Facile construction of drugs loaded lipid-coated calcium carbonate as a promising pH-Dependent drug delivery system for thyroid cancer treatment.

To develop innovative drug delivery carriers for controllable release and cancer-targeted delivery of therapeutic agents to accomplish efficient cancer chemotherapy. Herein we effectively fabricated CaCO3 primarily loaded biotin (BT) and directly the self-assembly of oxaliplatin (Pt (IV)) prodrugs form in liposomes. The acquired BT-Pt (IV)@PEG/CaCO3 with outstanding biological stability displays rapid pH-mediated degradations, thus allowing the effective pH-responsive delivery of BT. In vitro, anticancer assays proved that BT-Pt (IV)@PEG/CaCO3 effectively kills the thyroid cancer cells (B-CPAP and FTC-133). The biochemical staining assays investigated the morphological changes of thyroid cancer after treatment with nanoparticles. The DNA fragmentation of the cells was assessed by utilizing the comet assay. BT-Pt (IV)@PEG/CaCO3 increased ROS levels and caused mitochondrial membrane potential and DNA damage, which resulted in apoptosis. Due to its versatile drug-loading capability, this research demonstrates that CaCO3 liposomal formulation is a biocompatible and reliable substrate for establishing pH-mediated drug delivery methods and promising for possible therapeutic application.

Prognostic utility of preoperative inflammatory markers in patients with intrahepatic cholangiocarcinoma after hepatic resection: A systematic review and meta-analysis.

BACKGROUND: The prognostic value of preoperative systemic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), remains controversial in patients with intrahepatic cholangiocarcinoma (ICC). Therefore, this meta-analysis aimed to investigate the prognostic value of preoperative NLR, PLR, and LMR in patients with ICC who underwent hepatic resection. METHODS: We conducted a comprehensive search of four electronic databases. Two researchers assessed the quality of the available data using the Newcastle-Ottawa Scale. We selected overall survival (OS) as the primary outcome and recurrence-free survival (RFS) and disease-free survival (DFS) as secondary outcomes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were merged to evaluate the associations between inflammatory markers and ICC patient prognosis. RESULTS: Fifteen studies (18 cohorts) with 4123 cases were included in this meta-analysis. The results revealed that a high preoperative NLR was associated with short OS and RFS (HR = 1.04, 95% CI: 1.01-1.07, and HR = 1.29, 95% CI: 1.04-1.60, respectively) in patients with ICC. However, the association between PLR or LMR and ICC prognosis was not statistically significant. In addition, the publication bias and sensitivity analyses demonstrated that the results were reliable and stable. CONCLUSION: Our meta-analysis revealed that preoperative NLR may be a useful prognostic predictor for patients with ICC.

Predictive value of PD-L1 expression to the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer: A systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have been an emerging treatment strategy for advanced triple-negative breast cancer (TNBC). Some studies have shown that high expression of programmed death-ligand 1 (PD-L1) can achieve a better response of clinical efficacy. However, the efficacy of ICIs in advanced TNBC remains controversial. In this meta-analysis, we evaluated the correlation of PD-L1 expression with the efficacy of ICIs in patients with advanced TNBC. Methods: We conducted a systematic search using four databases until March 2022 to obtain eligible randomized controlled trials (RCTs). The quality of the studies was assessed by the Cochrane risk of bias tool. Hazard ratio (HR) was extracted to evaluate the relationship between PD-L1 expression and progression-free survival (PFS) or overall survival (OS) in patients with advanced TNBC. Results: Five randomized controlled clinical trials (RCTs) with 3104 patients were included in this meta-analysis. The results demonstrated that ICIs could significantly improve the OS (HR 0.77, 95% CI 0.60-0.98, p = 0.03) in PD-L1 positive TNBC group. In the subgroup analysis, longer OS was observed (HR: 0.70, 95% CI: 0.60-0.82, p = 0.00001) in PD-L1 positive TNBC patients receiving ICIs alone or ICIs combined with nab-paclitaxel. In terms of PFS, PFS was significantly improved (HR: 0.68, 95% CI: 0.58-0.79, p < 0.00001) in PD-L1 positive patients receiving first-line ICIs and chemotherapy compared to those with ICIs alone. No significant improvement was observed for OS or PFS in PD-L1 negative group. Conclusion: Our study indicated significant improvement for OS in advanced TNBC with ICIs therapy in the PD-L1 positive status, and ICIs alone or ICIs combined with nab-paclitaxel might be a excellent choice in terms of OS. Although PFS has no significant benefit in PD-L1 positive patients, the subgroup analysis showed that ICIs combined with chemotherapy could achieve the PFS benefit in the first-line treatment. However, further clinical studies are needed to validate our conclusions due to limited relevant research.

A UPLC-MS/MS method for simultaneous determination of eight special-grade antimicrobials in human plasma and application in TDM.

Linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin are eight special-grade antimicrobials commonly used for patients with severe infections. Changes in the pharmacodynamics and pharmacokinetics of critically ill patients severely affect the efficacy of antimicrobial drugs. Therefore, conventional or standard dosing regimens do not achieve satisfactory anti-infective effects. In the current study a simple and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneously determining the concentrations of the above-mentioned eight antimicrobials in human plasma only 3 min after one-step magnetic solid phase extraction pre-treatment. Multiple-reaction monitoring and positive ion modes were used for detection. The calibration curves were established over a concentration range of 0.1-25.0 µg/mL for teicoplanin, linezolid, micafungin, voriconazole, imipenem, igecyclin, and meropenem, and 0.2-50.0 µg/mL for vancomycin; the coefficient of correlation was > 0.9971 for all the compounds. The inter- and intra-day coefficients of variation were < 6.88% at the lower limit of quantification and quality control (QC) levels (low concentration-QC, medium concentration-QC, and high-concentration QC). The UPLC-MS/MS method was successfully used for clinical therapeutic drug monitoring of linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin for critically ill patients.

Microcystin-leucine arginine induces skin barrier damage and reduces resistance to pathogenic bacteria in Lithobates catesbeianus tadpoles.

Despite the importance of the skin mucosal barrier and commensal microbiota for the health of amphibians, the potential of environmental contaminants to disrupt the skin mucosal barrier and microbiota have rarely been studied in toxicology. In this study, tadpoles (Lithobates catesbeianus) were exposed to 0, 0.5, and 2 µg/L of microcystin-leucine arginine (MC-LR) for 30 days to explore the impacts of environmentally realistic MC-LR concentrations on the physical skin barrier, immune barrier, commensal microbiota, and skin resistance to pathogenic bacterial invasion. MC-LR exposure significantly reduced the collagen fibrils in the dermis of skin tissues and down-regulated tight junction and stratum corneum-related gene transcriptions, suggesting the damage caused by MC-LR to the physical barrier of the skin. Increased skin eosinophils and upregulated transcriptions of inflammation-related genes in the exposed tadpoles underline the development of skin inflammation resulting from MC-LR exposure even at environmentally realistic concentrations. Comparative transcriptome and immunobiochemical analyses found that antimicrobial peptides (Brevinin-1PLc, Brevinin-2GHc, and Ranatuerin-2PLa) and lysozyme were down-regulated in the exposed groups, while complement, pattern recognition receptor, and specific immune processes were up-regulated. However, the content of endotoxin lipopolysaccharide produced by bacteria increased in a dose-dependent pattern. The disc diffusion test showed a reduced ability of skin supernatant to inhibit pathogenic bacteria in the exposed groups. Analysis of microbial 16 S rRNA gene by high-throughput sequencing revealed that MC-LR interfered with the abundance, composition, and diversity of the skin commensal microbiota, which favored the growth of pathogen-containing genera Rhodococcus, Acinetobacter, and Gordonibacter. In summary, the current study provides the first clues about the impact of MC-LR on the integrity and function of skin barrier of amphibians. These new toxicological evidences can facilitate a more comprehensive evaluation of the ecological risk of MC-LR to amphibians.

Emerging nanomedicines of paclitaxel for cancer treatment.

Malignant tumor is still a leading threat to human health. Despite the rapid development of targeted therapeutic strategies, any treatment specifically acting on single target would inevitably suffer from tumor resistance, largely due to the genetic instability and variability of tumor cells. Thus, traditional therapies such as broad-spectrum chemotherapy would certainly occupy an important position in clinical cancer therapy. Nevertheless, most chemotherapeutic drugs have long been criticized for unsatisfactory therapeutic efficacy with severe off-target toxicity. Although several chemotherapeutic nanomedicines with improved therapeutic safety have been applied in clinics, the therapeutic outcomes still do not fulfill expectation. To address this challenge, enormous efforts have been devoted to developing novel nano-formulations for efficient delivery of chemotherapeutic drugs. Herein, we aim to outline the latest progression in the emerging nanomedicines of paclitaxel (PTX), with special attention to the functional nanocarriers, self-delivering prodrug-nanoassemblies and combination nanotherapeutics of PTX. Finally, the challenges and opportunities of these functional PTX nanomedicines in clinical translation are spotlighted.

Application of Bayesian network and regression method in treatment cost prediction.

Charging according to disease is an important way to effectively promote the reform of medical insurance mechanism, reasonably allocate medical resources and reduce the burden of patients, and it is also an important direction of medical development at home and abroad. The cost forecast of single disease can not only find the potential influence and driving factors, but also estimate the active cost, and tell the management and reasonable allocation of medical resources. In this paper, a method of Bayesian network combined with regression analysis is proposed to predict the cost of treatment based on the patient's electronic medical record when the amount of data is small. Firstly, a set of text-based medical record data conversion method is established, and in the clustering method, the missing value interpolation is carried out by weighted method according to the distance, which completes the data preparation and processing for the realization of data prediction. Then, aiming at the problem of low prediction accuracy of traditional regression model, this paper establishes a prediction model combined with local weight regression method after Bayesian network interpretation and classification of patients' treatment process. Finally, the model is verified with the medical record data provided by the hospital, and the results show that the model has higher prediction accuracy.

Prognostic Function of Programmed Cell Death-Ligand 1 in Esophageal Squamous Cell Carcinoma Patients Without Preoperative Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Studies investigating the correlation between the expression of programmed cell death-ligand 1 (PD-L1) and prognosis in patients with esophageal squamous cell carcinoma (ESCC) not receiving preoperative therapy have increased significantly, but conclusions remain inconclusive. Therefore, this study aimed to determine the association between clinical outcomes and expression of PD-L1 in ESCC patients without preoperative therapy. METHODS: We conducted a comprehensive literature search using four databases up to May 2020. Quality assessment was carried out according to the Newcastle-Ottawa Quality Assessment Scale (NOS). Hazard ratios (HRs) were used to analyze the association between PD-L1 expression with prognosis. Furthermore, we evaluated the correlation between PD-L1 and clinicopathological characteristics using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Twenty studies (19 publications) comprising 3,677 patients were included in this meta-analysis. We found that the expression of PD-L1 was not related to overall survival (OS, HR: 1.16, 95% CI: 0.94-1.42, p = 0.16) or disease-free survival (DFS, HR: 0.85, 95% CI: 0.66-1.10, p = 0.21) in ESCC. Furthermore, although PD-L1 expression was not significantly associated with sex, degree of differentiation, TNM stage, T stage, lymph node status, smoking, or alcohol use, the merged OR demonstrated that the expression of PD-L1 was higher in older patients compared to younger patients (OR: 1.40, 95% CI: 1.07-1.83, p = 0.01). No obvious publication bias was observed. CONCLUSIONS: Our present study illustrated that PD-L1 expression was not related to poor prognosis of ESCC patients not receiving preoperative therapy, albeit the association only showed a tendency for statistical significance. Notably, PD-L1 expression showed a significant association with age. This meta-analysis had several limitations; therefore, our results need to be verified through further large-scale and prospective studies.

Daporinad in vitro metabolite profiling via rat, dog, monkey and human liver microsomes by liquid chromatography/quadrupole-orbitrap mass spectrometry.

RATIONALE: Daporinad is a novel and potent inhibitor of nicotinamide phosphoribosyl transferase with potential antineoplastic and antiangiogenic activities. We aimed to explore the metabolites of daporinad generated from liver microsomes and to propose metabolic pathways. METHODS: The metabolites were generated by individually incubating daporinad (10 µM) with liver microsomes at 37°C for 60 min. The metabolites were identified by ultra-high-performance liquid chromatography/quadrupole-orbitrap mass spectrometry (UPLC/Q-Orbitrap-MS) using electrospray ionization in positive ion mode. They were deduced by accurate MS and MS/MS data. RESULTS: In total, 16 metabolites were found and their identities were characterized. In rat, dog and human, they were minor; in monkey, M11 was the most abundant. Daporinad was metabolized mainly through N-dealkylation, amide hydrolysis, hydrogenation, oxygenation and dehydrogenation. There was no human-specific metabolite. CONCLUSIONS: The current study provided an overview of the metabolism of daporinad, which is helpful in predicting in vivo metabolites and in selecting animal species for toxicology studies.

Dynamic transcriptome and histomorphology analysis of developmental traits of hindlimb thigh muscle from Odorrana tormota and its adaptability to different life history stages.

BACKGROUND: Systematic studies on the development and adaptation of hindlimb muscles in anura amphibians are rare. Here, we integrated analysis of transcriptome and histomorphological data for the hindlimb thigh muscle of Odorrana tormota (concave-eared torrent frog) at different developmental stages, to uncover the developmental traits of hindlimb thigh muscle from O. tormota and its adaptability to different life history stages. RESULTS: The development of hindlimb thigh muscle from O. tormota has the following characteristics. Before metamorphosis, myogenous cells proliferate and differentiate into myotubes, and form 11 muscle groups at G41; Primary myofibers and secondary myofibers appeared during metamorphosis; 11 muscle groups differentiated continuously to form myofibers, accompanied by myofibers hypertrophy after metamorphosis; During the growth process of O. tormota from G42 to G46, there were differences between the sexes in the muscle groups that differentiate into muscle fibers, indicating that there was sexual dimorphism in the hindlimb thigh muscles of O. tormota at the metamorphosis stages. Some genes and pathways related to growth, development, and movement ability of O. tormota at different developmental stages were obtained. In addition, some pathways associated with adaptation to metamorphosis and hibernation also were enriched. Furthermore, integrated analysis of the number of myofibers and transcriptome data suggested that myofibers of specific muscle groups in the hindlimbs may be degraded through lysosome and ubiquitin pathways to transform into energy metabolism and other energy-related substances to meet the physiological needs of hibernation. CONCLUSIONS: These results provide further understanding the hindlimb thigh muscle development pattern of frogs and their adaption to life history stages.

Binimetinib Is a Potent Reversible and Time-Dependent Inhibitor of Cytochrome P450 1A2.

Binimetinib is a selective MEK1/2 inhibitor, which is indicative of melanoma. We aimed to investigate the inhibitory effect of binimetinib on cytochrome P450 using human liver microsomes. Binimetinib was demonstrated to display reversible and time-dependent inhibitory effects on human CYP1A2. Binimetinib can inhibit the activity of phenacetin deethylation with IC50 of 5.6 µM. A 30 min preincubation of binimetinib with NADPH-supplemented human liver microsomes raised a significant left IC50 shift (6.5-fold), from 5.69-0.88 µM. The inactivation parameters Kinact and KI were 0.063 min-1 and 15.47 µM, and the half-life of inactivation was 11 min. Glutathione (GSH) and catalase/superoxide exhibited minor or no protective effect on binimetinib-induced enzyme inactivation. Trapping experiment by GSH induced a detection of GSH adduct, of which the formation was believed to be through the oxidation of electron-rich 1,4-benzenediamine to reactive 1,4-diiminoquinone species. Cytochrome P450 3A4, 2C9, and 2D6 were involved in the bioactivation of binimetinib. In conclusion, binimetinib was proven to display reversible and time-dependent inhibitory effect on CYP1A2, which may have implications for the toxicity of binimetinib.

Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Simultaneous Determination of Antipsychotic Drugs in Human Plasma and Its Application in Therapeutic Drug Monitoring.

PURPOSE: We developed and validated an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous therapeutic drug monitoring (TDM) and clinical pharmacokinetic antipsychotic drugs: clozapine (CLP), chlorpromazine (CPZ), risperidone (RPD), paliperidone (PLD), quetiapine (QTP;), aripiprazole (APZ), dehydroaripiprazole (DAP), olanzapine (OZP), ziprasidone (ZRD), and amisulpride (ASP). METHODS: Analytes and internal standards (ISs) were separated using a Phenomenex phenyl-hexyl column (50.0 × 2.1 mm, 1.7 µm) with water containing 0.1% formic acid and 2 mM ammonium acetate, and methanol containing 0.1% formic acid and 2 mM ammonium acetate as the mobile phase. The antipsychotic drugs and ISs were extracted from 50 µL of plasma using acetonitrile. RESULTS: The calibration ranges were 25.0-1500.0 ng/mL for CLP, CPZ, DAP, and QTP, 10.0-600.0 ng/mL for CPZ and ZRD, 2.5-150.0 ng/mL for RPD, 5.0-300.0 ng/mL for PLD and OZP, and 20.0-1200.0 ng/mL for ASP. Validation was carried out according to the guidelines for bioanalytical validation, including assessment of calibration curves, specificity, accuracy, precision, recovery, stability, dilution integrity, and matrix effect. All the results satisfied the requirements. CONCLUSION: The results provided significant information to support future clinical TDM and rational drug use research. The proposed method also provided a simple, reliable, specific, and suitable technique for TDM and pharmacokinetic studies.

A UPLC-MS/MS method for simultaneous determination of nine antiepileptic drugs in human plasma and its application in TDM.

With the purpose of carrying out therapeutic drug monitoring (TDM) of nine antiepileptic drugs simultaneously in the clinic, a UPLC-MS/MS assay method was developed and validated. Separation of antiepileptic drugs and internal standard (naproxen and diazepam) was performed on an Agilent Eclipse XDB-C18 column (50.0 × 2.1 mm, 1.7 µm) using water and acetonitrile as mobile phase for gradient elution. Polarity switch ionization mode (positive-negative-positive) was performed in a total run time of 3.0 min. The method validation was conducted based on bioanalytical method validation guidance, including specificity, calibration curve, precision, accuracy, recovery, matrix effect, stability and dilution integrity, and all of the results satisfied the requirements. Consequently, the proposed method was applied to the TDM of nine antiepileptic drugs and was proved to be sensitive, reliable and specific to determine antiepileptic drugs in human plasma simultaneously. Meanwhile, the TDM results showed that the plasma drug concentration of many patients was not within the effective therapeutic range, especially those taking topiramate, oxcarbazepine and levetiracetam, which was of great guiding significance to rational drug use and timely adjustment of the treatment plan. Therefore, individualized therapy based on advanced analytical methods and TDM theory is of great practical significance.

Berberine-10-hydroxy camptothecine-loaded lipid microsphere for the synergistic treatment of liver cancer by inhibiting topoisomerase and HIF-1α.

10-HCPT is a topoisomerase I inhibitor effective in the treatment of liver cancer but its use is hampered by its resistance. The expression of hypoxia-inducible factor-1α (HIF-1α) is reportedly upregulated in liver cancer tissues, which is directly linked to the resistance of 10-HCPT. While BBR can significantly decrease the level of HIF-1α according to the literature report. Thus, the aim of this study was to prepare a novel intravenous 10-HCPT-BBR-loaded lipid microsphere (LM) and evaluate their synergistic effect on liver cancer treatment. The optimal preparation mainly included 10.0% oil phase (medium-chain triglyceride:long-chain triglyceride = 1:1), emulsifier (egg lecithin E80 and pluronic F68), antioxidant (0.02% NaHSO3), and pH regulator (0.1 mol/L Hcl). Then, the behaviors of BBR-10-HCPT loaded LM in vitro and in vivo were systematically investigated. In vitro, it showed an obvious sustained-release effect in different release mediums, good physicochemical stability at accelerated and long-term storage conditions, and great anti-proliferative capability toward human liver cancer Hep-3B cells. In vivo, the prepared LM exhibited a longer half-life and higher AUC compared to BBR injection and 10-HCPT injection. More importantly, it was found that The LM was distributed more in the liver, spleen, and tumors, but less in the lungs and heart, especially in the lung. And then, it showed significant inhibition of tumor growth against nude mouse with Hep-3B tumor, and the tumor inhibition rate reached 91.55%. Thus, the data obtained in our study suggested that BBR combined with 10-HCPT can raise curative effect and reduce the toxicity of 10-HCPT.

Integrated analysis of mRNA and miRNA expression profiles reveals muscle growth differences between fast- and slow-growing king ratsnakes (Elaphe carinata).

In some countries, snakes are important protein sources in human diets, and their economic value depends predominantly on their muscle production, including in the king ratsnake (Elaphe carinata). Muscle growth in the king ratsnake clearly differs among individuals. To date, few potential molecular mechanisms underlying these differences in muscle growth and development have been reported. Here, we integrated mRNA and miRNA expression profiles to screen for genes, pathways, and predicted miRNA-mRNA networks associated with muscle growth and development in fast-growing and slow-growing King ratsnakes. Six hundred eight differentially expressed genes (DEGs) were identified, 48 of which were associated with muscle growth. The 37 genes upregulated in fast-growing individuals (FGIs) may be related to the promotion of muscle growth, whereas the 11 upregulated genes in slow-growing individuals (SGIs) may be related to the inhibition of muscle growth. Seven DEGs were enriched in the PI3K-AKT-MTOR signaling pathway, which appears to promote muscle growth in FGIs. Eleven DEGs were enriched in the ubiquitin-proteasome pathway, which appears to inhibit muscle growth in SGIs. It may interpret why muscle growth differences. Furthermore, 698 miRNA were identified, including 125 novel miRNAs. 63 differentially expressed miRNA (DEMs) were screened, and 950 negative miRNA-mRNA interactions with the 63 DEMs and 608 DEGs were predicted. The miRNA-targeted genes were enriched in pathways related to muscle growth, protein synthesis, and protein degradation. Therefore, in addition to the identified DEGs, miRNAs may play important roles in the differential regulation of muscle growth in FGIs and SGIs of the king ratsnake.

In vitro metabolism of ibrutinib in rat, dog and human hepatocytes using liquid chromatography combined with diode-array detection and Q-Exactive Orbitrap tandem mass spectrometry.

RATIONALE: Ibrutinib is a potent Bruton's tyrosine kinase inhibitor which has shown promising efficacy against various B-cell malignancies. Its metabolic profiles have not been disclosed. The aim of this study was to investigate the metabolism of ibrutinib in the hepatocytes of rat, dog and human. METHODS: Ibrutinib was incubated with hepatocytes at 37°C for 2 h, after which the samples were analyzed using ultrahigh-performance liquid chromatography with diode-array detection and Q-Exactive Orbitrap tandem mass spectrometry (UHPLC/DAD-Q-Exactive-Orbitrap-MS). The acquired data were processed using MetWorks™ software. RESULTS: A total of 20 metabolites were structurally identified by their MS and MS2 data. M1 and M5 were unambiguously identified using authentic standards. The biotransformation of ibrutinib involved hydroxylation, hydration, oxygenation, epoxide hydrolysis, dehydrogenation, dealkylation and GSH conjugation. CONCLUSIONS: Humans have a relatively low capability for metabolizing ibrutinib. Compared with rat, dog had closer metabolic profiles to humans and would be more suitable for toxicity studies. This study provides more valuable information with respect to the in vitro disposition of ibrutinib.

Emerging transporter-targeted nanoparticulate drug delivery systems.

Transporter-targeted nanoparticulate drug delivery systems (nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed, focusing on the specific transporter-based targeting strategies. Recent developments in transporter-mediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS.

Remodeling the Tumor Microenvironment with Emerging Nanotherapeutics.

The tumor microenvironment (TME) has profound impacts on cancer progression and remodeling of the TME has emerged as a strategy to facilitate cancer therapy. Recently, great progress in TME modulation has been made, especially with the rapid developments in nanomedicine. In this review we outline the latest advances in remodeling of the TME based on nanotherapeutics. First, novel strategies developed to modulate the tumor extracellular matrix (ECM) are discussed, including disruption, mimicking, and intervening in tumor ECM fabrication. Then, emerging tumor-associated fibroblast (TAF)-based nanotherapeutics are reviewed, including disruption and targeting of TAFs. Furthermore, recent developments in tumor vessel disruption and normalization are discussed. Finally, emerging approaches in response to tumor hypoxia are presented, with special emphasis on delivering oxygen, generating oxygen, and targeting tumor hypoxia.