GLUT3-mediated cigarette smoke-induced epithelial-mesenchymal transition in chronic obstructive pulmonary disease through the NF-kB/ZEB1 pathway.

BACKGROUND: Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) is a significant process during the occurrence of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear. METHODS: We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson's staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1. RESULTS: Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway. CONCLUSION: We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD.

Effectiveness and safety of camrelizumab-containing neoadjuvant therapy in patients with esophageal squamous cell carcinoma: a prospective multicenter observational cohort study.

Background: Camrelizumab has been demonstrated to be a feasible treatment option for locally advanced esophageal squamous cell carcinoma (ESCC) when combined with neoadjuvant chemotherapy. This trial was conducted to investigate the effectiveness and safety of camrelizumab-containing neoadjuvant therapy in patients with ESCC in daily practice. Methods: This prospective multicenter observational cohort study was conducted at 13 tertiary hospitals in Southeast China. Patients with histologically or cytologically confirmed ESCC [clinical tumor-node-metastasis (cTNM) stage I-IVA] who had received at least one dose of camrelizumab-containing neoadjuvant therapy were eligible for inclusion. Results: Between June 1, 2020 and July 13, 2022, 255 patients were enrolled and included. The median age was 64 (range, 27 to 82) years. Most participants were male (82.0%) and had clinical stage III-IVA diseases (82.4%). A total of 169 (66.3%) participants underwent surgical resection; 146 (86.4%) achieved R0 resection, and 36 (21.3%) achieved pathological complete response (pCR). Grades 3-5 adverse events (AEs) were experienced by 14.5% of participants. Reactive cutaneous capillary endothelial proliferation occurred in 100 (39.2%) of participants and all were grade 1 or 2. Conclusions: Camrelizumab-containing neoadjuvant therapy has acceptable effectiveness and safety profiles in real-life ESCC patients.

PSMC2 is a Novel Prognostic Biomarker and Predicts Immunotherapeutic Responses: From Pancreatic Cancer to Pan-Cancer.

Background: Proteasome 26S subunit ATPase 2 (PSMC2) is a part of the 19S regulatory complex, which catalyzes the unfolding and transport of substrates into the 20S proteasome. Our previous research demonstrated that PSMC2 participates in the tumorigenesis and progression of pancreatic cancer (PC). However, no systematic analysis has been conducted to conclude its expression pattern and correlation with tumor immunity. Aim: To investigate the expression level of PSMC2 in PC, its prognostic value and its relationship with tumor immunity. Methods: In numerous public and internal cohorts, the expression, prognostic significance, and immunological connections of PSMC2 in PC were investigated. Additionally, using data from The Cancer Genome Atlas (TCGA), a pan-cancer analysis was carried out to examine PSMC2's immunological assocaition, and the predictive power of PSMC2 for immunotherapy was also evaluated in numerous public cohorts. Results: PSMC2 was overexpressed in tumor tissues and linked to unfavorable prognosis in PC. PSMC2 was not only positively correlated with TIICs, also positively correlated with immune checkpoints in PC. In addition to PC, PSMC2 was expected to be an indicator of high immunogenicity in most cancer types. Importantly, PSMC2 could predict the immunotherapeutic responses in various cancer types, including urothelial carcinoma and breast cancer. Conclusion: From PC to pan-cancer analysis, we report that PSMC2 is a novel prognostic biomarker in multiple cancer types. PSMC2 is related to the immuno-hot phenotype and predicts the outcome of immunotherapy. Therefore, the current study emphasizes that cancer patients with high PMSC2 expression should actively receive immunotherapy to improve their prognosis.

Body composition and risk of liver cancer: a population-based prospective cohort study on gender difference.

Background: Obesity is a common and highly convincing risk factor for many cancers, including liver cancer. Sex disparities in the body composition and regulatory mechanisms involved in energy homeostasis may contribute to the difference in the incidence of cancer. However, evidence on the gender-specific association between body composition and liver cancer incidence is limited. We performed this study to investigate the linear and non-linear associations of body composition with liver cancer risk by gender. Materials and methods: This prospective analysis included 4,75,659 participants free of cancer, based on the UK Biobank. We used Cox proportional hazard models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders. Restricted cubic spline was performed to investigate the potential non-linear associations. Results: During a median follow-up, 275 cases (174 male patients and 101 female patients) of liver cancer were identified. Male patients in the highest body fat percentage group are more likely to develop liver cancer (HR = 1.89, 95% CI: 1.17-3.03) compared with those in the lowest group. The one-unit increase of whole-body fat mass, arm fat mass, and trunk fat mass was associated with 1.03-, 1.14-, and 1.05-fold increased risk of liver cancer in male subjects, respectively. U-shaped associations of body composition with liver cancer risk were observed in the female subjects. Both high and low levels of whole-body fat-free mass, particularly in the arm and trunk, were associated with an increased risk of liver cancer. Conclusion: This study found a gender-specific association between body composition and liver cancer risk and provided evidence for individualized weight management for the prevention of liver cancer.

GPX2 promotes EMT and metastasis in non-small cell lung cancer by activating PI3K/AKT/mTOR/Snail signaling axis.

Lung cancer, with non-small cell lung cancer (NSCLC) being the main subtype, is the leading cause of cancer death worldwide, which is mainly due to the cancer metastasis. Glutathione peroxidase 2 (GPX2), an antioxidant enzyme, is involved in tumor progression and metastasis. Nevertheless, the role of GPX2 in NSCLC metastasis has not been clarified. In this study, we found that GPX2 expression was elevated in NSCLC tissues and high GPX2 expression was correlated with poor prognosis in patients with NSCLC. In addtion, GPX2 expression was related to the patient's clinicopathological features, including lymph node metastasis, tumor size, and TNM stage. Overexpression of GPX2 promoted epithelial-mesenchymal transition (EMT), migration, and invasion of NSCLC cells in vitro. Knockdown of GPX2 showed the opposite effects in vitro and inhibited the metastasis of NSCLC cells in nude mice. Furthermore, GPX2 reduced reactive oxygen species (ROS) accumulation and activated the PI3K/AKT/mTOR/Snail signaling axis. Therefore, our results indicate that GPX2 promotes EMT and metastasis of NSCLC cells by activating the PI3K/AKT/mTOR/Snail signaling axis via the removal of ROS. GPX2 may be an effective diagnostic and prognostic biomarker for NSCLC.

MicroRNA Let-7 Induces M2 Macrophage Polarization in COPD Emphysema Through the IL-6/STAT3 Pathway.

Background: M2 polarized macrophages are involved in the occurrence and development of emphysema in COPD patients. However, the molecular mechanism of M2 macrophage polarization is still unclear. This study investigated the molecular mechanism of let-7 differentially expressed in bronchial epithelial cells of COPD patients participating in COPD emphysema by regulating the expression of IL-6 and inducing M2 polarization of alveolar macrophages (AM). Materials and Methods: We measured let-7c expression in human lung tissue, serum and the lung tissue of cigarette smoke (CS)-exposed mice by qRT‒PCR. We observed the M1/M2 AM polarization in the lungs of COPD patients and COPD model mice by immunofluorescence analysis. Western blotting was used to determine the expression of MMP9/12 in the lung tissue of COPD patients and CS-exposed mice. An in vitro experiment was performed to determine the molecular mechanism of let-7c-induced macrophage polarization. Results: Let-7c expression was downregulated in COPD patients, CS-exposed mice, and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. AMs in COPD patients and CS-exposed mice were dominated by the M2 type, and the release of MMP9/12 was increased. In vitro, the transfection of mimics overexpressing let-7 or the use of tocilizumab to block signal transduction between HBE cells and macrophages inhibited the IL-6/STAT3 pathway. M2 macrophage polarization was inhibited, and MMP9/12 release was reduced. Conclusion: Our results indicate that CS decreased let-7c expression in HBE cells, and M2 AM polarization was dominant in COPD. In HBE cells, let-7c could inhibit M2 polarization of AMs through the IL-6/STAT3 pathway, providing potential diagnostic and therapeutic value for slowing COPD emphysema.

Colonic tubular duplication combined with congenital megacolon: A case report.

BACKGROUND: Colonic duplication refers to a spherical or tubular cavity which shows similar properties with the native colon and is attached to the mesenteric side of the alimentary tract. It is the rarest in alimentary tract duplications. Based upon anatomic feature, colonic duplications can be classified as spherical (cystic) or tubular, with the latter being less common (approximately 20%). Symptoms of colonic duplication are dependent on the duplication site and extent, and patient age, etc. Usually, patients with colonic duplication manifest typical intestinal obstruction, potentially accompanied by recurrent dark or bright red bloody stool, varying degrees of anemia-related symptoms, and body wasting. CASE SUMMARY: A young male patient was admitted to our hospital due to recurrent abdominal pain. No definite diagnosis was achieved by computed tomography (CT) or electronic colonoscopy, and the bowel preparation efficacy was suboptimal. Hirschsprung disease was suspected, and thus laparoscopic exploration was performed. An approximately 60-cm-long inverted duplicated colon with severe edema and dilation was identified. It originated from the mesenteric side of the transverse colon and ended in the terminal part of the descending colon with a blind end. The parallel native colon had a thickened colonic wall, became stiff, and was poor in peristalsis. The patient then underwent subtotal colectomy and was discharged 7 d after the surgery. From 3 mo post-surgery to date, the patient had regular bowel movement once daily and a steady increase in body weight. CONCLUSION: Tubular colonic duplication is a rare type of alimentary tract duplication that can be detected by ultrasonography, CT, or magnetic resonance imaging based on the actual clinical situation. Surgical resection of aberrant colon (including the duplicated colonic segment and other potentially involved colonic segments) is the only approach to cure this medical condition.

A Wnt-related gene expression signature to improve the prediction of prognosis and tumor microenvironment in gastric cancer.

Background: Most gastric cancer (GC) patients were diagnosed in the advanced stages without obvious symptoms, which resulted in the increased risk of death. Although the combination therapies have showed survival benefit of patients, there is still urgent need to explore the underlying mechanisms of GC development and potential novel targets for clinical applications. Numerous studies have reported the upregulation of Wnt signaling pathway in human GC, which play important role during GC development and progression. However, the current understanding of Wnt signaling pathway is still limited due to its complexity and contradictory effect on different stages of GC tumor microenvironment. Method: We used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset to screen Wnt signaling pathway-associated genes by ssGSEA and correlation analysis. Three molecular subtypes were constructed based on a consistent clustering analysis. The key Wnt-related genes were screened through univariate cox analysis, lasso, and stepwise regression. In addition, the Gene Set Enrichment Analysis (GSEA) were performed to explore potential molecular pathways regulated by the Wnt-related gene signatures. ESTIMATE was utilized for evaluating the immune cell populations in GC tumor microenvironment. Results: Three molecular subtypes associated to Wnt were identified, and 7 key Wnt-related genes were screened to establish a predictive RiskScore model. These three molecular subtypes showed significant prognostic differences and distinct functional signaling pathways. We also found the downregulated immune checkpoint expression in the clust1 with good prognosis. The RiskScore model was successfully validated in GSE26942 dataset. Nomogram based on RiskScore and Gender had better prognostic predictive ability. Conclusion: In summary, our study showed that the Wnt-related genes could be used to predict prognosis of GC patients. The risk model we established showed high accuracy and survival prediction capability.

Everolimus ameliorates Helicobacter pylori infection-induced inflammation in gastric epithelial cells.

Helicobacter pylori (H.pylori) infection caused by gastric mucosal inflammation plays a pivotal role in the progression of gastric diseases. The recruitment and attachment of monocytes to the gastric mucosal epithelium are a major event in the early stages of H. pylori-associated gastric diseases. Everolimus is a mechanistic/mammalian target of rapamycin (mTOR) inhibitor used to prevent tumor growth by inhibiting the PI3K signaling pathway. Here, we examined the pharmacological role of Everolimus against H.pylori-induced damage in gastric epithelial cells. Firstly, we found that Everolimus ameliorated H.pylori-induced oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA). Secondly, Everolimus significantly reduced the expressions of the pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-8. Moreover, it decreased the production of the pro-inflammatory chemokines C-X-C motif ligand 1 (CXCL1) and macrophage chemoattractant protein-1 (MCP-1). Importantly, Everolimus suppressed the induction of the adhesion molecule intracellular adhesion molecule-1 (ICAM-1) and the attachment of THP-1 monocytes to gastric epithelial AGS cells. Our data also shows that Everolimus inhibited the activation of the NF-κB signaling pathway. Therefore, we conclude that Everolimus could protect gastric epithelial cells by mitigating H.pylori-induced inflammatory response and the attachment of monocytes to epithelial cells.

Diagnosis and treatment of pure arterial malformation: Three case reports and literature review.

RATIONALE: The incidence of pure arterial malformations is relatively low, and few cases have been reported. Only 2 cases with pure arterial malformation have been reported to receive surgery or endovascular treatment. PATIENT CONCERNS: We report 3 cases and review the relevant literatures. The head examinations of the patients suggested the presence of high-density shadows in front of the pons and midbrain, the dilation of the supraclinoid segment of the right internal carotid artery, and moyamoya in the left brain with an aneurysm-like expansion located on the left posterior communicating artery respectively. After admission, head digital subtraction angiography (DSA) was performed. DIAGNOSES: Digital subtraction angiography (DSA) for these 3 patients showed that the left posterior communicating artery, the supraclinoid segment of the right internal carotid artery, and the left posterior communicating artery appeared dilated, tortuous, and spirally elongated. In addition, the lesions in the latter 2 patients were accompanied with local aneurysmal changes. INTERVENTIONS: Two patients were given conservative treatment, and another patient was given endovascular treatment. A head DSA was reviewed 6 months after therapy. OUTCOMES: The prognosis status of the 3 patients was good. Two patients in the conservative treatment group showed no changes in the lesions on head DSA examination. The DSA examination of the third patient indicated that the vascular remodeling of the diseased vessels was good, the blood vessels were unobstructed, and the aneurysms had disappeared. LESSONS: Pure arterial malformations mostly occur in young women and may involve any blood vessels in the brain. It can be accompanied with local aneurysms and calcification. The patients are often given conservative treatment but need to be reviewed regularly. However, it is beneficial to give endovascular treatment to the patients with local aneurysms.

Coil embolisation of multiple cerebral aneurysms with lateral type I persistent primitive trigeminal artery: A case report and literature review.

The primitive trigeminal artery is an anastomotic vessel of the carotid-basilar artery system that occurs only transiently during the embryonic period. Persistent primitive trigeminal artery occurs in approximately 0.1-0.6% of the population. Here, we report the case of a 60-year-old woman with Fisher II grade subarachnoid haemorrhage. Computed tomography angiography demonstrated a lateral, Saltzman type I persistent primitive trigeminal artery with three cerebral aneurysms, including one anterior communicating artery aneurysm, one suspicious right anterior choroidal artery aneurysm and one distal basilar artery aneurysm supplied by the persistent primitive trigeminal artery. All three aneurysms were treated with coil embolisation. At the 8-month follow-up, the anterior communicating artery aneurysm had a neck remnant, the other two aneurysms exhibited complete occlusion. Persistent primitive trigeminal artery with multiple cerebral aneurysms is extremely rare, and only seven cases of persistent primitive trigeminal artery with multiple cerebral aneurysms have previously been reported in publications that included information on treatment. Most aneurysms were treated by open surgery. This is the first report of coil embolisation treatment of multiple aneurysms in persistent primitive trigeminal artery patients with follow-up results, and provides relevant and valuable information about the persistent primitive trigeminal artery and the endovascular treatment of multiple aneurysms in persistent primitive trigeminal artery patients.

Cemented K-wire fixation for the treatment of shaft fractures of middle phalanges.

BACKGROUND: The objective of this report is to introduce an external-fixation technique using the combination of K-wires and cement. METHODS: From February 2009 to January 2015, 51 patients with shaft fractures of middle phalanges were treated with cemented K-wire fixation. The mean age of patients at surgery was 41 years. The mean time interval from injury to operation was 6±5.78days. Injured digits included index (n=18), long (n=15), ring (n=7), and little (n=11) fingers. Types of fractures were transversal (n=32), short oblique or spiral (n=5), and comminuted (n=14) fractures. Active range of motion of the fingers was measured. Total active motion was scored based on the American Society for Surgery of the Hand. All measurements were compared with those on the opposite fingers. Patients also reported on their satisfaction using the 100-mm visual analogue scale. RESULTS: At the final follow-ups of 2 years, range of motion of metacarpophalangeal joint, proximal phalangeal joint, and distal interphalangeal joint reached 97%±2.88, 93%±6.65, and 96%±3.22 of the opposite fingers, respectively. Based on Total active motion scoring system, we obtained 36 excellent and 15 good results. Based on VAS, patient satisfaction was 96±3.44. CONCLUSIONS: The cemented K-wire fixation is a reliable technique for the treatment of shaft fractures of middle phalanges. The technique is a minimally invasive procedure with minimal complications. LEVEL OF EVIDENCE: Therapeutic study, Level IVa.

Inhibiting the proliferation, migration and invasion of triple negative breast cancer cells through anti-tumor human serum albumin nanoparticles loading aziditaxel as a novel taxane derivative.

Triple negative breast cancer (TNBC) is a severe breast cancer subtype with the high mortality rate, and still is lack of effective therapeutic means so far. Aziditaxel, a water-insoluble compound, is a novel taxane derivative with strong anti-tumor activity. In this study, we constructed an aziditaxel-loaded nano drug delivery system using human serum albumin as a carrier, and further investigated its anti-tumor effect on TNBC in vitro. An emulsion solvent evaporation method was employed to prepare aziditaxel-loaded human serum albumin nanoparticles (AT-NPs). Their physicochemical properties were characterized according to morphology, particle size, zeta potential, reconstitution stability and in vitro drug release. The in vitro anti-tumor effects of AT-NPs on TNBC were evaluated using a 4T1 murine triple negative mammary cancer cell lines as the TNBC model. The results showed that AT-NPs could be effectively taken up by 4T1 cells in a time-dependent manner. Cell Counting Kit-8 assay showed that the IC50 of AT-NPs was 0.17 µg/ml. Meanwhile, compared with AT, AT-NPs had a better ability to promote apoptosis and induce G2/M cycle arrest. On the other hand, AT-NPs had significantly inhibitory effects on the 4T1 cell adhesion, migration and invasion with the respective average inhibition ratios of 32.53%, 83.26% and 75.78%. Thus, our study revealed that AT-NPs had favorable antitumor activity in vitro and exhibited a good prospect for application in the field of TNBC therapy.

Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain.

Brain metastasis from triple-negative breast cancer (TNBC) has continued to lack effective clinical treatments until present. However, the feature of epidermal growth factor receptor (EGFR) frequently overexpressed in TNBC offers the opportunity to employ lapatinib, a dual-tyrosine kinase inhibitor of human epidermal growth factor receptor-2 (HER2) and EGFR, in the treatment of brain metastasis of TNBC. Unfortunately, the low oral bioavailability of lapatinib and drug efflux by blood-brain barrier have resulted in low drug delivery efficiency into the brain and limited therapeutic effects for patients with brain metastasis in clinical trials. To overcome such disadvantages, we developed lapatinib-loaded human serum albumin (HSA) nanoparticles, named LHNPs, by modified nanoparticle albumin-bound (Nab) technology. LHNPs had a core-shell structure and the new HSA/phosphatidylcholine sheath made LHNPs stable in bloodstream. Compared to free lapatinib, LHNPs could inhibit the adhesion, migration and invasion ability of high brain-metastatic 4T1 cells more effectively in vitro. Tissue distribution following intravenous administration revealed that LHNPs (i.v., 10 mg/kg) achieved increased delivery to the metastatic brain at 5.43 and 4.36 times the levels of Tykerb (p.o., 100 mg/kg) and lapatinib solution (LS, i.v., 10 mg/kg), respectively. Compared to the marketed Tykerb group, LHNPs had markedly better inhibition effects on brain micrometastasis and significantly extended the median survival time of 4T1 brain metastatic mice in consequence. The improved anti-tumor efficacy of LHNPs could be partly ascribed to down-regulating metastasis-related proteins. Therefore, these results clearly indicated that LHNPs could become a promising candidate for clinical applications against brain metastasis of TNBC.

Incorporation of lapatinib into human serum albumin nanoparticles with enhanced anti-tumor effects in HER2-positive breast cancer.

Lapatinib, a selective small-molecule dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in HER2-positive patients with advanced metastatic breast cancer. However, its low and variable oral absorption, large required daily dose and serious gastrointestinal side effects all limit its clinical use. Intravenous administration offers a good option to overcome these disadvantages. However, the poor solubility of lapatinib in water and organic solvents causes lapatinib to fail in a common injectable preparation. Considering lapatinib's high albumin binding ability (>99%), in this study, we developed human serum albumin nanoparticles loaded with lapatinib (LHNPs) by Nab technology for intravenous administration and investigated its efficacy against HER2-positive breast cancer. Raman shift, X-ray diffraction and X-ray photoelectron spectroscopy studies demonstrated that lapatinib was successfully incorporated into nanoparticles, and LHNPs exhibited good stability and sustained-release effect in vitro. LHNPs could be effectively taken up by SKBr3 cells in a concentration- and time-dependent manner, and the uptake was mediated by energy-dependent endocytosis, which involved clathrin-dependent pinocytosis. Furthermore, in vitro and in vivo data indicated that LHNPs presented the strong ability to induce apoptosis and superior anti-tumor efficacy in tumor-bearing mice to the commercial tablet Tykerb through the inhibition of HER2 phosphorylation. Subchronic toxicity assays indicated that LHNPs had no hepatic or kidney toxicity. With mature technology for industrial production and enhanced therapeutic effects, LHNPs are likely to have great potential as a safe therapeutic candidate against HER2-positive breast cancer in the clinic.

The potential use of lapatinib-loaded human serum albumin nanoparticles in the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. However, the shared feature of epidermal growth factor receptor (EGFR) expression in TNBC offers the opportunity for targeted molecular therapy for this breast cancer subtype. Previous studies have indicated that lapatinib, a selective small-molecular dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in reducing cancer progression and metastasis, indicating that it might be a candidate for TNBC treatment. However, its poor water solubility, low and variable oral absorption, and large daily dose all limit the clinical use of lapatinib. In this study, we developed human serum albumin (HSA) nanoparticles loaded with lapatinib for intravenous administration to overcome these disadvantages and enhance its efficacy against TNBC. 4T1 cells (a murine TNBC cells) were selected as the cell model because their growth and metastatic spread are very close to those of human breast cancer cells. Lapatinib-loaded HSA nanoparticles (LHNPs) were prepared by Nab technology. LHNPs displayed cytotoxicity similar to the free drug but exhibited superior capacity to induce early apoptosis in 4T1 monolayer cells. Importantly, LHNPs showed improved penetration and inhibition effects in tumor spheroids compared to lapatinib solution (LS). Pharmacokinetic investigations revealed that HSA nanoparticles (i.v.) effectively increased the accumulation of lapatinib in tumor tissue at 2.38 and 16.6 times the level of LS (i.v.) and Tykerb (p.o.), respectively. Consequently, it had markedly better suppression effects both on primary breast cancer and lung metastasis in tumor-bearing mice compared to the commercial drug Tykerb. The improved anti-tumor efficacy of LHNPs may be partly attributed to its close binding to SPARC, which is widely present in the extracellular matrix of tumor tissue. These results demonstrated that LHNPs might be a promising anti-tumor agent for TNBC.

The potential use of H102 peptide-loaded dual-functional nanoparticles in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease with few effective treatments. The non-targeted distribution of drugs decreases drug efficiency and cause side effects. The cascade targeting strategy has been suggested for precise drug delivery. We developed a dual-functional nanoparticle drug delivery system loaded with ß-sheet breaker peptide H102 (TQNP/H102). Two targeting peptides, TGN and QSH, were conjugated to the surface of the nanoparticles for blood-brain barrier transport and Aß42 targeting, respectively. The prepared nanoparticles were spherical and uniform. The brain distribution study of H102 was conducted with the HPLC-mass spectrometry method to evaluate whether this nano-carrier could achieve increased AD-lesion delivery. The highest uptake of H102 was observed in the hippocampi of the TQNP/H102 group mice 1h after administration, which was 2.62 and 1.86 times the level of non-modified nanoparticles (NP/H102) and TGN modified nanoparticles (TNP/H102), respectively. The neuroprotective effects of H102 preparations were evaluated using Morris water maze experiment, biochemical indexes assay and tissue histology. The spatial learning and memory of the AD model mice in the TQNP/H102 group were significantly improved compared with the AD control group, and were also better than other preparations at the same dosage, even the TNP/H102 group. These results were consistent with the values of biochemical indexes in mouse hippocampi as well as the histological observations. The results demonstrate that TQNP is a promising carrier for peptide or protein drugs, such as H102, for entry into the central nervous system (CNS) and subsequent location of brain AD lesions, thus offering a highly-specific method for AD therapy.