Identification of ceRNA networks in type H and L vascular endothelial cells through integrated bioinformatics methods. / 通过整合的生物信息学方法鉴定H和Låž‹è¡€ç®¡å† çš®ç»†èƒžä¸­çš„ceRNA网络（英文）.

OBJECTIVES: Type H blood vessels are a subtype of bone-specific microvessels (CD31hiEmcnhi) that play an important regulatory role in the coupling of angiogenesis and osteogenesis. Despite reports on the distinct roles of type H and L vessels under physiological and pathological bone conditions, their genetic differences remain to be elucidated. This study aims to construct a competitive endogenous RNA (ceRNA) network of key gene for differencial expression (DE) in type H and L vascular endothelial cells (ECs) through integrated bioinformatic methods. METHODS: We downloaded relevant raw data from the ArrayExpress and the Gene Expression Omnibus (GEO) database and used the Limma R-Bioconductor package to screen for DE lncRNAs, DE miRNAs, and DE mRNAs between type H and L vascular ECs. A total ceRNA network was constructed based on their interactions, followed by refinement using protein-protein interaction (PPI) networks to select upregulated and downregulated key genes. Enrichment analysis was performed on these key genes. Random validation was conducted using flow cytometry and real-time RT-PCR. RESULTS: A total of 1 761 DE mRNAs, 187 DE lncRNAs, and 159 DE miRNAs were identified, and a comprehensive ceRNA network was constructed based on their interactions. Six upregulated (Itga5, Kdr, Tjp1, Pecam1, Cdh5, and Ptk2) and 2 downregulated (Csf1r and Il10) key genes were selected via PPI network to construct a subnetwork of ceRNAs related to these key genes. Upregulated key genes were mainly enriched in negative regulation of angiogenesis and vascular apoptosis. Results from flow cytometry and real-time RT-PCR were consistent with bioinformatics analysis. CONCLUSIONS: This study proposes a ceRNA network associated with upregulated and downregulated type H and L vascular ECs based on selected key genes, providing new insights into the regulatory mechanisms of type H and L vascular ECs in bone metabolism.

Post-traumatic distal ulnar bifurcation in children: a case report.

BACKGROUND: Galeazzi fracture dislocation is a compound injury that encompasses fractures of the distal third of the radius and dislocation of the distal radial ulnar joint (DRUJ). Clinically, this condition is rare and often leads to distal ulnar bifurcation. In previous similar reports, patients were effectively managed through surgery. CASE PRESENTATION: In this case report, we describe an 11-year-old male child who presented with an ulnar bifida following trauma to the hand, and was treated with manipulation and conservative treatment without surgery. A follow-up performed over the years demonstrated that the patient recovered well, and had normal wrist movements without significant pain, and the patient expressed great satisfaction. CONCLUSIONS: Ulnar diaphyseal fracture may occur in children or adolescents due to injuries, and may be accompanied with manipulation and repositioning. Conservative treatment can be applied to avoid the trauma associated with surgery especially in the absence of severe joint mobility impairment with good outcomes.

Discovery of Tryptanthrin and Its Derivatives and Its Activities against NSCLC In Vitro via Both Apoptosis and Autophagy Pathways.

In this study, a series of novel tryptanthrin derivatives were synthesized and their inhibitory activities against selected human cancer cell lines, namely, lung (A549), chronic myeloid leukemia (K562), prostate (PC3), and live (HepG2), were evaluated using a methyl thiazolyl tetrazolium colorimetric (MTT) assay. Among the tested compounds, compound C1 exhibited a promising inhibitory effect on the A549 cell line with an IC50 value of 0.55 ± 0.33 µM. The observation of the cell morphological result showed that treatment with C1 could significantly inhibit the migration of A549 cells through the cell migration assay. Moreover, after treatment with C1, the A549 cells exhibited a typical apoptotic morphology and obvious autophagy. In addition, the detection of apoptosis and the mitochondrial membrane potential indicated that C1 induced A549 cell apoptosis via modulating the levels of Bcl2 family members and disrupted the mitochondrial membrane potential. Compound C1 also suppressed the expression of cyclin D1 and increased the expression of p21 in the A549 cells, inducing cell cycle arrest in the G2/M phase in a dose dependent manner. The further mechanism study found that C1 markedly increased the transformation from LC3-I to LC3-II. Taken together, our results suggest that C1 is capable of inhibiting the proliferation of non-small cell lung cancer (NSCLC) cells, inducing cell apoptosis, and triggering autophagy.

Discovery and Mechanism of Novel 7-Aliphatic Amine Tryptanthrin Derivatives against Phytopathogenic Bacteria.

Rice bacterial leaf blight is a destructive bacterial disease caused by Xanthomonas oryzae pv. oryzae (Xoo) that seriously threatens crop yields and their associated economic benefits. In this study, a series of improved dissolubility 7-aliphatic amine tryptanthrin derivatives was designed and synthesized, and their potency in antibacterial applications was investigated. Notably, compound 6e exhibited excellent activity against Xoo, with an EC50 value of 2.55 µg/mL, compared with the positive control bismerthiazol (EC50 = 35.0 µg/mL) and thiodiazole copper (EC50 = 79.4 µg/mL). In vivo assays demonstrated that 6e exhibited a significant protective effect on rice leaves. After exposure, the morphology of the bacteria was partially atrophied by SEM. Furthermore, 6e increased the accumulation of intracellular reactive oxygen species, causing cell apoptosis and the formation of bacterial biofilms. All the results indicated that 6e could be a potential agrochemical bactericide for controlling phytopathogenic bacteria.

Tannin-Mn coordination polymer coated carbon quantum dots nanocomposite for fluorescence and magnetic resonance bimodal imaging.

The MR/FI bimodal imaging has attracted widely studied due to combining the advantages of MRI and FI can bridge gaps in sensitivity and depth between these two modalities. Herein, a novel MR/FI bimodal imaging probe is facile fabricated by coating the Mn-phenolic coordination polymer on the surface of the carbon quantum dots. The structure of the as-prepared nanocomposite probe is carefully validated via SEM, TEM, and XPS. The content of Mn2+ is calculated through the EDS and TGA. The quantum yield (QY) and emission wavelength of the probe are about 7.24% and 490 nm, respectively. The longitudinal r1 value (2.43 mM-1 s-1) with low r2/r1 (4.45) of the probe is obtained. Subsequently, fluorescence and MR imaging are performed. The metabolic pathways in vivo are inferred by studying the bio-distribution of the probe in major organs. Thus, these results indicate that probe would be an excellent dual-modal imaging probe for enhanced MR imaging and fluorescence imaging. MR/FI bimodal imaging probe is built via in-situ coated Mn-phenolic coordination polymer on the surface of the carbon quantum dots. The in vitro and vivo image property of the probe is evaluated.

MiR-19b-3p regulates osteogenic differentiation of PDGFRα+ muscle cells by specifically targeting PTEN.

Heterotopic ossification (HO) is a common disturbing complication of intra-articular fractures. Its prevention and treatment are still difficult as its pathogenesis is unclear. It was reported that PDGFRα+ muscle cells in skeletal muscle may participate in the formation of HO; however, the specific mechanism is still unknown. This study investigated the function of miR-19b-3p in osteogenic differentiation of PDGFRα+ muscle cells. MiR-19b-3p was upregulated during PDGFRα+ muscle cell osteogenic differentiation. The exogenous expression of miR-19b-3p led to an increase in osteogenic marker gene transcription and translation during the osteogenic differentiation of PDGFRα+ muscle cells. Furthermore, both alkaline phosphatase and alizarin red staining increased in miR-19b-3p mimic transfected cells. Over-expression of miR-19b-3p led to the down-regulation of gene of phosphate and tension homology deleted on chromosome ten (PTEN). Additionally, the dual luciferase reporter assay demonstrated that PTEN was a direct target of miR-19b-3p. The increase of osteocalcin, osteopontin, and Runt-related transcription factor 2 protein levels induced by ectopic miR-19b-3p expression could be partially reversed by PTEN over-expression. In conclusion, our results suggested that miR-19b-3p may be a promising target in inhibiting PDGFRα+ muscle cell osteogenic differentiation and treatment of HO.

The association between CD31hiEmcnhi endothelial cells and bone mineral density in Chinese women.

Osteoporosis is the most common bone disease in humans. During bone remodeling, specialized blood vessels influenced by the endothelial cells (CD31hiEmcnhi, also called type H cells) are formatted to supply nutrients. Reductions in vascular supply are associated with bone loss resulting in osteoporosis. Therefore, the objective of the present study was to explore the association between the CD31hiEmcnhi endothelial cells and bone mineral density (BMD). In this prospective study, 134 Chinese women were enrolled and examined. BMD was measured by DEXA method while the percentage of CD31hiEmcnhi endothelial cells in the intertrochanteric part was measured by flow cytometry. The percentage of CD31hiEmcnhi endothelial cells in postmenopausal subjects was significantly lower compared with premenopausal women (8.7 ± 4.0% vs 13.2 ± 5.6%, P < 0.01). Meanwhile, the CD31hiEmcnhi endothelial cell levels in osteopenia and osteoporosis were significantly lower compared with subjects with normal BMD (9.84 ± 4.2% in osteopenia and 7.11 ± 3.2% in osteoporosis vs 12.7 ± 5.6% in subjects with normal T score, P < 0.01). Multiple regression analyses showed that the CD31hiEmcnhi endothelial cells level was positively associated with femur neck and total hip BMD, but not with lumbar BMD. Our study suggests a significantly positive association between CD31hiEmcnhi endothelial cells and local BMD in Chinese women. The proportion of CD31hiEmcnhi endothelial cells is a marker of bone quality and represents a potential target for treatment of bone loss.

CXCR4-mediated osteosarcoma growth and pulmonary metastasis is suppressed by MicroRNA-613.

Osteosarcoma is the most common primary bone malignancy. Recently, studies showed chemokine receptor 4 (CXCR4) played a critical role in osteosarcoma. However, the regulation of CXCR4 is not fully understood. microRNAs are short, non-coding RNAs that play an important roles in post-transcriptional regulation of gene expression in a variety of diseases including osteosarcoma. miR-613 is a newly discovered miRNA and has been reported to function as a tumor suppressor in many cancers. In this study, we confirmed that both Stromal Cell-Derived Factor (SDF-1) and CXCR4 could be prognostic markers for osteosarcoma. Meanwhile this study found that SDF-1/CXCR4 pathway regulated osteosarcoma cells proliferation, migration and reduced apoptosis. Besides, we demonstrated that miR-613 was significantly downregulated in osteosarcoma patients. Elevated expression of miR-613 directly suppressed CXCR4 expression and then decreased the proliferation, migration and induced apoptosis of osteosarcoma cells. Moreover, our study found that CXCR4 promoted the development of lung metastases and inhibition of CXCR4 by miR-613 reduced lung metastases. These data indicated that CXCR4 mediated osteosarcoma cell growth and lung metastases and this effect can be suppressed by miR-613 through directly downregulating CXCR4.

Synthesis and Fluorescence Properties of a New Heterotrinuclear Co(II)-Ce(III)Complex Constructed from a bis(salamo)-Type Tetraoxime Ligand.

[Co2(L)Ce(OAc)3(CH3CH2OH)]·1.5CH3OH∙0.5CH2Cl2, a heterotrinuclear Co(II)-Ce(III) bis(salamo)-type complex with a symmetric bi(salamo)-type ligand H4L and an acyclic naphthalenediol moiety, was designed, synthesized and characterized by elemental analyses, FT-IR, UV-Vis and fluorescence spectroscopy and X-ray crystallography. The X-ray crystallographic investigation revealed the heterotrinuclear complex consisted of two Co(II) atoms, one Ce(III) atom, one (L)4‒ unit, three µ2-acetate ions, one coordinated ethanol molecule, one and half crystallization methanol molecule and half crystallization dichloromethane molecule. Two Co(II) atoms located in the N2O2 coordination spheres, are both hexacoordinated, with slightly distorted octahedral geometries. The Ce(III) atom is nine-coordinated and located in the O6 cavity possesses a single square antiprismatic geometry. In addition, supramolecular interactions exist in the Co(II)-Ce(III) complex. Two infinite 2D supramolecular structures are built via intermolecular O-H···O, C-H···O and C-H···π interactions, respectively.

[Establishement for regional pelvic trauma database in Hunan Province].

OBJECTIVE: To establish a database for pelvic trauma in Hunan Province, and to start the work of multicenter pelvic trauma registry.
 Methods: To establish the database, literatures relevant to pelvic trauma were screened, the experiences from the established trauma database in China and abroad were learned, and the actual situations for pelvic trauma rescue in Hunan Province were considered. The database for pelvic trauma was established based on the PostgreSQL and the advanced programming language Java 1.6.
 Results: The complex procedure for pelvic trauma rescue was described structurally. The contents for the database included general patient information, injurious condition, prehospital rescue, conditions in admission, treatment in hospital, status on discharge, diagnosis, classification, complication, trauma scoring and therapeutic effect. The database can be accessed through the internet by browser/servicer. The functions for the database include patient information management, data export, history query, progress report, video-image management and personal information management.
 Conclusion: The database with whole life cycle pelvic trauma is successfully established for the first time in China. It is scientific, functional, practical, and user-friendly.

Study of G-quadruplexes in the STAT3 gene using electrospray ionization mass spectrometry.

RATIONALE: As a key signal transducer and transcription activator, STAT3 plays a very important role in many cell processes. We found that there were many G-rich sequences existing in the STAT3 gene including its promoter, intron, exon and 3'-flanking regions. These G-rich tracts can form G-quadruplexes under near physiological conditions. In this research, we systemically studied the G-quadruplexes in the STAT3 gene at a whole gene scale for the first time. METHODS: In this research, the formation of G-quadruplexes in the STAT3 gene was probed by electrospray ionization mass spectrometry (ESI-MS) and circular dichroism (CD). Their structures were constructed and refined by a molecular modeling method. We also used ESI-MS to study the recognition of the G-quadruplexes in the promoter of the STAT3 gene by flexible molecules which do not have a planar core like the other common quadruplex ligands. RESULTS: The results based on ESI-MS suggested that the G-quadruplexes in the promoter of the STAT3 gene formed and were further recognized by some small molecules. CONCLUSION: Our research proved that the G-rich sequences in the STAT3 gene could form G-quadruplexes under near physiological conditions. This provides a promising target to study the regulation of cell signal transduction in vivo and drug design that aims to target STAT3 G-quadruplexes. Copyright © 2016 John Wiley & Sons, Ltd.

Exploring the formation and recognition of an important G-quadruplex in a HIF1α promoter and its transcriptional inhibition by a benzo[c]phenanthridine derivative.

Four putative G-quadruplex sequences (PGSs) in the HIF1α promoter and the 5'UTR were evaluated for their G-quadruplex-forming potential using ESI-MS, CD, FRET, DMS footprinting, and a polymerase stop assay. An important G-quadruplex (S1) has been proven to inhibit HIF1α transcription by blocking AP2 binding. A benzo[c]phenanthridine derivative was found to target the S1 G-quadruplex and induce its conformational conversion from antiparallel to parallel orientation. The transcriptional suppression of HIF1α by this compound was demonstrated using western blotting, Q-RT-PCR, luciferase assay, and ChIP. Our new findings provided a novel strategy for HIF1α regulation and potential insight for cancer therapy.

Biodegradable chitin nanofiber-alginate dialdehyde hydrogel: An injectable, self-healing scaffold for anti-tumor drug delivery.

Injectable hydrogels fabricated from natural polymers have attracted increasing attentions for their potential in biomedical application owing to the biocompatibility and biodegradability. A new class of natural polymer based self-healing hydrogel is constructed through dynamic covalent bonds. The injectable self-healing hydrogels are fabricated by introducing alginate aldehyde to form Schiff base bonds with the chitin nanofibers. These hydrogels demonstrate excellent self-healing properties, injectability, and pH-responsive sol-gel transition behaviors. As a result, they can serve as carriers to allow an effective encapsulation of doxorubicin (DOX) for drug delivery. Furthermore, these hydrogels exhibit excellent biocompatibility and degradability in vitro and in vivo. The sustained release of DOX from the hydrogels effectively suppresses tumor growth in animal models without causing significant systemic toxicity, suggesting their potential application in anti-tumor therapies.

Photothermal Fibrous Chitosan/Polydopamine Sponge for Intraoperative Hemostasis and Prevention of Tumor Recurrence in Hepatocellular Carcinoma Resection.

Hepatectomy, a surgical procedure for liver cancer, is often plagued by high recurrence rates worldwide. The recurrence of liver cancer is primarily attributed to microlesions in the liver, changes in the immune microenvironment, and circulating tumor cells in the bloodstream. To address this issue, a novel intervention method that combines intraoperative hemostasis with mild photothermal therapy is proposed, which has the potential to ablate microlesions and improve the immune microenvironment simultaneously. Specifically, the integrated strategy is realized based on the fibrous chitosan/polydopamine sponge (CPDS), which is constructed from shearing-flow-induced oriented hybrid chitosan fibers and subsequent self-assembly of polydopamine. The CPDS demonstrates high elasticity, excellent water absorption, and photothermal conversion performance. The results confirm the efficient hemostatic properties of the fibrous CPDS in various bleeding models. Notably, in subcutaneous and orthotopic postoperative recurrence and metastasis models of hepatocellular carcinoma, the fibrous CPDS significantly inhibits local tumor recurrence and distant metastasis. Moreover, the combination with lenvatinib can substantially enhance the antitumor effect. This comprehensive treatment strategy offers new insights into hepatectomy of liver cancer, representing a promising approach for clinical management.

An unusual highly sensitive dual-channel bis(salamo)-like chemical probe for recognizing B4O72-, sensing mechanism, theoretical calculations and practical applications.

A bis(salamo)-like chemical sensor H3L ((1E,3E)-2-hydroxy-5-methylisophthalaldehyde O,O -di(3-((((E)-(2-hydroxynaphthalen-1-yl)methylene)amino)oxy)propyl) dioxime) was constructed. H3L is capable of recognizing B4O72- in H2O/DMF (1:9, v/v) solution by both fluorescent and colorimetric channels, bright green fluorescence was turned on when B4O72- was added to H3L and changed from colorless to yellow in natural light. The detection limit was 3.21 × 10-8 M. The identification has good anti-interfering ability, quickly responsive time (5 S) and broad pH detecting range (pH = 5-12). The mechanism of action was determined by 1H NMR titration, infrared spectrometry, HRMS spectra and further elucidated by theory calculations. The fluorescence imaging of bean sprouts and spiked recovery assays of actual water samples demonstrated the practical use of sensor H3L for the detection of B4O72-, which is expected to have applications for the detection of B4O72- in plants and the environment.

Engineering an injectable gellan gum-based hydrogel with osteogenesis and angiogenesis for bone regeneration.

Injectable hydrogels are currently a topic of great interest in bone tissue engineering, which could fill irregular bone defects in a short time and avoid traditional major surgery. Herein, we developed an injectable gellan gum (GG)-based hydrogel for bone defect repair by blending nano-hydroxyapatite (nHA) and magnesium sulfate (MgSO4). In order to acquire an injectable GG-based hydrogel with superior osteogenesis, nHA were blended into GG solution with an optimized proportion. For the aim of endowing this hydrogel capable of angiogenesis, MgSO4 was also incorporated. Physicochemical evaluation revealed that GG-based hydrogel containing 5% nHA (w/v) and 2.5 mM MgSO4 (GG/5%nHA/MgSO4) had appropriate sol-gel transition time, showed a porosity-like structure, and could release magnesium ions for at least 14 days. Rheological studies showed that the GG/5%nHA/MgSO4 hydrogel had a stable structure and repeatable self-healing properties. In-vitro results determined that GG/5%nHA/MgSO4 hydrogel presented superior ability on stimulating bone marrow mesenchymal stem cells (BMSCs) to differentiate into osteogenic linage and human umbilical vein endothelial cells (HUVECs) to generate vascularization. In-vivo, GG/5%nHA/MgSO4 hydrogel was evaluated via a rat cranial defect model, as shown by better new bone formation and more neovascularization invasion. Therefore, the study demonstrated that the new injectable hydrogel, is a favorable bioactive GG-based hydrogel, and provides potential strategies for robust therapeutic interventions to improve the repair of bone defect.

A Novel Tryptanthrin Derivative D6 Induces Apoptosis and DNA Damage in Non-small-cell Lung Cancer Cells Through Regulating the EGFR Pathway.

BACKGROUND: Non-small-cell lung cancer is a prevalent malignancy associated with significant morbidity and mortality rates. Tryptanthrin and its derivatives have exhibited potent antitumor activity. OBJECTIVE: This study aims to investigate the inhibitory effect of a novel synthesized tryptanthrin derivative D6 on proliferation and the possible mechanism of human non-small cell lung cancer cell lines (A549) in vitro. METHODS: In this study, MTT assay, cell migration, colony formation assay, cell cycle analysis, cell apoptosis, JC- 1 staining assay, reactive oxygen species analysis, proteomics, western blotting, high content screening and absorption titrations analysis were performed. RESULTS: We found that D6 inhibited both the proliferation and migration, induced cell cycle arrest in the G2/M phase, increased levels of ROS, decreased mitochondrial membrane potential, and promoted apoptosis in A549 cells. Further mechanistic studies found that D6 reduced EGFR expression in A549 cells and inhibited the EGFR pathway by decreasing phosphorylation levels of EGFR, Stat3, AKT and Erk1/2. Moreover, DNA damage induced by D6 involved an increase in p53/MDM2 ratio and concentration-dependent accumulation of micronuclei. CONCLUSION: D6 demonstrated significant antitumor activity against A549 cells by inhibiting the EGFR signaling pathway, inducing DNA damage, and subsequently leading to oxidative stress, apoptosis, and cell cycle arrest. Our findings suggest that D6 exhibits potential as an NSCLC drug, owing to its attributes such as antiproliferative activity and ability to induce apoptosis by attenuating the EGFR-mediated signaling pathway.

Three Birds, One Stone: An Osteo-Microenvironment Stage-Regulative Scaffold for Bone Defect Repair through Modulating Early Osteo-Immunomodulation, Middle Neovascularization, and Later Osteogenesis.

In order to repair critical-sized bone defects, various polylactic acid-glycolic acid (PLGA)-based hybrid scaffolds are successfully developed as bone substitutes. However, the byproducts of these PLGA-based scaffolds are known to acidify the implanted site, inducing tiresome acidic inflammation. Moreover, these degradation productions cannot offer an osteo-friendly microenvironment at the implanted site, matching natural bone healing. Herein, inspired by bone microenvironment atlas of natural bone-healing process, an osteo-microenvironment stage-regulative scaffold (P80/D10/M10) is fabricated by incorporating self-developed decellularized bone matrix microparticles (DBM-MPs) and multifunctional magnesium hydroxide nanoparticles (MH-NPs) into PLGA with an optimized proportion using low-temperature rapid prototyping (LT-RP) 3D-printing technology. The cell experiments show that this P80/D10/M10 exhibits excellent properties in mechanics, biocompatibility, and biodegradability, meanwhile superior stimulations in osteo-immunomodulation, angiogenesis, and osteogenesis. Additionally, the animal experiments determined that this P80/D10/M10 can offer an osteo-friendly microenvironment in a stage-matched pattern for enhanced bone regeneration, namely, optimization of early inflammation, middle neovascularization, and later bone formation. Furthermore, transcriptomic analysis suggested that the in vivo performance of P80/D10/M10 on bone defect repair is mostly attributed to regulating artery development, bone development, and bone remodeling. Overall, this study reveals that the osteo-microenvironment stage-regulative scaffold provides a promising treatment for bone defect repair.

Design, synthesis, antibacterial evaluation of isopropylamine linked with different substituted phenol and piperazine novel derivatives.

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) is often considered one of the most destructive bacterial pathogens causing bacterial leaf blight (BLB), resulting in significant yield and cost losses in rice. In this study, a series of novel derivatives containing the isopropanolamine moiety linked to various substituted phenols and piperazines were designed, synthesized and screened. RESULTS: Antibacterial activity results showed that most compounds had good inhibitory effects on Xoo, among which compound W2 (EC50 = 2.74 µg mL-1) exhibited the most excellent inhibitory activity, and W2 also had a certain curative effect (35.89%) on rice compared to thiodiazole copper (TC) (21.57%). Scanning electron microscopy (SEM) results indicated that compound W2 could cause rupture of the Xoo cell membrane. Subsequently, proteomics and quantitative real-time polymerase chain reaction revealed that compound W2 affected the physiological processes of Xoo and may exert antibacterial activity by targeting the two-component system pathway. Interestingly, W2 upregulated Xoo's methyltransferase to impact on its pathogenicity. CONCLUSION: The present study offers a promising phenolic-piperazine-sopropanolamine compound as an innovative antibacterial strategy by specifically targeting the two-component system pathway and inducing upregulation of methyltransferase to effectively impact Xoo's pathogenicity. © 2024 Society of Chemical Industry.

Combination of Chlorambucil and Mercaptopurine Show Effective Anti-Cancer Effects in Mice Model.

Background: Combination therapy employing multiple drugs has been shown to enhance the efficacy of cancer treatment. Chlorambucil (Chl) and 6-mercaptopurine (6MP) are the first-line medicines for chronic lymphocytic leukemia and ovarian cancer. However, both were limited by their short half-life of disintegration, unsatisfactory water solubility, and adverse reactions. Methods: In this work, the drug Chl and 6MP were introduced into the polymerized N-(2-hydroxypropyl) methacrylamide (polyHPMA) by pH and glutathione responsive linker to construct the polymer nanodrug delivery system for effective co-delivery. Results: The drug load capacities, release, morphology, and cytotoxicity of the pro-drug were systematic. The two drugs showed satisfactory synergism with a combination index of 0.81, and a better ability to induce apoptosis. In and ex vivo fluorescence imaging showed a rapid systemic distribution of the conjugate within mice, majorly metabolized by liver and kidneys and eliminated after 24 hr. No significant pathological damage was observed in the major organs. This polymeric prodrug system holds promise for improved therapeutic efficiency and reduced side effects through the synergistic delivery of various chemotherapeutics. Conclusion: The introduction of HPMA as a carrier not only enhanced the solubility and biocompatibilities of Chl and 6 MP but also improved their drug effect. This strategy might be a promising alternative for constructing multi-drug-release system.