Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical.

Cancer remains a serious threat to human health owing to the lack of effective treatments. Photodynamic therapy (PDT) has emerged as a promising non-invasive cancer treatment that consists of three main elements: photosensitizers (PSs), light and oxygen. However, some traditional PSs are prone to aggregation-caused quenching (ACQ), leading to reduced reactive oxygen species (ROS) generation capacity. Aggregation-induced emission (AIE)-PSs, due to their distorted structure, suppress the strong molecular interactions, making them more photosensitive in the aggregated state instead. Activated by light, they can efficiently produce ROS and induce cell death. PS is one of the core factors of efficient PDT, so proceeding from the design and preparation of AIE-PSs, including how to manipulate the electron donor (D) and receptor (A) in the PSs configuration, introduce heavy atoms or metal complexes, design of Type I AIE-PSs, polymerization-enhanced photosensitization and nano-engineering approaches. Then, the preclinical experiments of AIE-PSs in treating different types of tumors, such as ovarian cancer, cervical cancer, lung cancer, breast cancer, and its great potential clinical applications are discussed. In addition, some perspectives on the further development of AIE-PSs are presented. This review hopes to stimulate the interest of researchers in different fields such as chemistry, materials science, biology, and medicine, and promote the clinical translation of AIE-PSs.

[Effect on 6-23 months infants by Yingyangbao intervention in impoverished regions of Henan Province].

OBJECTIVE: To observe the effect of 6-23 months infants by Yingyangbao(YYB) intervention in impoverished areas of Henan Province. METHODS: A multi-stage random sampling method was used to select infants aged 6-23 months from 51 project counties in Henan Province from September to November 2019. Physical anthropometric measurement and hemoglobin detection were performed, and face-to-face questionnaires surveyed with caregivers of the children. Children in 12 regions covered by YYB were defined as intervention group, and controls were selected from the baseline survey of children in 39 regions not covered by YYB according to the 1∶1 matching principle. The analysis between YYB and control groups were analyzed by χ~2 or t test. χ~2 test for trend to compare trend of children health status. RESULTS: A total of 7738 subjects were selected in the study, including 3869 in the intervention group and 3869 in the control group. The average length, weight and hemoglobin level of YYB group were 1. 1 cm, 0. 67 kg and 3. 8 g/L, respectively, which were higher than that of the control group. The anemia rate, underweight rate, stunting rate and wasting rate in intervention group were 13.1%, 1.7%, 2.1% and 1.9%, respectively, significantly lower than control group. Compared with the control group, the two-week prevalence of fever and diarrhea in the intervention group decreased by 5. 6% and 7. 2%, respectively. In addition, nutrition knowledge score of the parents, minimum dietary diversity rate, minimum meal frequency rate and minimum acceptable diet rate of intervention group were 62. 4%, 71. 1%, 73. 7% and 55. 8%, respectively, significantly better than that of control group. From 2015 to 2019, the anemia rate, underweight rate, stunting rate of children in regions covered by YYB showed a downward trend. CONCLUSION: YYB can effectively improve the nutrition, physical development and health status of 6-24 months infants. Through the implementation of the project, the knowledge and skills of scientific feeding in impoverished regions were significantly improved.

Hydroxychloroquine treatment in COVID-19: A descriptive observational analysis of 30 cases from a single center in Wuhan, China.

Hydroxychloroquine (HCQ) garnered scientific attention in early February following publication of reports showing in vitro activity of chloroquine (CQ) against coronavirus disease 2019 (COVID-19). While studies are mixed on this topic, the therapeutic effect of HCQ or CQ still need more valid clinical evidence. In this descriptive observational study, we aimed to discuss the treatment response of HCQ in COVID-19 infected patients and 30 cases were included. The demographic, treatment, laboratory parameters of C-reactive protein (CRP) and interleukin-6 (IL-6) before and after HCQ therapy and clinical outcome in the 30 patients with COVID-19 were assessed. To evaluate the effect of mediation time point, we also divided these cases into two groups, patients began administrated with HCQ within 7 days hospital (defined as early delivery group) and 7 days after hospital (defined as later delivery group). We found that, the elevated IL-6, a risk factor in severe patients were reduced to normal level after HCQ treatment. More importantly, patients treated with HCQ at the time of early hospital recovered faster than those who treated later or taken as second line choose for their obvious shorter hospitalization time. In summary, early use of HCQ was better than later use and the effect of IL-6 and CRP level cannot be ruled out.

Paenibacillus solisilvae sp. nov., isolated from birch forest soil.

A Gram-stain-positive, motile, rod-shaped bacterium, designated strain LAM7113T, was isolated from soil sample collected from a birch forest in Xinjiang Uygur Autonomous Region, PR China. Strain LAM7113T grew optimally at pH 8.0, 30 °C and in the presence of 1.0 % NaCl (w/v). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain LAM7113T was closely related to members of the genus Paenibacillus, with the highest similarity to Paenibacillus baekrokdamisoli Back-11T (96.2 %). The genomic DNA G+C content was 43.4 mol%. The values of average nucleotide identity and DNA-DNA hybridization were 66.1 and 27.0 %, respectively, by comparing the draft genome sequences of strain LAM7113T and P. baekrokdamisoli Back-11T. Anteiso-C15 : 0 and iso-C15 : 0 were identified as the major cellular fatty acids. Menaquinone-7 was detected as the predominant respiratory quinone. The major polar lipids were found to be diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, three unidentified aminophospholipids, three unidentified glycolipids, one unidentified phospholipid and two unknown polar lipids. Based on its phenotypic, phylogenetic and chemotaxonomic characteristics, strain LAM7113T is proposed to represent a novel species of the genus Paenibacillus with the name Paenibacillus solisilvae sp. nov. The type strain is LAM7113T (=CGMCC 1.16619T=JCM 32513T).

Actinoplanes solisilvae sp. nov., Isolated from Birch Forest Soil.

A novel actinomycete, designated strain LAM7112T, was isolated from soil sample collected from a birch forest in Xinjiang Uygur Autonomous Region, China. The new isolate was found to be able to grow at 20-45 °C (optimum: 35 °C), pH 5.0-10.0 (optimum: 7.0) and in the presence of 0-10.0% (optimum: 3.0%) (w/v) NaCl. The isolate formed very scantily irregular sporangia containing motile spores on the substrate mycelium. Phylogenetic analysis of 16S rRNA gene sequences indicated that the new isolate was closely related to members of the family Micromonosporaceae, with highest similarites to Actinoplanes ferrugineus X-14695T (97.4%), Micromonospora zamorensis DSM 45600T (97.3%) and Micromonospora aurantiaca ATCC 27029T (97.3%). In the phylogenetic trees, strain LAM7112T formed a stable phylogenetic subclade within the genus Actinoplanes. The genomic DNA G + C content was 70.0 mol%. The major fatty acids (> 10%) were determined to be iso-C16:0, anteiso-C15:0 and anteiso-C17:0. The predominant menaquinones were identified as MK-9 (H2), MK-9 (H4) and MK-9 (H6). The major polar lipids were found to be diphosphatidylglycerol, phosphatidylinositol and phosphatidylethanolamine. The diagnostic amino acid of the cell wall peptidoglycan was determined to be meso-diaminopimelic acid. The diagnostic sugars in cell hydrolysates were determined to be glucose and ribose. On the basis of its phenotypic, phylogenetic and chemotaxonomic characteristics, strain LAM7112T (= CGMCC 4.7580T = JCM 32512T) is proposed to represent the type strain of a novel species of the genus Actinoplanes, for which the name Actinoplanes solisilvae is proposed.

Testicular spermatozoon is superior to ejaculated spermatozoon for intracytoplasmic sperm injection to achieve pregnancy in infertile males with high sperm DNA damage.

The purpose of this study was to compare the clinical outcome of testicular spermatozoon versus ejaculated spermatozoon in the treatment of infertile males with high sperm DNA damage, referred as sperm DNA fragmentation index (DFI), that attending intracytoplasmic sperm injection (ICSI) programme in terms of clinical pregnancy, births delivered as the primary and pregnancy loss and embryo fertilisation as the secondary outcome. A total of 102 males fulfilling the inclusion criteria were enrolled in the present study. Of the 102 males, 61 infertile males underwent testicular spermatozoon combined with ICSI while the remaining 41 males applied ejaculated spermatozoa in their first ICSI cycles, and the data of them were collected and analysed. In a 18-month follow-up, testicular spermatozoon achieved higher pregnancy rate and deliver rate than those in ejaculated sperm group (pregnancy rate, 36% vs. 14.6%, p = 0.017; deliver rate, 38.5% vs. 9.8%, p = 0.001). Nevertheless, there were no significant differences in the number of oocytes aspirated and number of embryos transferred between the two groups. Additionally, the fertilisation rate in the testicular sperm study cohort (70.4%) was also similar to that in the ejaculated sperm group (75.0%). Based on the current data, we conclude that testicular spermatozoon is the prior option in the treatment of infertile males with high sperm DFI in ICSI programme. More high-quality studies with larger samples size are needed in the future due to the relative small size and the nonrandomized design of the present study.

Enhancing the therapeutic effect via elimination of hepatocellular carcinoma stem cells using Bmi1 siRNA delivered by cationic cisplatin nanocapsules.

Resistance of hepatocellular carcinoma (HCC) to systemic chemotherapy is partially due to presence of drug-resistant cancer stem cells. Bmi1 protein is essential for survival and proliferation of HCC cancer stem cells (CSCs). Here, we report that Bmi1 siRNA (Bmi1siR) loaded in cationic nanocapsules of cisplatin (NPC) eliminated stem cells in situ HCC in mice. NPC/Bmi1siR was fabricated via electrostatic complexation of Bmi1 siRNA to NPCs, which had cores composed of cisplatin and were coated with cationic lipids. In vivo, NPC/Bmi1siR showed higher anti-tumor activity in HCC bearing mice compared with cisplatin or NPC. Critically, both flow cytometry (FACS) analysis in vitro and histological examination in vivo revealed that side population or CD133+ HCC cells were dramatically decreased by NPC/Bmi1siR treatment, suggesting that HCC CSCs were eliminated. Altogether, our results suggest that drug resistance of HCC can be overcome by co-delivering Bmi1 siRNA with cisplatin in cationic nanocapsules.

CRISPR-Cas9 for medical genetic screens: applications and future perspectives.

CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) systems have emerged as versatile and convenient (epi)genome editing tools and have become an important player in medical genetic research. CRISPR-Cas9 and its variants such as catalytically inactivated Cas9 (dead Cas9, dCas9) and scaffold-incorporating single guide sgRNA (scRNA) have been applied in various genomic screen studies. CRISPR screens enable high-throughput interrogation of gene functions in health and diseases. Compared with conventional RNAi screens, CRISPR screens incur less off-target effects and are more versatile in that they can be used in multiple formats such as knockout, knockdown and activation screens, and can target coding and non-coding regions throughout the genome. This powerful screen platform holds the potential of revolutionising functional genomic studies in the near future. Herein, we introduce the mechanisms of (epi)genome editing mediated by CRISPR-Cas9 and its variants, introduce the procedures and applications of CRISPR screen in functional genomics, compare it with conventional screen tools and at last discuss current challenges and opportunities and propose future directions.

Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial.

Importance: Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective: To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants: A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions: Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures: The primary outcome was live birth. Secondary outcomes included adverse events. Results: Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, -0.6%; 95% CI, -5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance: Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration: clinicaltrials.gov Identifier: NCT01573858.

Structure and Function Analysis of Cultivated Meconopsis integrifolia Soil Microbial Community Based on High-Throughput Sequencing and Culturability.

(1) Background: The structure, function, and community interactions of soil microbial communities of cultivated Meconopsis integrifolia were characterized by studying this alpine flower and traditional endangered Tibetan medicine. (2) Methods: Soil bacteria and fungi were studied based on high-throughput sequencing technology. Bacteria were isolated using culturomics and functionally identified as IAA-producing, organic phosphorus-dissolving, inorganic phosphorus-dissolving, and iron-producing carriers. (3) Results: The dominant bacterial phyla were found to be Proteobacteria and Acidobacteria, and unclassified_Rhizobiales was the most abundant genus. Ascomycota and Mortierellomycota were the dominant fungal phyla. The bacteria were mainly carbon and nitrogen metabolizers, and the fungi were predominantly Saprotroph-Symbiotroph. The identified network was completely dominated by positive correlations, but the fungi were more complex than the bacteria, and the bacterial keystones were unclassified_Caulobacteraceae and Pedobacter. Most of the keystones of fungi belonged to the phyla Ascomycetes and Basidiomycota. The highest number of different species of culturable bacteria belonged to the genus Streptomyces, with three strains producing IAA, 12 strains solubilizing organic phosphorus, one strain solubilizing inorganic phosphorus, and nine strains producing iron carriers. (4) Conclusions: At the cost of reduced ecological stability, microbial communities increase cooperation toward promoting overall metabolic efficiency and enabling their survival in the extreme environment of the Tibetan Plateau. These pioneering results have value for the protection of endangered Meconopsis integrifolia under global warming and the sustainable utilization of its medicinal value.

Microneedle Device Delivering Aggregation-Induced Emission Photosensitizers for Enhanced Metronomic Photodynamic Therapy of Cancer.

Metronomic photodynamic therapy (mPDT), which induces cancer cell death by prolonged intermittent continuous irradiation at lower light power, has profoundly promising applications. However, the photobleaching sensitivity of the photosensitizer (PS) and the difficulty of delivery pose barriers to the clinical application of mPDT. Here, we constructed a microneedle-based device (Microneedles@AIE PSs) that combined with aggregation-induced emission (AIE) PSs to achieve enhanced mPDT for cancer. Due to the strong anti-photobleaching property of the AIE PS, it can maintain superior photosensitivity even after long-time light exposure. The delivery of the AIE PS to the tumor through a microneedle device allows for greater uniformity and depth. This Microneedles@AIE PSs-based mPDT (M-mPDT) offers better treatment outcomes and easier access, and combining M-mPDT with surgery or immunotherapy can also significantly improve the effectiveness of these clinical therapies. In conclusion, M-mPDT offers a promising strategy for the clinical application of PDT due to its better efficacy and convenience.

Placental Immune Tolerance and Organ Transplantation: Underlying Interconnections and Clinical Implications.

The immune system recognizes and attacks non-self antigens, making up the cornerstone of immunity activity against infection. However, during organ transplantation, the immune system also attacks transplanted organs and leads to immune rejection and transplantation failure. Interestingly, although the embryo and placenta are semi-allografts, like transplanted organs, they can induce maternal tolerance and be free of a vigorous immune response. Also, embryo or placenta-related antibodies might adversely affect subsequent organ transplantation despite the immune tolerance during pregnancy. Therefore, the balance between the immune tolerance in maternal-fetal interface and normal infection defense provides a possible desensitization and tolerance strategy to improve transplantation outcomes. A few studies on mechanisms and clinical applications have been performed to explore the relationship between maternal-fetal immune tolerance and organ transplantation. However, up to now, the mechanisms underlying maternal-fetal immune tolerance remain vague. In this review, we provide an overview on the current understanding of immune tolerance mechanisms underlying the maternal-fetal interface, summarize the interconnection between immune tolerance and organ transplantation, and describe the adverse effect of pregnancy alloimmunization on organ transplantation.

Effectiveness of early treatment of lopinavir-ritonavir in patients with severe COVID-19: a case series.

AIM: The inconsistent effects of lopinavir-ritonavir (LPV/r) on COVID-19 seem to be caused by the therapeutic window. In the present study, we aim to present the effects of early LPV/r treatment on patients with severe COVID-19. METHODS: The demographics, characteristics, treatments, SARS-CoV-2 test results and outcomes of 19 patients with severe COVID-19 treated with LPV/r within 12 days of onset of symptoms were retrospectively assessed. RESULTS: Within 3 days of admission, three (15.79%) patients received noninvasive ventilation, and 16 (84.21%) patients received high-flow oxygen support. The median duration between the onset of symptoms and initiating LPV/r therapy was 9 (range 2-12) days. The median course of LPV/r treatment was 11 (range 7-17) days. One of the 19 patients (5.26%) died. Of the 18 patients discharged, the median hospital stay was 17 (range 11-45) days. At day 6 after LPV/r therapy was initiated, 68.42% of patients were virologically cured, increasing to 84.22% at day 12. CONCLUSION: In this cohort of patients with severe COVID-19 who were treated with LPV/r within 12 days of the onset of symptoms, clinical improvement was observed in 18/19 patients (94.74%). Randomised controlled trials are urgently needed to further evaluate this strategy.

Serum Actinin-4 Levels as a Potential Diagnostic and Prognostic Marker in Cervical Cancer.

PURPOSE: The present study was aimed at determining the serum levels of actinin-4 (ACTN4) in cervical cancer (CC) and investigating the diagnostic and prognostic value of serum ACTN4 in CC. MATERIALS AND METHODS: We included 93 CC patients, 52 cervical intraepithelial neoplasia (CIN) patients, and 70 healthy women. Serum ACTN4 levels were assessed using an ELISA method. A receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of serum ACTN4. The survival curves were used to display the overall survival distributions. RESULTS: Serum ACTN4 levels in CC patients were 48.39 ± 13.98 pg/mL which is significantly higher than those in CIN patients (32.72 ± 9.44 pg/mL; P < 0.001) and those in healthy controls (30.84 ± 8.08 pg/mL; P < 0.001). The ROC analysis demonstrated that the area under the curve (AUC) of ACTN4 was 0.852 (95%CI = 0.796-0.908), with sensitivity of 76.3% and specificity of 87.7%. Serum ACTN4 levels were associated with the FIGO stage, lymph node metastasis, and lymphovascular space invasion of CC (all P < 0.05). The survival curve suggested that high serum ACTN4 levels were related to poor prognosis. CONCLUSION: Our findings suggest that serum ACTN4 levels may be valuable diagnostic and prognostic biomarkers for CC.

Comparative efficacy and safety of sunitinib vs sorafenib in renal cell carcinoma: A systematic review and meta-analysis.

To evaluate the safety and efficiency of sunitinib and sorafenib in the treatment of renal cell carcinoma (RCC).Databases were searched up till February 28, 2018. Two reviewers independently assessed trials for eligibility, quality, and extracted relevant data. Results are expressed as risk ratio (RR) or hazard ratio (HR) with 95% confidence intervals (CI). Six studies including 3112 patients were accessed. Sorafenib group exhibited higher median progression-free survival (mPFS) compared to sunitinib group (MD, -1.30; 95% CI, -2.56 to -0.03), especially in the first-line treatment (MD, -1.33; 95% CI, -2.61 to -0.04). However, sunitinib significantly reduced the risk of progression-free survival (PFS) compared to sorafenib (HR, 0.71; 95% CI, 0.6-0.82). Sunitinib also significantly reduced risk of overall survival (OS) compared to sorafenib (HR, 0.79; 95% CI, 0.65-0.92), while median OS was similar in both groups (MD, -0.48; 95% CI, -3.40-2.43). With regards to safety, the risk of rash (RR, 0.31, 95% CI, 0.12-0.79) was greater in sunitinib than sorafenib group, while the risk of decreased appetite (RR 2.10, 95% CI: 1.33-3.30) and dehydration (RR 2.73, 95% CI: 1.14-6.56) was smaller in contrast.Based on risk of PFS and OS, sunitinib was a better treatment option for RCC treatment while patients faced with severe skin reaction. And for those Asian patients classified under MSKCC moderate risk, whether in first or second-line treatment, had difficulty in feeding, sorafenib is a better choice for prolong mPFS.

Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis.

Metformin was proposed to be a candidate for host-directed therapy for COVID-19. However, its efficacy remains to be validated. In this study, we compared the outcome of metformin users and nonusers in hospitalized COVID-19 patients with diabetes. Hospitalized diabetic patients with confirmed COVID-19 in the Tongji Hospital of Wuhan, China, from January 27, 2020 to March 24, 2020, were grouped into metformin and no-metformin groups according to the diabetic medications used. The demographics, characteristics, laboratory parameters, treatments, and clinical outcome in these patients were retrospectively assessed. A total of 283 patients (104 in the metformin and 179 in the no-metformin group) were included in this study. There were no significant differences between the two groups in gender, age, underlying diseases, clinical severity, and oxygen-support category at admission. The fasting blood glucose level of the metformin group was higher than that of the no-metformin group at admission and was under effective control in both groups after admission. Other laboratory parameters at admission and treatments after admission were not different between the two groups. The length of hospital stay did not differ between the two groups (21.0 days for metformin versus 19.5 days for no metformin, P = 0.74). However, in-hospital mortality was significantly lower in the metformin group (3/104 (2.9%) versus 22/179 (12.3%), P = 0.01). Antidiabetic treatment with metformin was associated with decreased mortality compared with diabetics not receiving metformin. This retrospective analysis suggests that metformin may offer benefits in patients with COVID-19 and that further study is indicated.

Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma.

Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application.

Gold nanoparticles delivered miR-375 for treatment of hepatocellular carcinoma.

MiR-375 is a tumor suppressor miRNA that is downregulated in hepatocellular carcinoma (HCC). However, due to the lack of effective delivery strategies, miR-375 replacement as a therapy for HCC has not been investigated. In the present study, we have developed a straightforward strategy to deliver miR-375 into HCC cells by assembling miR-375 mimics on the surface of AuNPs and forming AuNP-miR-375 nanoparticles. AuNP-miR-375 exhibits high cellular uptake and preserves miR-375's activities to suppress cellular proliferation, migration/invasion, and colony formation, and to induce apoptosis in HCC cells. Furthermore, AuNP-delivered miR-375 efficiently downregulated its target genes through RNA interference. In primary and xenograft tumor mouse models, AuNP-miR-375 showed high tumor uptake, therapeutic efficacy, and no apparent toxicity to the host mice. In conclusion, our findings indicate that AuNPs is a reliable strategy to deliver miR-375 into HCC cells and tissue, and that AuNP-miR-375 has the potential in the clinic for treatment of unresectable HCC.

Anti-tumor Efficiency of Lipid-coated Cisplatin Nanoparticles Co-loaded with MicroRNA-375.

One of the major challenges in the hepatocellular carcinoma (HCC) treatment is its insensitivity to chemotherapeutic drugs. Here, we report the development of novel lipid-coated cisplatin nanoparticles co-loaded with microRNA-375 (NPC/miR-375) as a potential treatment for chemotherapy insensitive HCC. The NPC/miR-375 was fabricated by mixing two reverse microemulsions containing KCl solution and a highly soluble cis-diaminedihydroplatinum (II) coated with a cationic lipid layer. Subsequently, the miR-375 was incorporated into the lipid-coated cisplatin nanoparticles. The NPC/miR375 nanoparticles were expected to further decrease cell proliferation and to enhance the anti-tumor effect of cisplatin in chemotherapy resistant HCC cells. In vitro analysis of intracellular trafficking revealed that NPC/miR-375 were able to escape from the late endosomes instead of lysosomes thus avoiding degradation of the miR-375 in lysosomes. Importantly, NPC/miR-375 enhanced apoptosis and induced cell cycle arrest in HCC cells in vitro. In the double oncogenes Akt/Ras-induced primary HCC mouse model, multiple doses of NPC/miR-375 significantly inhibited tumor growth and delayed the tumor relapse. Our results indicate that cisplatin nanoparticles co-loaded with miR-375 represent a potential therapeutic agent for chemotherapy-insensitive HCC.