Association between triglyceride glucose index and risk of cerebrovascular disease: systematic review and meta-analysis.

BACKGROUND: The triglyceride glucose (TyG) index, which is a new surrogate indicator of insulin resistance (IR), is thought to be associated with many diseases, such as cardiovascular disease, but its relationship with cerebrovascular disease is still controversial. METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science and Medline databases were searched until March 2022 to evaluate the association between the TyG index and cerebrovascular disease risk. A random‒effects model was used to calculate the effect estimates and 95% confidence intervals (CIs). RESULTS: A total of 19 cohort studies and 10 case‒control/cross‒sectional studies were included in our study, which included 11,944,688 participants. Compared with a low TyG index, a higher TyG index increased the risk of cerebrovascular disease (RR/HR = 1.22, 95% CI [1.14, 1.30], P< 0.001; OR = 1.15, 95% CI [1.07, 1.23], P< 0.001). Furthermore, the results of the dose-response analysis of the cohort study demonstrated that the risk of cerebrovascular disease increased by 1.19 times per 1 mg/dl increment of the TyG index (relative risk = 1.19, 95% CI [1.13,1.25], P< 0.001). CONCLUSION: TyG index is related to cerebrovascular disease. More data and basic research are needed to confirm the association.

Intestinal Microbiota Is Altered in Patients with Gastric Cancer from Shanxi Province, China.

BACKGROUND: Many diseases have been associated with intestinal microbial dysbiosis. Host-microbial interactions regulate immune function, which influences the development of gastric cancer. AIMS: The aims were to investigate the characteristics of intestinal microbiota composition in gastric cancer patients and correlations between the intestinal microbiota and cellular immunity. METHODS: Fecal samples were collected from 116 gastric cancer patients and 88 healthy controls from Shanxi Province, China. The intestinal microbiota was investigated by 16S rRNA gene sequencing. Peripheral blood samples were also collected from the 66 gastric cancer patients and 46 healthy controls. The populations of peripheral T lymphocyte subpopulations and NK cells were analyzed by flow cytometry. RESULTS: The intestinal microbiota in gastric cancer patients was characterized by increased species richness, decreased butyrate-producing bacteria, and the enrichment of other symbiotic bacteria, especially Lactobacillus, Escherichia, and Klebsiella. Lactobacillus and Lachnospira were key species in the network of gastric cancer-associated bacterial genera. The combination of the genera Lachnospira, Lactobacillus, Streptococcus, Veillonella, and Tyzzerella_3 showed good performance in distinguishing gastric cancer patients from healthy controls. There was no significant difference in enterotype distribution between healthy controls and gastric cancer patients. The percentage of CD3+ T cells was positively correlated with the abundance of Lactobacillus and Streptococcus, and CD3+ T cells, CD4+ T cells, and NK cells were associated with Lachnospiraceae taxa. CONCLUSIONS: Our study revealed a dysbiotic intestinal microbiota in gastric cancer patients. The abundance of some intestinal bacterial genera was correlated with the population of peripheral immune cells.

iDNA-OpenPrompt: OpenPrompt learning model for identifying DNA methylation.

Introduction: DNA methylation is a critical epigenetic modification involving the addition of a methyl group to the DNA molecule, playing a key role in regulating gene expression without changing the DNA sequence. The main difficulty in identifying DNA methylation sites lies in the subtle and complex nature of methylation patterns, which may vary across different tissues, developmental stages, and environmental conditions. Traditional methods for methylation site identification, such as bisulfite sequencing, are typically labor-intensive, costly, and require large amounts of DNA, hindering high-throughput analysis. Moreover, these methods may not always provide the resolution needed to detect methylation at specific sites, especially in genomic regions that are rich in repetitive sequences or have low levels of methylation. Furthermore, current deep learning approaches generally lack sufficient accuracy. Methods: This study introduces the iDNA-OpenPrompt model, leveraging the novel OpenPrompt learning framework. The model combines a prompt template, prompt verbalizer, and Pre-trained Language Model (PLM) to construct the prompt-learning framework for DNA methylation sequences. Moreover, a DNA vocabulary library, BERT tokenizer, and specific label words are also introduced into the model to enable accurate identification of DNA methylation sites. Results and Discussion: An extensive analysis is conducted to evaluate the predictive, reliability, and consistency capabilities of the iDNA-OpenPrompt model. The experimental outcomes, covering 17 benchmark datasets that include various species and three DNA methylation modifications (4mC, 5hmC, 6mA), consistently indicate that our model surpasses outstanding performance and robustness approaches.

A dichotomy color quantization algorithm for the HSI color space.

Color quantization is used to obtain an image with the same number of pixels as the original but represented using fewer colors. Most existing color quantization algorithms are based on the Red Green Blue (RGB) color space, and there are few color quantization algorithms for the Hue Saturation Intensity (HSI) color space with a simple uniform quantization algorithm. In this paper, we propose a dichotomy color quantization algorithm for the HSI color space. The proposed color quantization algorithm can display images with a smaller number of colors than other quantization methods of RGB color space. The proposed algorithm has three main steps as follows: first, a single-valued monotonic function of the Hue (H) component in the from RGB color space to HSI color space (RGB-HSI) color space conversion is constructed, which can avoid the partition calculation of the H component in the RGB-HSI color space; second, an iterative quantization algorithm based on the single-valued monotonic function is proposed; and third, a dichotomy quantization algorithm is proposed to improve the iterative quantization algorithm. Both visual and numerical evaluations reveal that the proposed method presents promising quantization results.

[Changes in the proportion of lymphocyte subsets and the expression of surface receptors in peripheral blood of patients with colorectal cancer].

Objective To identify the sets of lymphocytes that could systematically evaluate immune function of colorectal cancer patients, based on the expression of colorectal cancer T cells, natural killer (NK) cells, and NKT cell surface protein receptors. Methods Peripheral blood samples from 144 patients with colorectal cancer and 87 healthy controls were collected, and the differences in surface receptors of lymphocyte subsets in peripheral blood of patients and healthy controls were analyzed by means of flow cytometry and cell culture. Results Compared with healthy control group, the percentage of peripheral blood total lymphocytes, CD16brightCD56dimNK cells and NKT cells decreased in patients with colorectal cancer. The percentage of T cells, CD16brightCD56dimNK cells and NKT cell surface inhibitory receptors T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) increased; T cells, NK cells, NKT cell surface chemokine receptor C-C motif chemokine receptor 7 (CCR7) slightly decreased. Conclusion There are differences in the proportion of NK cell subsets and the expression profile of surface receptors in peripheral blood of patients with colorectal cancer.

DRSN4mCPred: accurately predicting sites of DNA N4-methylcytosine using deep residual shrinkage network for diagnosis and treatment of gastrointestinal cancer in the precision medicine era.

Introduction: The DNA N4-methylcytosine (4mC) site levels of those suffering from digestive system cancers were higher, and the pathogenesis of digestive system cancers may also be related to the changes in DNA 4mC levels. Identifying DNA 4mC sites is a very important step in studying the analysis of biological function and cancer prediction. Extracting accurate features from DNA sequences is the key to establishing a prediction model of effective DNA 4mC sites. This study sought to develop a new predictive model, DRSN4mCPred, which aimed to improve the performance of the predicting DNA 4mC sites. Methods: The model adopted multi-scale channel attention to extract features and used attention feature fusion (AFF) to fuse features. In order to capture features information more accurately and effectively, this model utilized Deep Residual Shrinkage Network with Channel-Wise thresholds (DRSN-CW) to eliminate noise-related features and achieve a more precise feature representation, thereby, distinguishing the sites in DNA with 4mC and non-4mC. Additionally, the predictive model incorporated an inverted residual block, a Multi-scale Channel Attention Module (MS-CAM), a Bi-directional Long Short Term Memory Network (Bi-LSTM), AFF, and DRSN-CW. Results and Discussion: The results indicated the predictive model DRSN4mCPred had extremely good performance in predicting the DNA 4mC sites across different species. This paper will potentially provide support for the diagnosis and treatment of gastrointestinal cancer based on artificial intelligence in the precise medical era.

Does vitamin D have a potential role in precocious puberty? A meta-analysis.

Background: Precocious puberty, one of the common pediatric endocrine system diseases, has been related to reduced adult height, adverse psychological outcomes and long-term health consequences. Previous findings have found that low levels of vitamin D appear to be associated with the characteristics of precocious puberty such as early menarche. However, the effect of vitamin D on precocious puberty remains controversial. Methods: The published literature was searched from PubMed, Web of Science, Cochrane Library, MEDLINE, EMBASE, CNKI, Wan Fang and VIP databases up to October 2022. A randomized effect model was used to perform a meta-analysis to evaluate differences in vitamin D concentration between precocious puberty subjects and normal subjects, the risk of precocious puberty in subjects with low vitamin D levels, and the effect of supplementation of vitamin D on subjects with precocious puberty on medication. Results: Our study found that precocious puberty subjects had lower serum vitamin D levels than the normal population (standardized mean difference (SMD) = -1.16 ng ml-1 and 95% confidence interval (CI) = -1.41 and -0.91 ng ml-1). Meanwhile, the lower level of vitamin D was associated with the risk of precocious puberty (odd ratio (OR) = 2.25 and 95% CI = 1.66 and 3.04). Moreover, compared with gonadotropin-releasing hormone analogue (GnRHa) intervention alone, subjects receiving GnRHa + vitamin D intervention had significantly lower luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels and bone age, and higher predicted adult height (PAH). Conclusions: Vitamin D may have a potential role in precocious puberty and more data from large clinical trials are needed to confirm the findings.

The Diagnostic and Prognostic Value of the Triglyceride-Glucose Index in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): A Systematic Review and Meta-Analysis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has been related to a series of harmful health consequences. The triglyceride-glucose index (TyG index) appears to be associated with MAFLD. However, no consistent conclusions about the TyG index and incident MAFLD have been reached. PubMed, MEDLINE, Web of Science, EMBASE and the Cochrane Library were searched. Sensitivities, specificities and the area under the receiver operating characteristic (AUC) with a random-effects model were used to assess the diagnostic performance of the TyG index in NAFLD/MAFLD participants. Potential threshold effects and publication bias were evaluated by Spearman's correlation and Deeks' asymmetry test, respectively. A total of 20 studies with 165725 MAFLD participants were included. The summary receiver operator characteristic (SROC) curve showed that the sensitivity, specificity and AUC were 0.73 (0.69−0.76), 0.67 (0.65, 0.70) and 0.75 (0.71−0.79), respectively. Threshold effects (r = 0.490, p < 0.05) were confirmed to exist. Subgroup analyses and meta-regression showed that some factors including country, number of samples, age and disease situation were the sources of heterogeneity (p < 0.05). Our meta-analysis suggests that the TyG index can diagnose and predict MAFLD patients with good accuracy. The number of studies remains limited, and prospective studies are needed.

Association between triglyceride glucose index and risk of cancer: A meta-analysis.

Background: Triglyceride glucose (TyG) index as a more convenient and reliable predictor of insulin resistance (IR) is thought to be associated with many diseases, but its relationship with cancer remains unclear. Methods: The meta-analysis was conducted to evaluate the effects of TyG index on cancer risk utilizing the available evidence. PubMed, EMBASE, Medline, Cochrane Library and Web of Science were searched from their inception up to July 2022. A random-effects model was used to calculate the effect estimates and 95% confidence intervals (CIs). Results: A total of 6 observational studies met our inclusion criteria, which including 992292 participants. The meta-analysis indicated that the higher TyG index increased cancer risk compared to the lower TyG index group (total effect size =1.14, 95% CI [1.08, 1.20], P<0.001). Conclusions: Our meta-analysis found that higher TyG index may increase the risk of cancer. More prospective cohort studies and basic research are warranted to verify the relationship.

Reversal of epithelial-mesenchymal transition and inhibition of tumor stemness of breast cancer cells through advanced combined chemotherapy.

The abnormal activation of the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/ß-catenin signaling pathway-related genes (ß-catenin, LRP6, LEF1, and TCF12) and target genes (Cyclin D1, Cmyc, and Fibronectin) as well as CSC stemness-related genes (Oct4, Nanog, and Hes1) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression (E-cadherin and Vimentin) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and ß-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs), as an important part of tumor heterogeneity, can survive against conventional chemotherapy and initiate tumorigenesis, recurrence, and metastasis. Moreover, non-CSCs can convert into the CSC state through the abnormal Wnt/ß-catenin pathway, which is closely related to the epithelial-mesenchymal transition (EMT) process. Here, redox-degradable binary drug-loaded micelles (PPH/DOX+SL) were designed to target CSCs and overcome drug resistance of breast cancer cells. The combined chemotherapy of salinomycin (SL) and doxorubicin (DOX) reversed drug resistance, while the PPH/DOX+SL micelles enhanced the intracellular accumulation and drug penetration of BCSC spheres. The introduction of SL downregulated the expression of tumor stemness genes and the Wnt/ß-catenin pathway-related genes and inverted the EMT process. PPH/DOX+SL continuously inhibited tumor growth and invasion in vivo.

Nanohydroxyapatite Stimulates PD-L1 Expression to Boost Melanoma Combination Immunotherapy.

Although checkpoint-inhibitor immunotherapy held tremendous advances, improving immune response during treatment has always been an urgent clinical issue. With the help of mRNA microarray technology, it was found that short rod-like nanohydroxyapatite (nHA) promoted the upregulation of CD274 and PD-L1 related gene transcription, which was confirmed by the significantly enhanced PD-L1 expression level in B16, B16F10, and 4T1 cells in vitro. Hence, an injectable in situ responsive hydrogel reservoir embed with nHA and PD-1/PD-L1 inhibitor was engineered for a combination immunotherapy by peritumoral administration. The results confirmed that the combinational strategy effectively suppressed tumorigenesis and tumor growth, recovered the abnormal lactate dehydrogenase, aspartate transaminase, and alanine aminotransferase indicators, and significantly elongated the life span of a tumor-bearing mouse. The substantive progress mainly derived from nHA-induced T cell infiltration reinforcement in a tumor site and CD8+ T cell polarization in spleen, implying that nHA might function as an immunomodulator for melanoma immunotherapy.

Reductive responsive micelle overcoming multidrug resistance of breast cancer by co-delivery of DOX and specific antibiotic.

The residual tumor cells after chemotherapy, even in very small numbers, are generally drug-resistant and invasive, which might result in the progress of tumor metastasis and recurrence. In this research, a new combination chemotherapy strategy of salinomycin (SL) that could selectively inhibit multidrug-resistant tumor cells and a traditional broad-spectrum antitumor drug, doxorubicin (DOX), based on redox-degradable nano-micelles was developed to overcome drug resistance in vitro. The results in vitro indicated that DOX + SL co-loaded nano-micelles could not only escape from the drug efflux of adriamycin-resistant MCF-7 cells (A/MCF-7) but also penetrated and infiltrated into 3D-cultured MCF-7 and 4T1 tumor spheres in vitro more effectively, resulting in a strong antiproliferative effect. In the allogeneic metastatic 4T1 tumor model, the combination chemotherapy of DOX + SL encapsulated in nano-micelles effectively suppressed tumor growth with no splenomegaly and no other major tissue damage, and reversed the EMT progress, and inhibited tumor recurrence and metastasis more effectively after drug withdrawal.

Synergistic chemotherapeutic effect of sorafenib-loaded pullulan-Dox conjugate nanoparticles against murine breast carcinoma.

pH-Sensitive pullulan-doxorubicin conjugates encapsulating sorafenib (P-Dox/S) nanoparticles were developed as a synergistic combinatorial delivery system against murine breast carcinoma. The nanoparticles can encapsulate Dox and sorafenib with ultra-high loading capacity (65.34 wt%) through chemical conjugation and physical loading, whereas can remain stable under physiological conditions and gradually release Dox and sorafenib with the decreasing pH. These conjugates can be effectively internalized and clearly suppress 4T1 cell growth in vitro. Furthermore, research data of in vivo animal models revealed that the synergistic combinatorial P-Dox/S nanoparticles heavily accumulated in solid tumor tissue sites to maximize therapeutic efficacy; they also significantly inhibited solid tumor growth, even remarkably reduced solid tumor volume in comparison to the initial volume, and obviously diminished adverse effects. The anti-tumor therapeutic effect obviously outperformed the delivery of combinational chemotherapy of free drugs or single drug-loaded P-Dox nanoparticles at the same concentration. These promising results indicate the high-efficiency synergistic chemotherapeutic effects of these nanoparticles. Combinational chemotherapy using P-Dox/S nanoparticles has important potential in the clinical treatment of malignancy for overcoming drug resistance and heterogeneity.

Localized multidrug co-delivery by injectable self-crosslinking hydrogel for synergistic combinational chemotherapy.

Significant progress has been made in the use of injectable hydrogels as drug carrier systems to treat cancers by the peritumoral-localized co-delivery of multiple drugs with different therapeutic mechanisms. In this study, a novel, injectable self-crosslinking HA-SH hydrogel was able to concurrently encapsulate multiple drugs (sorafenib, doxorubicin, and metformin) to enhance chemotherapy efficacy. The hydrogel was relatively stable under physiological conditions and could quickly and directly release the loaded drugs to the tumor site in a reductive tumor microenvironment. The in vitro antitumor activity and cell-apoptosis assay demonstrated that the hydrogel loaded with multiple drugs (Gel + DS or Gel + DSM) showed obvious synergistic effects against breast cancer cells. The combinational chemotherapy enhanced the sensitivities of tumor cells and promoted tumor cell apoptosis after peritumoral administration. Compared with the single drug-loaded hydrogel, the hydrogel co-loaded with multiple drugs (Gel + DSM) showed the best tumor growth inhibition. Moreover, the monitoring of mice weight and ex vivo histological analysis of the main organs indicated that localized treatment with the hydrogel co-loaded with multiple drugs (Gel + DSM) obviously relieved the systemic toxicity and showed promise for inhibiting tumor metastasis, suggesting the superiority and potential application prospects of the injectable, self-crosslinking hydrogel co-loaded with multiple drugs.

Temperature and ion dual responsive biphenyl-dipeptide supramolecular hydrogels as extracellular matrix mimic-scaffolds for cell culture applications.

Stimuli-responsive supramolecular hydrogels composed of aromatic short peptide gelators have attracted intensive attention in the field of biomedicine because of their stable chemical structure, simple and convenient synthetic route and intelligent response to external stimuli. In this paper, several dipeptides were coupled to biphenylacetic acid (BPAA) to generate aromatic short peptide compounds through the standard solid phase peptide synthesis. These BPAA-dipeptide compounds presented clearly different gelation behaviors from the generally employed Fmoc-dipeptide and Nap-dipeptide compounds, but only BPAA-diphenylalanine was able to form homogeneous and transparent hydrogels through temperature switching or ion induction. Utilizing the biphenyl group not only expanded the scope of aromatic molecules serving as building blocks of aromatic short peptide gelators but also demonstrated the critical role of aromatic molecules in the self-assembling process. Moreover, supramolecular hydrogels initiated by heating-cooling or salt addition could be exploited as extracellular matrix (ECM) mimic scaffolds to support the adhesive growth and proliferation of L929 cells in 2D/3D culture under physiological conditions, demonstrating their potential applications in regenerative medicine.

Reduction-Degradable Polymeric Micelles Decorated with PArg for Improving Anticancer Drug Delivery Efficacy.

In this study, five kinds of reduction-degradable polyamide amine-g-polyethylene glycol/polyarginine (PAA-g-PEG/PArg) micelles with different proportions of hydrophilic and hydrophobic segments were synthesized as novel drug delivery vehicles. Polyarginine not only acted as a hydrophilic segment but also possessed a cell-penetrating function to carry out a rapid transduction into target cells. Polyamide amine-g-polyethylene glycol (PAA-g-PEG) was prepared for comparison. The characterization and antitumor effect of the DOX-incorporated PAA-g-PEG/PArg cationic polymeric micelles were investigated in vitro and in vivo. The cytotoxicity experiments demonstrated that the PAA-g-PEG/PArg micelles have good biocompatibility. Compared with DOX-incorporated PAA-g-PEG micelles, the DOX-incorporated PAA-g-PEG/PArg micelles were more efficiently internalized into human hepatocellular carcinoma (HepG2) cells and more rapidly released DOX into the cytoplasm to inhibit cell proliferation. In the 4T1-bearing nude mouse tumor models, the DOX-incorporated PAA-g-PEG/PArg micelles could efficiently accumulate in the tumor site and had a longer accumulation time and more significant aggregation concentration than those of PAA-g-PEG micelles. Meanwhile, it excellently inhibited the solid tumor growth and extended the survival period of the tumor-bearing Balb/c mice. These results could be attributed to their appropriate nanosize and the cell-penetrating peculiarity of polyarginine as a surface layer. The PAA-g-PEG/PArg polymeric micelles as a safe and high efficiency drug delivery system were expected to be a promising delivery carrier that targeted hydrophobic chemotherapy drugs to tumors and significantly enhanced antitumor effects.

DOX-encapsulated intelligent PAA-g-PEG/PEG-Fa polymeric micelles for intensifying antitumor therapeutic effect via active-targeted tumor accumulation.

Stimuli-responsive targeted polymeric micelles as drug delivery systems have recently attracted significant attention for the treatment of various cancers, which could improve delivery efficiency by tumor-specific recognition via active targeting strategies. In this research, DOX-incorporated bioreducible polymeric micelles based on PAA-g-PEG/PEG-Fa conjugated polymers were prepared and characterized as nanocarriers for promoting intracellular anti-tumor drug delivery efficiency via folate receptor-mediated endocytosis. The anti-proliferative activity on cancer cells, biodistribution, active-/passive-targeting efficiency, tumor growth inhibition efficiency, and biological toxicity were evaluated in vitro and in vivo. The MTT assay demonstrated that the DOX-encapsulated active-targeting PAA-g-PEG/PEG-Fa micelles had much greater growth inhibition effect against 4T1 and KB than passive-targeting micelles. These active-targeting micelles showed superior tumor accumulation and excellent tumor growth inhibition effect as revealed by the fluorescence optical imaging technique and tumor volume change investigation, as well as the survival study of the tumor-bearing Balb/c mice. Furthermore, the active targeting micelles greatly decreased the toxicity of DOX on the heart and other organs. These potential results encouraged us to further optimize the molecular structure to achieve more excellent targeted therapeutic effect.

Efficient Delivery of DOX to Nuclei of Hepatic Carcinoma Cells in the Subcutaneous Tumor Model Using pH-Sensitive Pullulan-DOX Conjugates.

A series of pullulan-doxorubicin conjugates (Pu-DOXs) were investigated for effectively delivering DOX to nuclei of hepatic carcinoma cells in subcutaneous tumor model. These Pu-DOXs were prepared by conjugating DOX onto pullulan molecule via pH-responsive hydrazone bond using spacers with different alkane chain length. The highest drug loading content of Pu-DOXs went up to nearly 50%, and the diameter of Pu-DOX nanoparticles ranged from 50 to 170 nm, as measured by DLS and TEM. These Pu-DOX nanoparticles could rapidly release DOX in the acidic environment at pH = 5.0 while being kept relatively stable in neural conditions. The in vitro cell coculture experiments revealed that these Pu-DOX nanoparticles were selectively internalized by hepatic carcinoma cells through receptor-mediated endocytosis via asialoglycoprotein receptor on the hepatic carcinoma cell surface. DOX was rapidly released from Pu-DOX nanoparticles in acidic endosome/lysosome, diffused into cell nuclei due to its strong affinity to nucleic acid, inhibited the cell proliferation, and accelerated the cell apoptosis. In the nude mice subcutaneous hepatic carcinoma model, Pu-DOX nanoparticles efficiently accumulated in the tumor site through the enhanced permeation and retention effect. Then DOX was specifically internalized by hepatic carcinoma cells and rapidly diffused into the nuclei of cells. Compared with the control group in in vivo experiments, these Pu-DOX nanoparticles effectively inhibited solid tumor growth, prolonging the lifetime of the experimental animal. These pH sensitive nanoparticles might provide an important clinical implication for targeted hepatic carcinoma therapy with high efficiency and low systematic toxicity.

Reduction breakable cholesteryl pullulan nanoparticles for targeted hepatocellular carcinoma chemotherapy.

In this study, a novel nanoparticulate drug delivery platform with inherent targeting ability to hepatic carcinoma cells and reduction-triggered drug release property was developed based on reducible cholesterol-modified pullulan (rCHP). The nanoparticle characteristics and antitumor effects were investigated in vitro and in vivo. The results revealed that drug-loaded rCHP nanoparticles were spherical and their diameter ranged between 80 and 160 nm with a change of molecular structure and drug loading content. rCHP nanoparticles with pullulan shells could anchor to human hepatocellular carcinoma cells (HepG2) due to specific recognition of asialoglycoprotein receptors (ASGPRs) overexpressing at the cytomembrane, reduction-sensitively release doxorubicin (DOX) in tumor cells, and effectively suppress the growth of HepG2 in vitro. In a hepatoma-bearing nude mouse model, attributed to their uncharged pullulan surface layer, the nanoparticles efficiently accumulated in the tumor site and were internalized by tumor cells. After cellular uptake, DOX release triggered by the reductive circumstance of tumor cells was achieved benefiting from the reduction-sensitive DOX release property. These nanoparticles showed significantly better antitumor effect and biosafety than DOX·HCl in the nude mice bearing hepatocellular carcinoma tumor.

Reduction-triggered breakable micelles of amphiphilic polyamide amine-g-polyethylene glycol for methotrexate delivery.

Reduction-triggered breakable polymeric micelles incorporated with MTX were prepared using amphiphilic PAA-g-PEG copolymers having S-S bonds in the backbone. The micelles were spherical with diameters less than 70 nm. The micelles could encapsulate the hydrophobic MTX in the hydrophobic core. The drug loading content and drug loading efficiency of the micelles were highly dependent on the copolymer chemical structure, ranging from 2.9 to 7.5% and 31.9 to 82.5%, respectively. Both the drug loading content and drug loading efficiency increased along with more hydrophobic segments in the copolymers. In normal circumstance, these micelles were capable of keeping stable and hold most of the MTX in the core, stabilizing the incorporated MTX through the π-π stacking with the phenyl groups in the backbone of the copolymers. In reductive environments that mimicked the intracellular compartments, the entire MTX payload could be quickly released due to the reduction-triggered breakage of the micelles. These micelles showed good antiproliferative activity against several cancer cell lines, including KB, 4T-1 and HepG2, especially within the low drug concentration scope.