prostate cancer (CRPC); yet, some CRPC patients develop docetaxel drug resistance. Cabazitaxel is approved in the post-docetaxel treatment setting. However, recent studies suggested cross-resistance between the development of drug resistance and current treatments. In this study, we used docetaxel-resistant cell lines DU145/DTX50 and PC-3/DTX30 to measure the responses to cabazitaxel. Our findings demonstrated that docetaxel resistance could lead to cross-resistance to cabazitaxel. After docetaxel-resistant cells were treated with cabazitaxel, transcriptome analysis was performed, and the results were analyzed in combination with survival analysis and correlation analysis with Gleason score to screen the cross-resistance genes. The continuously increased expression of kinesin family member 14 (KIF14) was identified as the main cause of cross-resistance to cabazitaxel in docetaxel-resistant cells. Silencing the expression of KIF14 could restore the sensitivity of resistant PCa cells to docetaxel and cabazitaxel, attenuate proliferation and promote apoptosis of the resistant PCa cells. Notably, the depressed expression of KIF14 inhibited the phosphorylation of Akt located downstream. In summary, KIF14 mediates the cross-resistance between docetaxel and cabazitaxel, and targeting KIF14 could be an effective measurement for reversing docetaxel or cabazitaxel chemotherapy failure or enhancing the anti-tumor effects of docetaxel or cabazitaxel.

Effect of Chitosan Drug-Loaded Nanoparticles on Proliferation of Gastric Cancer Cells and Expression of Prdx6 Protein

Since there are many problems in the clinical application of traditional chemotherapy drugs for gastric cancer (GC), including poor water solubility and insufficient targeting, the preparation of docetaxel nanoparticles (NPs) with chitosan (CS) as the carrier under nanotechnology can improve its water solubility and targeting and thus improve the bioavailability and antitumor effect. GX1 was used as a GC target molecule, N-deoxycholic acid (DCA) hydroxyethyl CS was used as a nanodrug carrier, and docetaxel was used as an antitumor angiogenesis drug to fabricate GC target NPs. The physical characterization was analyzed, the sustained release performance was further analyzed, and the anticancer performance was tested from in vitro and in vivo perspectives. After the NPs were transfected into GC cells, Prdx6 protein level in the cancer cells was determined by western blotting, and the survival rate of GC cells was determined by cholecystokinin octapeptide (CCK-8). Experiments showed that the encapsulation efficiency and drug loading rate of GC-targeted NPs reached 51.8% and 24.3%, respectively. The average particle size was 148.7 nm, and the surface showed smooth and homogeneous aggregation. docetaxel in the NPs belongs to pH-responsive sustained release, and the drug diffusion type belongs to non-Fickian diffusion. in vitro tests showed that GX1 can improve the uptake rate of the NPs by gastric vascular endothelial cells, and in vivo tests showed that the NPs can greatly limit the growth rate of GC tumors in nude mice (P &lt; 0.01). Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) results of tumor sections showed that NPs could induce a large amount of tumor cell apoptosis. The expression of Prdx6 protein in GC cells was decreased after transfection with NPs (P &lt; 0.05), and NPs notably inhibited the proliferation of GC cells (P &lt; 0.01).

Advances In the Study of Hypoxia Inducible Factors and Prognosis of Hepatocellular Carcinoma Development

Hypoxia-inducible factors (HIF) plays a major role in the regulation of hypoxia. It occurs not only under normal physiological conditions but also under pathological conditions such as some inflammatory reactions and tumor diseases. Studies have shown that the mechanisms of hepatocarcinogenesis include cellular molecules signaling pathways and gene levels in which Hypoxia-inducible factors play an important role. At present, surgical resection liver transplantation and chemotherapy are still the main treatment methods in the clinical treatment of patients with liver cancer but conventional chemotherapy drugs have toxic side effects on human body and the prognosis is poor. HIF is not only involved in reducing the efficacy of radiotherapy chemotherapy and targeted therapy but also closely related to angiogenesis and immune escape. In this article, we will focus on the Hypoxia-inducible factors of liver cancer and discuss its relationship with the development and prognosis of liver cancer and provide new ideas for the precise treatment of malignant liver tumors.

Time dependent cisplatin dosing differences on hypoalgesia focusing on oxidative stress

Although cisplatin is a key drug in cancer chemotherapy, it often causes sensory peripheral neuropathy, presenting as allodynia in the early stage and hypoalgesia in the serious stage. Chronotherapy has previously been shown to ameliorate cisplatin-induced peripheral neuropathy that was severe enough to cause hypoalgesia in rats. It also has adverse effects such as renal dysfunction and ototoxicity, which are induced by oxidative stress. Here, we show that oxidative stress causes severe cisplatin-induced peripheral neuropathy, and that differences in oxidative stress occur depending on the dosing time of cisplatin.Cisplatin was administered to rats at 5:00 or 17:00 every seven days for four weeks. The antioxidant agent, 1,3-Dimethylthiourea (DMTU), was administered before and after the administration of cisplatin. The hot plate test was used to assess hypoalgesia. Oxidative stress in the sciatic nerve was assessed from thiobarbituric acid reactive substances (TBARs) and superoxide dismutase (SOD) activity. Nerve apoptosis was analysed with qRT-PCR.We observed an increase in TBARs and a decrease in SOD activity with the development of cisplatin-induced hypoalgesia, which was ameliorated by DMTU treatment. Furthermore, differences in the dosing time of cisplatin caused differences in oxidative stress which were correlated with cisplatin-induced hypoalgesia.Severe oxidative stress caused cisplatin-induced hypoalgesia, and chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress. In the future, chronotherapy with cisplatin may contribute to the treatment of cancer in humans.

Enhanced De Novo Lipid Synthesis Mediated by FASN Induces Chemoresistance in Colorectal Cancer.

Oxaliplatin is one of the most widely used chemotherapy drugs for colorectal cancer (CRC). Resistance to oxaliplatin threatens the prognosis of CRC. Since previous studies have aroused interest in fatty acid metabolism in cancer, in this study, we determined whether fatty acid biosynthesis and the related regulating mechanism contribute to oxaliplatin resistance in CRC. The effect of the fatty acid synthase (FASN) and its inhibitor Orlistat was characterized in Gene Expression Omnibus (GEO) databases, oxaliplatin-resistant cell lines, and xenografts. MRNA-seq and analysis identified related pathway changes after the application of Orlistat, which was verified by Western blotting. By leveraging the GEO databases, FASN and closely related gene signatures were identified as being correlated with the response to oxaliplatin-based chemotherapy and poor prognosis. Additionally, FASN-upregulated expression promoted oxaliplatin resistance in CRC cell lines. We then applied Orlistat, a typical FASN inhibitor, in cell culture and xenograft models of oxaliplatin-resistant CRC, which attenuated the resistance to oxaliplatin. Additionally, the combination of the FASN inhibitor and oxaliplatin significantly increased cell cycle arrest and facilitated apoptosis, partly due to the diminished phosphorylation of the MAPK/ERK and PI3K/AKT pathways. In vivo studies showed that inhibiting fatty acid biosynthesis with Orlistat restrained the growth of xenograft tumors and increased the responsiveness to oxaliplatin. Our study revealed that FASN enhanced resistance to oxaliplatin in CRC. The inhibition of FASN could rescue the response to oxaliplatin by regulating MAPK/ERK and PI3K/AKT pathways.

A New Fuzzy Reinforcement Learning Method for Effective Chemotherapy

A key challenge for drug dosing schedules is the ability to learn an optimal control policy even when there is a paucity of accurate information about the systems. Artificial intelligence has great potential for shaping a smart control policy for the dosage of drugs for any treatment. Motivated by this issue, in the present research paper a Caputo–Fabrizio fractional-order model of cancer chemotherapy treatment was elaborated and analyzed. A fix-point theorem and an iterative method were implemented to prove the existence and uniqueness of the solutions of the proposed model. Afterward, in order to control cancer through chemotherapy treatment, a fuzzy-reinforcement learning-based control method that uses the State-Action-Reward-State-Action (SARSA) algorithm was proposed. Finally, so as to assess the performance of the proposed control method, the simulations were conducted for young and elderly patients and for ten simulated patients with different parameters. Then, the results of the proposed control method were compared with Watkins’s Q-learning control method for cancer chemotherapy drug dosing. The results of the simulations demonstrate the superiority of the proposed control method in terms of mean squared error, mean variance of the error, and the mean squared of the control action—in other words, in terms of the eradication of tumor cells, keeping normal cells, and the amount of usage of the drug during chemotherapy treatment.

Development of a novel sialic acid-conjugated camptothecin prodrug for enhanced cancer chemotherapy.

Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent in vitro properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.

Comprehensive analysis of hypoxia-related genes for prognosis, immune features, and drugs treatment strategy in gastric cancer using bulk and single-cell RNA-sequencing

Hypoxia is one of the malignant characteristics of solid tumors and is related to the multiple malignant characteristics of the tumor. No study has not yet reported a systematical analysis of the characteristics of hypoxia from single-cell resolution in gastric cancer. In our research, we investigated the hypoxia features of various types of cells in single-cell resolution, identified hypoxia-related genes by the weighted gene co-expression network analysis method. Through the hypoxia-related genes from single-cell levels, we screened out 13 genes and established a prognostic model. This model performs well in the training dataset and multiple independent verification data sets. We thought that tumor hypoxia might affect the DNA methylation of cells and promote the transcription of genes associated with malignant features, thereby promoting tumor progression. We found that the more tumor associated genes in the high-risk group showed hypomethylation and high hypoxia-risk score group have more tumor-related genes, more immunosuppressive immune cells and more enrichment of cancer -related pathways. The lower risk group is more sensitive to three chemotherapy drugs for gastric cancer. Our study illustrates the crucial role of hypoxia in gastric cancer. Hypoxia-related gene prognostic model has been established and has good performance. Hypoxia-related risk score can also be used to guide a patient’s drug treatment strategy.

Paclitaxel-Loaded Cationic Fluid Lipid Nanodiscs and Liposomes with Brush-Conformation PEG Chains Penetrate Breast Tumors and Trigger Caspase-3 Activation.

Novel approaches are required to address the urgent need to develop lipid-based carriers of paclitaxel (PTX) and other hydrophobic drugs for cancer chemotherapy. Carriers based on cationic liposomes (CLs) with fluid (i.e., chain-melted) membranes (e.g., EndoTAG-1) have shown promise in preclinical and late-stage clinical studies. Recent work found that the addition of a cone-shaped poly(ethylene glycol)-lipid (PEG-lipid) to PTX-loaded CLs (CLsPTX) promotes a transition to sterically stabilized, higher-curvature (smaller) nanoparticles consisting of a mixture of PEGylated CLsPTX and PTX-containing fluid lipid nanodiscs (nanodiscsPTX). These CLsPTX and nanodiscsPTX show significantly improved uptake and cytotoxicity in cultured human cancer cells at PEG coverage in the brush regime (10 mol % PEG-lipid). Here, we studied the PTX loading, in vivo circulation half-life, and biodistribution of systemically administered CLsPTX and nanodiscsPTX and assessed their ability to induce apoptosis in triple-negative breast-cancer-bearing immunocompetent mice. We focused on fluid rather than solid lipid nanodiscs because of the significantly higher solubility of PTX in fluid membranes. At 5 and 10 mol % of a PEG-lipid (PEG5K-lipid, molecular weight of PEG 5000 g/mol), the mixture of PEGylated CLsPTX and nanodiscsPTX was able to incorporate up to 2.5 mol % PTX without crystallization for at least 20 h. Remarkably, compared to preparations containing 2 and 5 mol % PEG5K-lipid (with the PEG chains in the mushroom regime), the particles at 10 mol % (with PEG chains in the brush regime) showed significantly higher blood half-life, tumor penetration, and proapoptotic activity. Our study suggests that increasing the PEG coverage of CL-based drug nanoformulations can improve their pharmacokinetics and therapeutic efficacy.