Intraperitoneal administration of doxorubicin-encapsulated Brucea javanica oil nanoemulsion against malignant ascites.

Malignant ascites is a common complication of advanced cancers, which reduces survival rates and diminishes patients' quality of life. Intraperitoneal chemotherapy is a conventional method for treating cancer-related ascites, but the poor drug retention of conventional drugs requires frequent administration to maintain sustained anti-tumor effects. In this study, we encapsulated doxorubicin (DOX) into Brucea javanica oil (BJO) to develop a water-in-oil (W/O) nanoemulsion called BJO@DOX for the treatment of malignant ascites through in-situ intraperitoneal administration. BJO significantly induced apoptosis of S180 cells by upregulating the expression of p53 and caspase-3 (cleaved). Additionally, BJO notably downregulated the expression of Bcl-2, further promoting apoptosis of S180 cells. Cell apoptosis significantly inhibited ascites formation and tumor cell proliferation in a mouse model. The combination of DOX and BJO exhibited satisfactory synergistic effects, consequently prolonging the survival period of mice. Histological examination of major organs indicated that the nanoemulsion had excellent biosafety in vivo. The BJO@DOX nanoemulsion represents a promising platform for in-situ chemotherapy of malignant ascites.

An oral bioactive chitosan-decorated doxorubicin nanoparticles/bacteria bioconjugates enhance chemotherapy efficacy in an in-situ breast cancer model.

Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Despite significant advancements in chemotherapy, its effectiveness is often limited by poor drug distribution and systemic toxicity caused by the weak targeting ability of conventional therapeutic agents. The hypoxic tumor microenvironment (TME) also plays a vital role in treatment outcomes. Oral anticancer therapeutic agents have gained popularity and show promising results due to their ease of repeated administration. This study introduces autopilot biohybrids (Bif@BDC-NPs) for the effective delivery of doxorubicin (DOX) to the tumor site. This hybrid combines albumin-encapsulated DOX nanoparticles (BD-NPs) coated with chitosan (CS) for breast cancer chemotherapy, along with anaerobic Bifidobacterium infantis (B. infantis, Bif) serving as self-propelled motors. Due to Bif's specific anaerobic properties, Bif@BDC-NPs precisely anchor hypoxic regions of tumor tissue and significantly increase drug accumulation at the tumor site, thereby promoting tumor cell death. In an in-situ mouse breast cancer model, Bif@BDC-NPs achieved 94 % tumor inhibition, significantly prolonging the median survival of mice to 62 days, and reducing the toxic side effects of DOX. Therefore, the new bacteria-driven oral drug delivery system, Bif@BDC-NPs, overcomes multiple physiological barriers and holds great potential for the precise treatment of solid tumors.

Intraperitoneal administration of thermosensitive hydrogel Co-loaded with norcantharidin nanoparticles and oxaliplatin inhibits malignant ascites of hepatocellular carcinoma.

Malignant ascites is a common complication of some advanced cancers. Although intraperitoneal (IP) administration of chemotherapy drugs is routinely used to treat cancerous ascites, conventional drugs have poor retention and therefore need to be administered frequently to maintain a sustained anti-tumor effect. In this study, a thermosensitive hydrogel composite loaded with norethindrone nanoparticles (NPs) and oxaliplatin (N/O/Hydrogel) was developed to inhibit ascites of hepatocellular carcinoma (HCC) through IP injection. N/O/Hydrogel induced apoptosis in the H22 cells in vitro, and significantly inhibited ascites formation, tumor cell proliferation and micro-angiogenesis in a mouse model of advanced HCC with ascites, and prolonged the survival of tumor-bearing mice. Histological examination of the major organs indicated that the hydrogel system is safe. Taken together, the N/O/Hydrogel system is a promising platform for in-situ chemotherapy of malignant ascites.

Erythrocyte membrane-camouflaged gefitinib/albumin nanoparticles for tumor imaging and targeted therapy against lung cancer.

Conventional chemotherapeutic drugs may cause serious side effects such as hepatotoxicity and renal toxicity due to lack of targeting, which affects therapy outcome and the prognosis of patients. Therefore, biomimetic nanoparticles with long blood circulation and active targeting have attracted increasing attention. In this work, we fabricated a biomimetic R-RBC@GEF-NPs nano-system by encapsulating gefitinib-loaded albumin nanoparticles (GEF-NPs) inside cRGD-modified red blood cell (RBC) membranes. The complete RBC membrane structure and membrane proteins enabled the NPs to escape phagocytosis by macrophages. In addition, the cRGD moiety significantly improved tumor cell targeting and uptake. R-RBC@GEF-NPs inhibited the growth of A549 cells in vitro in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest at the G1 phase. Likewise, the R-RBC@GEF-NPs also decreased tumor weight and volume in the mice injected with A549 cells and prolonged survival time. In addition, the 99Tc-labeled R-RBC@GEF-NPs selectively accumulated in the tumor tissues in vivo, and enabled real time tumor imaging. Finally, blood and histological analyses showed that R-RBC@GEF-NPs did not cause any obvious systemic toxicity. Taken together, the biomimetic R-RBC@GEF-NPs is a promising therapeutic formulation for the treatment of lung cancer.

Patient-Derived Organoids Can Guide Personalized-Therapies for Patients with Advanced Breast Cancer.

Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.

Injectable hydrogel loaded with paclitaxel and epirubicin to prevent postoperative recurrence and metastasis of breast cancer.

Post-operative recurrence and metastasis is a major challenge for breast cancer treatment. Local chemotherapy is a promising strategy that can overcome this problem. In this study, we synthesized an injectable hyaluronic acid (HA)-based hydrogel loaded with paclitaxel (PTX) nanoparticles and epirubicin (EPB) (PPNPs/EPB@HA-Gel). PPNPs/EPB@HA-Gel steadily released the encapsulated drugs to achieve long-term inhibition of tumor recurrence and metastasis in a murine post-operative breast tumor model, which prolonged their survival without any systemic toxicity. The drug-loaded hydrogel inhibited the proliferation and migration of tumor cells in vitro, and significantly increased tumor cell apoptosis in vivo. Therefore, PPNPs/EPB@HA-Gel can be used as a local chemotherapeutic agent to prevent postoperative recurrence and metastasis of breast cancer.

Curcumin nanoparticles incorporated in PVA/collagen composite films promote wound healing.

Skin repair remains a common problem in plastic surgery. Wound dressing plays an important role in promoting local skin healing and has been widely studied. This study aimed to manufacture a composite film (CPCF) containing curcumin nanoparticles, collagen, and polyvinyl alcohol (PVA) to effectively promote the healing of skin wounds. Sustained drug release from the composite film provides long-term protection and treatment for skin wounds. Both antibacterial property and good histocompatibility of the CPCF were examined by analyzing antibacterial activity and cytotoxicity to validate its applicability for wound management. Moreover, in vivo studies proved that the CPCF had a rapid healing rate of 98.03%±0.79% and mature epithelialization on day 15 after surgery. Obvious hair follicles and earlier re-epithelialization was also noticed in the CPCF group using H&E staining. The result of Masson's trichrome staining confirmed that CPCF could promote the formation of collagen fibers. In summary, CPCF may be promising as a wound dressing agent in wound management owing to its rapid wound-healing effects.

Co-delivery of paclitaxel and curcumin by biodegradable polymeric nanoparticles for breast cancer chemotherapy.

Multi-drug chemotherapy has been one of the most popular strategies for the treatment of malignant tumors, and has achieved desirable therapeutic outcomes. The objective of the present study is to develop biodegradable PCEC nanoparticles (NPs) for the co-delivery of paclitaxel (PTX) and curcumin (CUR), and investigate the antitumor effect of the drug delivery system (DDS: PTX-CUR-NPs) against breast cancer both in vitro and in vivo. The prepared PTX-CUR-NPs had a small size of 27.97 ± 1.87 nm with a low polydispersity index (PDI, 0.197 ± 0.040). The results exhibited slow release of PTX and CUR from the DDS without any burst effect. Further, the PTX-CUR-NPs displayed a dose-dependent cytotoxicity in MCF-7 cells with a higher apoptosis rate (64.29% ± 1.97%) as compared to that of free drugs (PTX + CUR, 34.21% ± 0.81%). The cellular uptake study revealed that the drug loaded PCEC polymeric nanoparticles were more readily uptaken by tumor cells in vitro. To evaluate the in vivo anti-tumor effect, the PTX-CUR-NPs were intravenously administered to BALB/c nude mouse xenografted with MCF-7 cells and the results exhibited significant inhibition of tumor growth with prolonged survival time and reduced side effect when compared with free drugs (PTX + CUR). Moreover, the administration of PTX-CUR-NPs treatment led to lower Ki67 expression (p < 0.05), and enhanced TUNEL positivity (higher apoptosis, p < 0.01) in tumor cells as compared to other treatment groups, suggesting the therapeutic efficacy of the DDS. Altogether, the present study suggests that the DDS PTX-CUR-NPs could be employed for the effective treatment of breast cancers in near future.

Self-assembled dihydroartemisinin nanoparticles as a platform for cervical cancer chemotherapy.

Dihydroartemisinin (DHA) is a potent anti-cancer drug that has limited clinical applications due to poor water solubility and low bioavailability. We designed a biodegradable poly(ethylene glycol) methyl ether-poly(ε-caprolactone) (MPEG-PCL) micelle carrier for DHA using the self-assembly method. The DHA/MPEG-PCL nanoparticles were spherical with an average particle size of 30.28 ± 0.27 nm, and released the drug in a sustained manner in aqueous solution. The drug-loaded nanoparticles showed dose-dependent toxicity in HeLa cells by inducing cycle arrest and apoptosis. Furthermore, compared to free DHA, the DHA/MPEG-PCL nanoparticles showed higher therapeutic efficacy and lower toxicity in vivo, and significantly inhibited tumor growth and prolonged the survival of tumor-bearing nude mice. In addition, the tumor tissues of the DHA/MPEG-PCL-treated mice showed a marked decline in the in situ expression of proliferation and angiogenesis markers. Taken together, the self-assembled DHA/MPEG-PCL nanoparticles are a highly promising delivery system for targeted cancer treatment.

Identification of Circulating MicroRNAs as a Promising Diagnostic Biomarker for Cervical Intraepithelial Neoplasia and Early Cancer: A Meta-Analysis.

BACKGROUND: Cervical cancer (CC) is one of the most common female malignant tumors. And cervical intraepithelial neoplasia (CIN) is the precancerous lesion of CC, which can progress to invasive CC. MicroRNAs (miRNAs) have been found to be potential diagnostic biomarkers for CIN or CC. However, recently, the lack of sufficient studies about the diagnostic value of miRNAs for CIN made it challenging to separately investigate the diagnostic efficacy of miRNAs for CIN. Likewise, the conclusions among those studies were discordant. Therefore, we conducted this meta-analysis, aimed at evaluating the diagnostic efficacy of miRNAs for CIN and CC patients. METHODS: Literature search was performed in PubMed, Embase, and Web of Science databases. Pooled sensitivity, specificity, and other diagnostic parameters were calculated through Stata 14.0 software. Furthermore, subgroup analyses and metaregression analysis were conducted to explore the main sources of heterogeneity. RESULTS: Ten articles covering 50 studies were eligible, which included 5,908 patients and 4,819 healthy individuals. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.81 (95% CI, 0.77-0.85), 0.86 (95% CI, 0.83-0.89), 5.9 (95% CI, 4.5-7.7), 0.22 (95% CI, 0.17-0.28), 27 (95% CI, 17-44), and 0.91 (95% CI, 0.88-0.93), respectively. Additionally, the ethnicity and internal reference were the main sources of heterogeneity. CONCLUSIONS: Circulating miRNAs can be a promising noninvasive diagnostic biomarker for CIN and early CC, especially miR-9 and miR-205, which need to be verified by large-scale studies.

Intraperitoneal administration of biocompatible hyaluronic acid hydrogel containing multi-chemotherapeutic agents for treatment of colorectal peritoneal carcinomatosis.

Colorectal peritoneal carcinomatosis (CRPC) is an advanced stage of colorectal cancer (CRC), which significantly decreases patient survival and quality of life. Here, the naturally occurring polysaccharide hyaluronic acid (HA) was used to prepare an injectable hydrogel and simultaneously deliver 5-fluorouracil (5-FU), cisplatin (DDP) and paclitaxel (PTX) microspheres for intraperitoneal CRPC chemotherapy. The drug-loaded HA hydrogel released the drugs in a sustained manner, and showed low toxicity both in vitro and in a mouse model of CRPC. Furthermore, direct injection of the drug-loaded HA hydrogel in the abdominal cavity of tumor-bearing mice significantly decreased tumor growth and liver/lung metastasis, along with decreasing the volume of ascites and inhibiting local intestinal infiltration of the tumor cells. Therefore, this novel multi-drug hydrogel delivery system may effectively clear CRPC tumors without any adverse effects when used in intraperitoneal chemotherapy.

Injectable Hyaluronic Acid Hydrogel for the Co-Delivery of Gemcitabine Nanoparticles and Cisplatin for Malignant Ascites Therapy.

Malignant ascites indicate the presence of malignant cells in the peritoneal cavity that lower patient survival and reduce quality of life. Current chemotherapy regimens suffer from the dilution of ascites and rapid metabolism limiting their therapeutic efficacy. The storage and sustained release of drugs at the tumor site represents a promising strategy to improve drug efficacy. The aim of this study was to develop injectable hyaluronic acid hydrogel containing polymeric gemcitabine nanoparticles and cisplatin for the local treatment of malignant ascites through a dual sustained drug release pattern. Cell uptake assays showed that the drug-loaded nanoparticles readily entered tumor cells. Apoptosis and cell cycle analysis showed that the hydrogel system could enhance tumor cell apoptosis and arrest more cells in the G1 phase. In vivo experiments indicated that mice treated with the drug-loaded hydrogels manifested the most significant efficacy in ascites volume, tumor nodules, body weight, abdominal circumference, and survival. The expression of Ki-67 and CD31 also significantly decreased compared with other groups, indicative of anti-tumor activity. In addition, intraperitoneal administration of the hydrogel system led to no significant damage to vital organs. These findings confirm the clinical potential of the drug-loaded hydrogel system for the treatment of malignant ascites.

Naproxen Nanoparticle-Loaded Thermosensitive Chitosan Hydrogel for Prevention of Postoperative Adhesions.

Postoperative adhesions are the most common complications of peri-abdominal surgery; they not only affect the patient's quality of life but also increase the risk of a subsequent surgery. The use of implantable dressings to physically block surgical wounds is the primary solution to prevent postoperative adhesions. In this study, we prepared naproxen nanoparticles that were loaded with chitosan hydrogel (CS/Nap hydrogel) to prevent postoperative adhesions. Our data confirmed that the prepared CS/Nap hydrogel was thermosensitive and suitable for injection. The efficacy of anti-adhesion in a rat model revealed that the hydrogel effectively separated from the wounds of the abdominal wall and cecum. On day 7 postsurgery, the wounds were completely covered by a new epithelial layer, whereas wounds in the negative control group were glued together. Additionally, the in vivo toxicity study showed that the CS/Nap hydrogel had fewer toxic and side effects on major tissues and organs, including the liver, spleen, heart, lung, and kidney. We showed that a drug delivery system based on CS/Nap hydrogel has the potential not only to prevent postoperative abdominal adhesions and relieve pain but also to contribute to the administration of the hydrophobic drug naproxen.

Nanoscale Manipulation of Spinel Lithium Nickel Manganese Oxide Surface by Multisite Ti Occupation as High-Performance Cathode.

A novel two-step surface modification method that includes atomic layer deposition (ALD) of TiO2 followed by post-annealing treatment on spinel LiNi0.5 Mn1.5 O4 (LNMO) cathode material is developed to optimize the performance. The performance improvement can be attributed to the formation of a TiMn2 O4 (TMO)-like spinel phase resulting from the reaction of TiO2 with the surface LNMO. The Ti incorporation into the tetrahedral sites helps to combat the impedance growth that stems from continuous irreversible structural transition. The TMO-like spinel phase also alleviates the electrolyte decomposition during electrochemical cycling. 25 ALD cycles of TiO2 growth are found to be the optimized parameter toward capacity, Coulombic efficiency, stability, and rate capability enhancement. A detailed understanding of this surface modification mechanism has been demonstrated. This work provides a new insight into the atomic-scale surface structural modification using ALD and post-treatment, which is of great importance for the future design of cathode materials.

JNK pathway inhibition enhances chemotherapeutic sensitivity to Adriamycin in nasopharyngeal carcinoma cells.

The role of c-Jun N-terminal kinases (JNKs) in the pathogenesis of cancer is well-known due to their involvement in carcinogenesis. Although previous studies have discussed different functions of JNKs depending on cell type, the present study aimed to investigate the function of JNKs in nasopharyngeal carcinoma (NPC) cells, as well as their involvement in chemotherapy sensitivity to Adriamycin. The present results showed that Adriamycin administration reduced cell viability and led to elevated expressions of c-Jun, phosphorylated JNK and phosphorylated c-Jun, indicating an activated JNK pathway. Notably, JNK inhibition by SP600125 also reduced cell growth. Thus, Adriamycin treatment combined with SP600125 was more effective on cell growth inhibition than each agent alone. The apoptosis analysis confirmed the reduction in cell growth. Therefore, these data provide evidence that the JNK pathway activity is negatively associated with cell viability, and its decline could sensitize NPC cells to Adriamycin.

Oncogenic role of the TP53-induced glycolysis and apoptosis regulator in nasopharyngeal carcinoma through NF-κB pathway modulation.

The TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target gene, which functions to suppress reactive oxygen species (ROS) damage and protect cells from apoptosis. In this study, we investigated the role of TIGAR in nasopharyngeal carcinoma (NPC) tumorigenesis. Imnunohistochemical analysis of the tissue specimens from nasopharyngeal carcinoma patients showed a higher expression level of TIGAR in tumor tissues, compared with normal nasopharyngeal epithelium. Knockdown of TIGAR by lentivirus-shRNA in CNE-2 or 5-8F cells resulted in decreased cell growth, colony formation, migration, invasion, and induced apoptosis. TIGAR overexpression exerted the opposite effects except for apoptosis reduction. In the xenograft tumor models, TIGAR knockdown reduced tumor growth rate and weight, whereas TIGAR overexpression showed the opposite effects. In addition, the NF-κB signaling pathway was decreased in TIGAR silenced cells. In conclusion, our data demonstrated that TIGAR acted as an oncogene in NPC tumorigenesis, and knockdown of TIGAR inhibited NPC tumor growth through the NF-κB pathway.

Combining CXCL10 gene therapy and radiotherapy improved therapeutic efficacy in cervical cancer HeLa cell xenograft tumor models.

Radiotherapy is an important treatment method for cervical cancer, but the efficacy requires improvement. Therefore, novel methods of treatment are required. Previous data have demonstrated that the CXC chemokine ligand 10 (CXCL10) inhibits angiogenesis, induces apoptosis and causes avoidance of the S phase of the cell cycle in cervical cancer cells. The aim of the present study was to evaluate the anti-tumor effect of radiotherapy combined with CXCL10 gene therapy. Mouse models of cervical carcinoma were created by inoculation with HeLa cells, and were treated by combining intravenously administered plasmid-encoding CXCL10, administered 5 times (days 12, 15, 18, 21 and 24 following inoculation), with direct radiation (20 Gy/5 fractions) administered on 5 consecutive days (~day 27 after inoculation). The vessel density and tumor cell proliferation were observed by immunostaining, and apoptosis was determined using a TUNEL assay. The results revealed a significant increase in the inhibition of tumor growth, reduced vessel density, decreased cell proliferation and increased apoptosis in the tumor cells of the combination therapy group. Overall, these findings resulted in the conclusion that CXCL10 gene therapy in combination with radiotherapy is a novel effective therapeutic strategy for cervical cancer.

Acceleration of dermal wound healing by using electrospun curcumin-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) fibrous mats.

This study prepared a composite scaffold composed of curcumin and poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymer using coelectrospinning technology. Incorporation of curcumin into the polymeric matrix had an obvious effect on the morphology and dimension of PCEC/curcumin fibers. The results of in vitro anti-oxidant tests and of the cytotoxicity assay demonstrated that the curcumin-loaded PCEC fibrous mats had significant anti-oxidant efficacy and low cytotoxicity. Curcumin could be sustainably released from the fibrous scaffolds. More importantly, in vivo efficacy in enhancing wound repair was also investigated based on a full-thickness dermal defect model for Wistar rats. The results indicated that the PCEC/curcumin fibrous mats had a significant advantage in promoting wound healing. At 21 days post-operation, the dermal defect was basically recovered to its normal condition. A percentage of wound closure reached up to 93.3 ± 5.6% compared with 76.9 ± 4.9% of the untreated control (p < 0.05). Therefore, the as-prepared PCEC/curcumin composite mats are a promising candidate for use as wound dressing.

In vitro mineralization of hydroxyapatite on electrospun poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) fibrous scaffolds for tissue engineering application.

In this study, a fibrous scaffold was prepared by electrospinning triblock PCL-PEG-PCL (PCEC) copolymer. Afterwards, in vitro biomimetic mineralization was carried out through incubation of the PCEC fibrous mats in a simulated body fluid (SBF) for different time. The apatite-deposited PCEC composite scaffolds were characterized by using Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscope (SEM) observation and weighing. Due to the importance of biocompatibility, rat ROS 17/2.8 osteoblasts were cultured on mineralized PCEC scaffolds, and the cell proliferation was investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. The obtained results confirmed that the deposited apatite had the chemical composition and crystalline phase similar to those of hydroxyapatite (HA). After 21 days incubation, the mass increase of PCEC scaffold reached up to 22%. Moreover, in vitro cell culture also confirmed that osteoblasts could attach on the mineralized composite scaffolds, and the HA-deposited PCEC mats had less cytotoxicity. So, the mineralized PCEC composite scaffolds had a great potential for tissue engineering application.

CXCL10 enhances radiotherapy effects in HeLa cells through cell cycle redistribution.

Radiotherapy is a crucial treatment for cervical cancer, the second most common type of cancer in women worldwide. In this study, we investigated the effects of CXC chemokine ligand 10 (CXCL10) gene therapy combined with radiotherapy on cervical cancer using HeLa cells. TUNEL assay revealed that the apoptotic rate in the combined treatment of CXCL10 gene therapy and radiotherapy was greatly increased compared with that of CXCL10 or radiotherapy alone. Flow cytometry showed that CXCL10 overexpression in HeLa cells resulted in a prolonged G1 phase and shortened S phase at 72 h post-transfection. Western blot analysis revealed that p27(Kip1) was up-regulated in CXCL10-treated HeLa cells; however, cyclin E was down-regulated. These results indicate that the combination of CXCL10 gene therapy and radiotherapy is an effective strategy for the growth suppression of HeLa cells, and that CXCL10 enhances the radiotherapy effects through cell cycle redistribution. Our data provide new insight into the treatment of cervical carcinoma, involving an effective combination of gene therapy and radiotherapy against tumors.