KDM6A-SND1 interaction maintains genomic stability by protecting the nascent DNA and contributes to cancer chemoresistance.

Genomic instability is one of the hallmarks of cancer. While loss of histone demethylase KDM6A increases the risk of tumorigenesis, its specific role in maintaining genomic stability remains poorly understood. Here, we propose a mechanism in which KDM6A maintains genomic stability independently on its demethylase activity. This occurs through its interaction with SND1, resulting in the establishment of a protective chromatin state that prevents replication fork collapse by recruiting of RPA and Ku70 to nascent DNA strand. Notably, KDM6A-SND1 interaction is up-regulated by KDM6A SUMOylation, while KDM6AK90A mutation almost abolish the interaction. Loss of KDM6A or SND1 leads to increased enrichment of H3K9ac and H4K8ac but attenuates the enrichment of Ku70 and H3K4me3 at nascent DNA strand. This subsequently results in enhanced cellular sensitivity to genotoxins and genomic instability. Consistent with these findings, knockdown of KDM6A and SND1 in esophageal squamous cell carcinoma (ESCC) cells increases genotoxin sensitivity. Intriguingly, KDM6A H101D & P110S, N1156T and D1216N mutations identified in ESCC patients promote genotoxin resistance via increased SND1 association. Our finding provides novel insights into the pivotal role of KDM6A-SND1 in genomic stability and chemoresistance, implying that targeting KDM6A and/or its interaction with SND1 may be a promising strategy to overcome the chemoresistance.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Image Guided Energy Ablation for Palliation of Painful Bony Metastases - A Systematic Review.

PURPOSE: To analyze the effectiveness of image-guided energy ablation techniques with and without concurrent therapies in providing palliative pain relief in patients with bone metastases. MATERIALS AND METHODS: OVID Embase, OVID Medline, and Pubmed were searched from inception to April 14th, 2023 using search terms relating to bone lesions and MeSH terms regarding ablation therapy. English peer-reviewed primary articles were included that reported pain scores following image-guided energy-based ablation of bone metastases. Exclusion criteria included 1) non-palliative treatment, 2) pain scores associated with specific treatment modalities not reported, and 3) non-metastatic bone lesions. Mean percentage reduction in pain score was calculated. RESULTS: 1396 studies were screened and 54 were included. All but one study demonstrated decreased pain scores at final follow-up. Mean reduction in pain scores at final follow-up were 49% for radiofrequency ablation (RFA), 58% for radiofrequency ablation and adjunct (RFA-A), 54% for cryoablation (CA), 72% for cryoablation and adjunct (CA-A), 48% for microwave ablation (MWA), 81% for microwave ablation and adjunct (MWA-A), and 64% for high-intensity focused ultrasound (HIFU). Post-procedural adverse event rates were 4.9% for RFA, 34.8% for RFA-A, 9.6% for CA, 12.0% for CA-A, 48.9% for MWA, 33.5% for MWA-A and 17.0% for HIFU. CONCLUSION: Image-guided energy ablation demonstrated consistently strong reduction in pain across all modalities, with variable post-procedural adverse event rates. Due to heterogeneity of included studies, quantitative analysis was not appropriate. Future primary research should focus on creating consistent prospective studies with established statistical power, explicit documentation and comparison to other techniques.

Dielectric engineered graphene transistors for high-performance near-infrared photodetection.

Graphene, known for its ultrahigh carrier mobility and broadband optical absorption, holds significant potential in optoelectronics. However, the carrier mobility of graphene on silicon substrates experienced a marked decrease due to surface roughness, phonon scattering affects. Here we report carrier mobility enhancement of graphene dielectric engineering. Through the fabrication of devices utilizing Si/SiO2/Al2O3/graphene layers and subsequent electrical characterization, our findings illustrate the navigable nature of the Al2O3 dielectric layer is navigable for reducing the SiO2 phonon scattering and increasing graphene's carrier mobility by up to ∼8000 cm2V-1s-1. Furthermore, the improvement in carrier mobility of graphene has been utilized in the hybrid near-infrared photodetector, resulting in outstanding responsivity of ∼400 AW-1, detectivity of ∼2.2 ✕ 1011 Jones in the graphene/Ag2Te detector. Our study establishes pathways for the seamless integration of graphene or other 2D materials within the standard CMOS processes, thereby facilitating the fabrication of advanced optoelectronic devices.

Dbl family RhoGEFs in cancer: different roles and targeting strategies.

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.

HIF-1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid-induced osteonecrosis of the femoral head.

With the prevalence of coronavirus disease 2019, the administration of glucocorticoids (GCs) has become more widespread. Treatment with high-dose GCs leads to a variety of problems, of which steroid-induced osteonecrosis of the femoral head (SONFH) is the most concerning. Since hypoxia-inducible factor 1α (HIF-1α) is a key factor in cartilage development and homeostasis, it may play an important role in the development of SONFH. In this study, SONFH models were established using methylprednisolone (MPS) in mouse and its proliferating chondrocytes to investigate the role of HIF-1α in cartilage differentiation, extracellular matrix (ECM) homeostasis, apoptosis and glycolysis in SONFH mice. The results showed that MPS successfully induced SONFH in vivo and vitro, and MPS-treated cartilage and chondrocytes demonstrated disturbed ECM homeostasis, significantly increased chondrocyte apoptosis rate and glycolysis level. However, compared with normal mice, not only the expression of genes related to collagens and glycolysis, but also chondrocyte apoptosis did not demonstrate significant differences in mice co-treated with MPS and HIF-1α inhibitor. And the effects observed in HIF-1α activator-treated chondrocytes were similar to those induced by MPS. And HIF-1α degraded collagens in cartilage by upregulating its downstream target genes matrix metalloproteinases. The results of activator/inhibitor of endoplasmic reticulum stress (ERS) pathway revealed that the high apoptosis rate induced by MPS was related to the ERS pathway, which was also affected by HIF-1α. Furthermore, HIF-1α affected glucose metabolism in cartilage by increasing the expression of glycolysis-related genes. In conclusion, HIF-1α plays a vital role in the pathogenesis of SONFH by regulating ECM homeostasis, chondrocyte apoptosis, and glycolysis.

Assessment of Hepatic Lesions After non-Thermal Tumor Ablation by Irreversible Electroporation in a Pig Model.

Irreversible electroporation (IRE) is a non-thermal and minimal invasive modality to ablate pathologic lesions such as hepatic tumors. Histological analysis of the initial lesions after IRE can help predict ablation efficacy. We aimed to investigate the histological characteristics of early hepatic lesions after IRE application using animal models. IRE (1500 V/cm, a pulse length of 100 µs, 60 or 90 pulses) was applied to the liver of miniature pigs. H&E and TUNEL staining were performed and analyzed. Ablated zones of pig liver were discolored and separated from the normal zone after IRE. Histologic characteristics of ablation zones included preserved hepatic lobular architecture with a unique hexagonal-like structure. Apoptotic cells were detected, and sinusoidal dilatation and blood congestion were observed, but hepatic arteries and bile ducts were intact around the ablation zones. The early lesions obtained by delivering monophasic square wave pulses through needle electrodes reflected typical histological changes induced by IRE. Therefore, it was found that the histological assessment of the early hepatic lesion after IRE can be utilized to predict the IRE ablation effect.

Ferroptosis regulation by methylation in cancer.

Epigenetic regulation plays a critical role in cancer development and progression. Methylation is an important epigenetic modification that influences gene expression by adding a methyl group to nucleic acids and proteins. Ferroptosis is a new form of regulated cell death triggered by the accumulation of iron and lipid peroxidation. Emerging evidence have shown that methylation regulation plays a significant role in the regulation of ferroptosis in cancer. This review aims to explore the methylation regulation of ferroptosis in cancer, including reactive oxygen species and iron bio-logical activity, amino acid and lipid metabolism, and drugs interaction. The findings of this review may provide new insights and strategies for the prevention and treatment of cancer.

FXR agonist GW4064 enhances anti-PD-L1 immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is one of the top three malignant tumors in terms of morbidity, and the limited efficacy of existing therapies urges the discovery of potential treatment strategies. Immunotherapy gradually becomes a promising cancer treatment method in recent decades; however, less than 10% of CRC patients could really benefit from immunotherapy. It is pressing to explore the potential combination therapy to improve the immunotherapy efficacy in CRC patients. It is reported that Farnesoid X receptor (FXR) is deficiency in CRC and associated with immunity. Herein, we found that GW4064, a FXR agonist, could induce apoptosis, block cell cycle, and mediate immunogenic cell death (ICD) of CRC cells in vitro. Disappointingly, GW4064 could not suppress the growth of CRC tumors in vivo. Further studies revealed that GW4064 upregulated PD-L1 expression in CRC cells via activating FXR and MAPK signaling pathways. Gratifyingly, the combination of PD-L1 antibody with GW4064 exhibited excellent anti-tumor effects in CT26 xenograft models and increased CD8+ T cells infiltration, with 33% tumor bearing mice cured. This paper illustrates the potential mechanisms of GW4064 to upregulate PD-L1 expression in CRC cells and provides important data to support the combination therapy of PD-L1 immune checkpoint blockade with FXR agonist for CRC patients.

Research on Data Poisoning Attack against Smart Grid Cyber-Physical System Based on Edge Computing.

Data poisoning attack is a well-known attack against machine learning models, where malicious attackers contaminate the training data to manipulate critical models and predictive outcomes by masquerading as terminal devices. As this type of attack can be fatal to the operation of a smart grid, addressing data poisoning is of utmost importance. However, this attack requires solving an expensive two-level optimization problem, which can be challenging to implement in resource-constrained edge environments of the smart grid. To mitigate this issue, it is crucial to enhance efficiency and reduce the costs of the attack. This paper proposes an online data poisoning attack framework based on the online regression task model. The framework achieves the goal of manipulating the model by polluting the sample data stream that arrives at the cache incrementally. Furthermore, a point selection strategy based on sample loss is proposed in this framework. Compared to the traditional random point selection strategy, this strategy makes the attack more targeted, thereby enhancing the attack's efficiency. Additionally, a batch-polluting strategy is proposed in this paper, which synchronously updates the poisoning points based on the direction of gradient ascent. This strategy reduces the number of iterations required for inner optimization and thus reduces the time overhead. Finally, multiple experiments are conducted to compare the proposed method with the baseline method, and the evaluation index of loss over time is proposed to demonstrate the effectiveness of the method. The results show that the proposed method outperforms the existing baseline method in both attack effectiveness and overhead.

Notch-RBPJ Pathway for the Differentiation of Bone Marrow Mesenchymal Stem Cells in Femoral Head Necrosis.

Femoral head necrosis (FHN) is a common leg disease in broilers, resulting in economic losses in the poultry industry. The occurrence of FHN is closely related to the decrease in the number of bone marrow mesenchymal stem cells (BMSCs) and the change in differentiation direction. This study aimed to investigate the function of differentiation of BMSCs in the development of FHN. We isolated and cultured BMSCs from spontaneous FHN-affected broilers and normal broilers, assessed the ability of BMSCs into three lineages by multiple staining methods, and found that BMSCs isolated from FHN-affected broilers demonstrated enhanced lipogenic differentiation, activated Notch-RBPJ signaling pathway, and diminished osteogenic and chondrogenic differentiation. The treatment of BMSCs with methylprednisolone (MP) revealed a significant decrease in the expressions of Runx2, BMP2, Col2a1 and Aggrecan, while the expressions of p-Notch1/Notch1, Notch2 and RBPJ were increased significantly. Jagged-1 (JAG-1, Notch activator)/DAPT (γ-secretase inhibitor) could promote/inhibit the osteogenic or chondrogenic ability of MP-treated BMSCs, respectively, whereas the differentiation ability of BMSCs was restored after transfection with si-RBPJ. The above results suggest that the Notch-RBPJ pathway plays important role in FHN progression by modulating the osteogenic and chondrogenic differentiation of BMSCs.

Epidemiological features and trends in the mortality rates of 10 notifiable respiratory infectious diseases in China from 2004 to 2020: Based on national surveillance.

Objectives: The aim of this study is to describe, visualize, and compare the trends and epidemiological features of the mortality rates of 10 notifiable respiratory infectious diseases in China from 2004 to 2020. Setting: Data were obtained from the database of the National Infectious Disease Surveillance System (NIDSS) and reports released by the National and local Health Commissions from 2004 to 2020. Spearman correlations and Joinpoint regression models were used to quantify the temporal trends of RIDs by calculating annual percentage changes (APCs) in the rates of mortality. Results: The overall mortality rate of RIDs was stable across China from 2004 to 2020 (R = -0.38, P = 0.13), with an APC per year of -2.2% (95% CI: -4.6 to 0.3; P = 0.1000). However, the overall mortality rate of 10 RIDs in 2020 decreased by 31.80% (P = 0.006) compared to the previous 5 years before the COVID-19 pandemic. The highest mortality occurred in northwestern, western, and northern China. Tuberculosis was the leading cause of RID mortality, and mortality from tuberculosis was relatively stable throughout the 17 years (R = -0.36, P = 0.16), with an APC of -1.9% (95% CI -4.1 to 0.4, P = 0.1000). Seasonal influenza was the only disease for which mortality significantly increased (R = 0.73, P = 0.00089), with an APC of 29.70% (95% CI 16.60-44.40%; P = 0.0000). The highest yearly case fatality ratios (CFR) belong to avian influenza A H5N1 [687.5 per 1,000 (33/48)] and epidemic cerebrospinal meningitis [90.5748 per 1,000 (1,010/11,151)]. The age-specific CFR of 10 RIDs was highest among people over 85 years old [13.6551 per 1,000 (2,353/172,316)] and was lowest among children younger than 10 years, particularly in 5-year-old children [0.0552 per 1,000 (58/1,051,178)]. Conclusions: The mortality rates of 10 RIDs were relatively stable from 2004 to 2020 with significant differences among Chinese provinces and age groups. There was an increased mortality trend for seasonal influenza and concerted efforts are needed to reduce the mortality rate of seasonal influenza in the future.

Geographical patterns of Fejervarya limnocharis gut microbiota by latitude along mainland China's coastline.

The gut microbiota affects many aspects of host biology and plays key roles in the coevolutionary association with its host. Geographical gradients may play a certain role on gut microbiota variation in the natural environment. However, the distribution pattern of amphibian gut microbiota in the latitudinal gradient remains largely unexplored. Here, we sampled six natural populations of Fejervarya limnocharis along the eastern coastline of mainland China (spanning 20°-30° N = 1,300 km) using 16S rRNA amplicon sequencing to characterize the gut microbiota. First of all, a significant correlation between gut microbial diversity and latitude was observed in our research system. Second, we discovered that latitude influenced the composition of the gut microbiota of F. limnocharis. Finally, we detected that geographical distance could not determine gut microbiota composition in F. limnocharis. These results indicate that latitude can play an important role in shaping the gut microbial diversity of amphibian. Our study offers the first evidence that gut microbial diversity of amphibian presents a latitudinal pattern and highlights the need for increased numbers of individuals to be sampled during microbiome studies in wild populations along environmental gradients.

Effects of Simvastatin on Cartilage Homeostasis in Steroid-Induced Osteonecrosis of Femoral Head by Inhibiting Glucocorticoid Receptor.

Steroid-induced osteonecrosis of femoral head (SONFH) is one of the most common bone disorders in humans. Statin treatment is beneficial in preventing the development of SONFH through anti-inflammation effects and inhibition of the glucocorticoid receptor (GR). However, potential mechanisms of statin action remain to be determined. In this study, pulse methylprednisolone (MP) treatment was used to induce SONFH in broilers, and then MP-treated birds were administrated with simvastatin simultaneously to investigate the changes in cartilage homeostasis. Meanwhile, chondrocytes were isolated, cultured, and treated with MP, simvastatin, or GR inhibitor in vitro. The changes in serum homeostasis factors, cell viability, and expression of GR were analyzed. The results showed that the morbidity of SONFH in the MP-treated group increased significantly compared with the simvastatin-treated and control group. Furthermore, MP treatment induced apoptosis and high-level catabolism and low-level anabolism in vitro and vivo, while simvastatin significantly decreased catabolism and slightly recovered anabolism via inhibiting GR and the hypoxia-inducible factor (HIF) pathway. The GR inhibitor or its siRNA mainly affected the catabolism of cartilage homeostasis in vitro. In conclusion, the occurrence of SONFH in broilers was related to the activation of GR and HIF pathway, and imbalance of cartilage homeostasis. Simvastatin and GR inhibitor maintained cartilage homeostasis via GR and the HIF pathway.

Downregulation of miR-30b-5p Facilitates Chondrocyte Hypertrophy and Apoptosis via Targeting Runx2 in Steroid-Induced Osteonecrosis of the Femoral Head.

As a widely used steroid hormone medicine, glucocorticoids have the potential to cause steroid-induced osteonecrosis of the femoral head (SONFH) due to mass or long-term use. The non-coding RNA hypothesis posits that they may contribute to the destruction and dysfunction of cartilages as a possible etiology of SONFH. MiR-30b-5p was identified as a regulatory factor in cartilage degeneration caused by methylprednisolone (MPS) exposure in our study through cell transfection. The luciferase reporter assay confirmed that miR-30b-5p was downregulated and runt-related transcription factor 2 (Runx2) was mediated by miR-30b-5p. The nobly increased expression of matrix metallopeptidase 13 (MMP13) and type X collagen (Col10a1) as Runx2 downstream genes contributed to the hypertrophic differentiation of chondrocytes, and the efficiently upregulated level of matrix metallopeptidase 9 (MMP9) may trigger chondrocyte apoptosis with MPS treatments. The cell transfection experiment revealed that miR-30b-5p inhibited chondrocyte hypertrophy and suppressed MPS-induced apoptosis. As a result, our findings showed that miR-30b-5p modulated Runx2, MMP9, MMP13, and Col10a1 expression, thereby mediating chondrocyte hypertrophic differentiation and apoptosis during the SONFH process. These findings revealed the mechanistic relationship between non-coding RNA and SONFH, providing a comprehensive understanding of SONFH and other bone diseases.

Psychrophilic phage VSW-3 RNA polymerase reduces both terminal and full-length dsRNA byproducts in in vitro transcription.

RNA research and applications are underpinned by in vitro transcription (IVT), but RNA impurities resulting from the enzymatic reagents severely impede downstream applications. To improve the stability and purity of synthesized RNA, we have characterized a novel single-subunit RNA polymerase (RNAP) encoded by the psychrophilic phage VSW-3 from a plateau lake. The VSW-3 RNAP is capable of carrying out in vitro RNA synthesis at low temperatures (4-25°C). Compared to routinely used T7 RNAP, VSW-3 RNAP provides a similar yield of transcripts but is insensitive to class II transcription terminators and synthesizes RNA without redundant 3'-cis extensions. More importantly, through dot-blot detection with the J2 monoclonal antibody, we found that the RNA products synthesized by VSW-3 RNAP contained a much lower amount of double-stranded RNA byproducts (dsRNA), which are produced by transcription from both directions and are significant in T7 RNAP IVT products. Taken together, the VSW-3 RNAP almost eliminates both terminal loop-back dsRNA and full-length dsRNA in IVT and thus is especially advantageous for producing RNA for in vivo use.

Pheophorbide A and SN38 conjugated hyaluronan nanoparticles for photodynamic- and cascadic chemotherapy of cancer stem-like ovarian cancer.

In this study, we designed photo-triggered reactive oxygen species (ROS)-generating pheophorbide A and ROS-cleavable thioketal-SN38 conjugated hyaluronan-cholesterol nanoparticles (PheoA-SN38-HC NPs). And we observed the combined therapeutic effects of PheoA-SN38-HC NPs against HEY-T30 human ovarian cancer (OC) model. Clinical Proteomic Tumor Analysis Consortium (CPTAC) data showed that the expression of cancer stem cell (CSC) markers (CD44, ALDH1A1, and CD117) is highly associated with poor clinical outcomes in OC patients. We proved that HEY-T30 cells overexpress CSC markers and much more invasive than other cancer cells. Flow cytometry (FACS) and microscopic analysis revealed the active targeting property of PheoA-SN38-HC NPs to CD44+ HEY-T30 cells. Moreover, the combination therapeutic effect of PheoA-SN38-HC NPs was clearly demonstrated against in vitro HEY-T30 cells and an in vivo xenograft mouse model. In particular, the paracrine cytotoxic effect of SN38 probably compensates the locoregional therapeutic limitation of photodynamic therapy.

Changes in Kidney Fat upon Dietary-Induced Weight Loss.

As the metabolic role of kidney fat remains unclear, we investigated the effects of dietary weight loss on kidney fat content (KFC) and its connection to kidney function and metabolism. Overweight or obese participants (n = 137) of a dietary intervention trial were classified into quartiles of weight loss in a post hoc manner. Kidney sinus (KSF) and cortex fat (KCF) were measured by magnetic resonance imaging at baseline, week 12 and week 50. Weight loss effects on KFC were evaluated by linear mixed models. Repeated measures correlations between KFC, other body fat measures and metabolic biomarkers were obtained. KSF, but not KCF, decreased significantly across weight loss quartiles at week 12 (quartile 4: -21.3%; p = 0.02) and 50 (-22.0%, p = 0.001), which remained significant after adjusting for VAT. There were smaller improvements regarding creatinine (-2.5%, p = 0.02) at week 12, but not week 50. KSF, but not KCF, correlated with visceral (rrm = 0.38) and subcutaneous fat volumes (rrm = 0.31) and liver fat content (rrm = 0.32), as well as diastolic blood pressure and biomarkers of lipid, glucose and liver metabolism. Dietary weight loss is associated with decreases in KSF, but not KCF, which suggests that KSF may be the metabolically relevant ectopic fat depot of the kidney. KSF may be targeted for obesity-related disease prevention.

Enhanced thermodynamic, pharmacokinetic and theranostic properties of polymeric micelles via hydrophobic core-clustering of superparamagnetic iron oxide nanoparticles.

BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIO) have been applied for decades to design theranostic polymeric micelles for targeted cancer therapy and diagnostic MR imaging. However, the effects of SPIO on the physicochemical, and biological properties of polymeric micelles have not yet been fully elucidated. Therefore, we investigated potential effect of SPIO on the physical and biological properties of theranostic polymeric micelles using representative cancer drug (doxorubicin; Doxo) and polymer carrier (i.e., poly (ethylene glycol)-co-poly(D,L-lactide), PEG-PLA). METHODS: SPIO were synthesized from Fe(acetyl acetonate)3 in an aryl ether. SPIO and Doxo were loaded into the polymeric micelles by a solvent-evaporation method. We observed the effect of SPIO-clustering on drug loading, micelle size, thermodynamic stability, and theranostic property of PEG-PLA polymeric micelles. In addition, cellular uptake behaviors, pharmacokinetic and biodistribution study were performed. RESULTS: SPIO formed hydrophobic geometric cavity in the micelle core and significantly affected the integrity of micelles in terms of micelle size, Doxo loading, critical micelle concentration (CMC) and in vitro dissociation. In vivo pharmacokinetic studies also showed the enhanced Area Under Curve (AUC) and elongated the half-life of Doxo. CONCLUSIONS: Clustered SPIO in micelles largely affects not only MR imaging properties but also biological and physical properties of polymeric micelles.

Retinoic acid-conjugated chitosan/manganese porphyrin ionic-complex nanoparticles for improved T1 contrast MR imaging of hepatic fibrosis.

Noninvasive and precise diagnosis of hepatic fibrosis is very important for the preventive therapeutic regimen of hepatic cirrhosis and cancer. In this study, we fabricated T1 contrast Mn-porphyrin (MnTPPS4 )/retinoic acid-chitosan ionic-complex nanoparticles (MRC NPs). The functional properties of MRC NPs were evaluated via transmission electron microscopy (TEM) imaging, release study, cytotoxicity assay, hepatocyte-specific uptake assay, and magnetic resonance (MR) imaging study. TEM images confirmed the typical structure of an ionic-complex NPs with around 100-200 nm of diameter. MnTPPS4 is released from MRC NPs for up to 24 hr in controlled pattern which implies that more reliable and convenient hepatic MR imaging is possible using of MRC NPs in clinical practice. Hepatocytes uptake assay proved retinoic acid-specific targeting of MRC NPs. The same results were observed in animal pharmacokinetic studies. In vitro MR phantom study, MRC NPs showed an increased T1 relaxivity (r1  = 6.772 mM-1  s-1 ) in comparison with 3.242 mM-1  s-1 of MnTPPS4 . The result was confirmed again in vivo MR imaging studies. Taken together, MRC NPs displayed a potential for noninvasive diagnostic T1 MR imaging of hepatic fibrosis with improved target specificity and prolonged MR imaging time window.