The safety and effectiveness of a self-made negative pressure suction device in the treatment of chronic wounds.

INTRODUCTION: Chronic wounds are wounds that are not healed or have no healing tendency for more than 1 month due to various factors. In clinical nursing, chronic wounds are often not properly treated, and the treatment efficiency is low. Therefore, it is very important to explore effective methods to deal with chronic wounds. OBJECTIVE: To explore the effect of a self-made negative pressure suction device (NPSD) in the nursing of chronic wounds in the elderly. METHODS: A total of 50 elderly patients with chronic wounds who were hospitalised in our hospital from January 2020 to December 2022 were selected as participants by convenient sampling. According to the random number table method, they were divided into a control group and an observation group, with 25 people in each group. The control group was treated with chloroplast foam dressing, debridement gel and alginate dressing. The observation group was treated with a self-made NPSD on the basis of the control group. The wound healing of the two groups was observed. RESULTS: After the intervention of the self-made NPSD, the granulation tissue coverage rate and wound volume reduction rate of the observation group were significantly increased (p < 0.05), and the positive rate of bacterial infection was significantly decreased (p < 0.05). After 3 months of intervention, the total effective rate of the observation group was significantly higher than that of the control group (χ2  = 3.869, p = 0.0492). CONCLUSION: The self-made NPSD can effectively promote the healing of a chronic wound.

Maintenance therapy improves the survival outcomes of patients with metastatic nasopharyngeal carcinoma responding to first-line chemotherapy: a multicentre, randomized controlled clinical study.

PURPOSE: To explore the safety and role of tegafur/gimeracil/oteracil (S1) maintenance therapy (MT) in metastatic nasopharyngeal carcinoma (NPC) patients after response to first-line chemotherapy and to assess outcome-associated biomarkers. METHODS: This was a multicentre, open-label, randomized controlled study involving metastatic NPC patients recruited (from May 2015 to May 2019) at five hospitals in China. The participants were randomized to S1-MT (receiving S1 MT until disease progression or intolerance) or non-MT (followed up until disease progression) groups. The primary endpoint was the progression-free survival (PFS). The secondary endpoints were the overall survival (OS), the correlation between EBV-DNA, serum amyloid A (SAA) status, and outcomes after the first-line chemotherapy, and safety. RESULTS: The median follow-up was 24.3 months; 88 and 95 participants were evaluable in the S1-MT and non-MT groups, respectively. Compared with non-MT, S1-MT prolonged PFS (16.9 vs. 9.3 months, P < 0.001) and OS (33.6 vs. 20.6 months, P < 0.001). Regardless of their EBV-DNA status after first-line chemotherapy, participants were able to benefit from S1 MT, but EBV-DNA-positive participants benefited more significantly (PFS: HR = 0.600, 95% CI = 0.373-0.965, P = 0.035; OS: HR = 0.393, 95% CI = 0.227-0.681, P = 0.001). MT only improved PFS and OS in patients with an SAA decline after first-line chemotherapy (PFS: HR = 0.570, 95% CI = 0.350-0.919, P = 0.021; OS: HR = 0.404, 95% CI = 0.230-0.709, P = 0.002). The median S1 treatment was 23 cycles. Grade 1-2 skin pigmentation, oral mucositis, and hand and foot syndrome were the main adverse reactions. CONCLUSION: For metastatic NPC patients with first-line chemotherapy response, S1 MT can improve PFS and OS, with good tolerability. EBV-DNA and SAA can better help us identify patients who can benefit from MT after standard treatment. TRIAL REGISTRATION: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR-IOR-16007939).

Clinical Significance of Pim-1 in Human Cancers: A Meta-analysis of Association with Prognosis and Clinicopathological Characteristics.

BACKGROUND: Pim-1 is overexpressed in cancer tissues and plays a vital role in carcinogenesis. However, its clinical significance in cancers is not fully verified by meta-analysis, especially in relation to prognosis and clinicopathological features. METHODS: Four databases, PubMed, Embase, Cochrane Library, and Web of Science, were searched. Literature screening and data extraction according to the inclusion and exclusion criteria. The quality of the included literatures was evaluated using the Newcastle-Ottawa scale and the data analysis was performed using STATA and Review Manager software. RESULTS: 15 articles were finally included for meta-analysis, involving 1651 patients. Effect-size pooling analysis showed that high Pim-1 was related to poor overall survival (OS) (HR 1.68 [95% CI 1.17-2.40], P = .004) and disease-free survival (DFS) (HR 2.15 [95 %CI 1.15-4.01], P = .000). Subgroup analysis indicated that the detection techniques of Pim-1 were the main sources of heterogeneity, and 2 literatures using quantitative polymerase chain reaction (qPCR) for Pim-1mRNA had high homogeneity (I2 = .0%, P = .321) in OS. Another 13 studies that applied immunohistochemistry (IHC) for Pim-1 protein had significant heterogeneity (I2=82.2%, P = .000; I2=92%, P = .000) in OS and DFS, respectively, and further analysis demonstrated that ethnicity, sample size, and histopathological origin were considered to be the main factors affecting their heterogeneity. In addition, high Pim-1 was associated with lymph node metastasis (OR 1.40 [95% CI 1.02-1.92], P = .04), distant metastasis (OR 2.69 [95%CI 1.67-4.35], P < .0001), and clinical stage III-IV (OR .7 [95% CI .50-.96, P = .03). Sensitivity analysis suggested that the pooled results of each effect-size were stable and reliable, and there was no significant publication bias (P = .138) in all included articles. CONCLUSION: High Pim-1 can not only predict poor OS and DFS of cancer, but also help to infer the malignant clinical characteristics of tumor metastasis. Pim-1 may be a potential and promising biomarker for early diagnosis, prognostic analysis and targeted therapy of tumors.

Association of Epstein-Barr virus DNA and SAA with S1 maintenance therapy outcomes in patients with metastatic nasopharyngeal carcinoma.

Objectives: The relevant biomarkers in predicting maintenance therapy (MT) outcomes in metastatic nasopharyngeal carcinoma (NPC) are yet unclear. Patients & methods: Metastatic NPC patients were randomly divided into MT (S1-MT) and non-MT groups. The association of Epstein-Barr virus DNA (EBV-DNA) and SAA with survival was assessed. Results: A total of 183 patients were included. S1-MT significantly increased the progression-free survival (PFS) and overall survival (OS) of the metastatic NPC patients (both p < 0.001). For patients who were EBV-DNA positive or had decreased SAA, the PFS and OS increased significantly after S1-MT (both p < 0.001), while patients with stable SAA did not benefit from S1-MT. Conclusion: S1-MT improved the PFS and OS of metastatic NPC patients. EBV-DNA and SAA status were closely associated with the outcomes of S1-MT. Clinical trial registration number: ChiCTR-IOR-16007939.

Prognostic Role of EGFR/p-EGFR in Patients With Nasopharyngeal Carcinoma: A Meta-Analysis.

BACKGROUND: The prognostic value of epidermal growth factor receptor (EGFR)/phosphorylated EGFR (p-EGFR) expression in nasopharyngeal carcinoma remains controversial. A meta-analysis was performed to investigate prognostic significance of EGFR/p-EGFR expression in patients with nasopharyngeal carcinoma. METHODS: Literatures published before November 2020 were systematically searched in relevant databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan fang databases. STATA 13 statistical software was used to analyze the pooled hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity of the studies was examined by I2. Sensitivity and subgroup analysis were performed to explore sources of heterogeneity. The potential publication bias was assessed using both Egger's and Begg's tests. RESULTS: A total of 20 literatures with 1545 patients were included for the meta-analysis. The meta-analysis results suggested that high expression of EGFR was significantly associated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.24-3.15, P = 0.001) and disease-free survival (DFS) (HR = 2.58, 95% CI: 1.87-3.56, P = 0.000). However, it was not significantly associated with progression-free survival (PFS) (HR = 1.85, 95% CI: 0.90-3.82, P = 0.09) and distant metastasis-free survival (DMFS) (HR = 1.39, 95% CI: 0.73-2.67, P = 0.319). The subgroup analysis indicated that patients with EGFR high expression in studies of higher TNM stage (III-IV) ratio had significantly poor OS (HR = 2.27, 95% CI: 1.09-4.73, P = 0.03), but heterogeneity existed in studies (I2 = 95.1%, P = 0.000). Sensitivity analyses revealed that EGFR expression did not significantly affect OS by an individual study solely, indicating there was inherent heterogeneity in OS cohorts. There was no significant heterogeneity among eight studies in the DFS cohorts (I2 = 0%, P = 0.606). There was significant heterogeneity between EGFR expression and DMFS (I2 = 82.8%, P = 0.000). Sub-group analysis in differentiated carcinoma demonstrated a smaller heterogeneity (I2 = 33.2%). In addition, p-EGFR high expression had no significant correlation with OS (HR = 1.00, 95% CI: 0.88-1.14, P = 0.982) and DMFS (HR = 1.21, 95% CI: 0.96-1.52, P = 0.112). The heterogeneity among p-EGFR and OS studies was small (I2 = 21%, P = 0.26). There was no significant heterogeneity in the DMFS cohorts (I2 = 0%, P = 0.497). CONCLUSION: EGFR high-expression was significantly associated with poor OS and DFS, which may serve as a prognostic predictor for nasopharyngeal cancer. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/PROSPERO], identifier [number CRD42021258457].

CD166 promotes cancer stem cell-like phenotype via the EGFR/ERK1/2 pathway in the nasopharyngeal carcinoma cell line CNE-2R.

AIMS: The present study aimed to investigate the role and underlying mechanisms of CD166 in cancer stem cell-like (CSCs) phenotype of the radioresistant nasopharyngeal carcinoma cell CNE-2R. MAIN METHODS: Established CD166-shRNA- CNE-2R cell line by lentivirus-mediated silencing CD166. Then, CSC-related genes mRNAs and proteins, and EGFR/ERK1/2 signaling pathway were detected using RT-PCR and western blot. Sphere formation assay was performed to evaluate the sphere formation capacity in CD166-shRNA- CNE-2R cells. The tumorigenesis ability in vivo was examined in nude mice mode. KEY FINDINGS: Downregulation of CD166 inhibited the expression of the CSC-related genes, pEGFR and pERK in vitro and vivo. The capacity to form spheres and tumorigenesis was significantly decreased in CD166-shRNA cells. Furthermore, EGF-stimulated CD166-shRNA cells exhibited an increase in CSC-like traits by activating EGFR/ERK1/2 signaling. SIGNIFICANCE: CD166 induced CSCs formation by activating the EGFR/ERK1/2 signaling pathway in nasopharyngeal carcinoma, which may serve as a critical molecular target for NPC therapeutic strategies.

VEGF knockdown enhances radiosensitivity of nasopharyngeal carcinoma by inhibiting autophagy through the activation of mTOR pathway.

Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.

Inhibition of post-trabeculectomy fibrosis via topically instilled antisense oligonucleotide complexes co-loaded with fluorouracil.

Trabeculectomy is the mainstay of surgical glaucoma treatment, while the success rate was unsatisfying due to postoperative scarring of the filtering blebs. Clinical countermeasures for scar prevention are intraoperative intervention or repeated subconjunctival injections. Herein, we designed a co-delivery system capable of transporting fluorouracil and anti-TGF-ß2 oligonucleotide to synergistically inhibit fibroblast proliferation via topical instillation. This co-delivery system was built based on a cationic dendrimer core (PAMAM), which encapsulated fluorouracil within hydrophobic cavity and condensed oligonucleotide with surface amino groups, and was further modified with hyaluronic acid and cell-penetrating peptide penetratin. The co-delivery system was self-assembled into nanoscale complexes with increased cellular uptake and enabled efficient inhibition on proliferation of fibroblast cells. In vivo studies on rabbit trabeculectomy models further confirmed the anti-fibrosis efficiency of the complexes, which prolonged survival time of filtering blebs and maintained their height and extent during wound healing process, exhibiting an equivalent effect on scar prevention compared to intraoperative infiltration with fluorouracil. Qualitative observation by immunohistochemistry staining and quantitative analysis by Western blotting both suggested that TGF-ß2 expression was inhibited by the co-delivery complexes. Our study provided a potential approach promising to guarantee success rate of trabeculectomy and prolong survival time of filtering blebs.

Anti-EGFR therapies in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China and South-East Asia. Regardless of initiative high response to radiotherapy, parts of patients still have relapses and metastases. It is reported that epidermal growth factor receptor (EGFR) is highly expressed in most of NPC and is a poor prognostic factor. Targeting EGFR therapies including monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs), offer different benefits and toxicities for patients with NPC. Herein, we summarize the clinical evidence of anti-EGFR therapies in the management of NPC and provide a direction for the treatment and research of NPC in the future.

A positive feedback loop between Wnt/ß-catenin signaling and hTERT regulates the cancer stem cell-like traits in radioresistant nasopharyngeal carcinoma cells.

Radioresistance may be induced by cancer stem cells (CSCs), while the biological traits of CSCs need to be retained by telomerase. The telomerase activity mainly depends on the transcriptional regulation of human telomerase reverse transcriptase (hTERT). Moreover, Wnt/ß-catenin signaling is also considered essential for maintaining the CSC phenotypes. In the previous study, we discovered that the radioresistant nasopharyngeal carcinoma cells CNE-2R displayed CSC-like traits, as well as high expression of hTERT and ß-catenin, but whether hTERT and ß-catenin were involved in regulating the CSC-like traits and radiosensitivity of CNE-2R cells remained unclear. In this study, our results suggested that hTERT could positively regulate the expression of CSC-related proteins, as well as the cytoplasm- and nucleus-ß-catenin, but it could not markedly regulate the expression of total ß-catenin in CNE-2R cells. Meanwhile, Wnt/ß-catenin signaling had a positive regulatory effect on the expression of hTERT and CSC-related proteins. Moreover, there was a ß-catenin/hTERT protein complex in CNE-2R cells, indicating that ß-catenin could directly interact with hTERT protein. Our results also revealed that silencing hTERT or suppressing Wnt/ß-catenin signaling could attenuate telomerase activity and radioresistance of CNE-2R cells; while suppressing Wnt/ß-catenin signaling, the telomerase activity and radioresistance could be reversed through overexpressing hTERT. Taken together, we have outlined a positive feedback loop between Wnt/ß-catenin signaling and hTERT in CNE-2R cells, which can regulate the telomerase activity and CSC-like traits, thus regulating the radiosensitivity. Therefore, blocking Wnt/ß-catenin signaling transduction and interfering with hTERT expression may be a promising approach for targeting radioresistant nasopharyngeal carcinoma cells with CSC-like traits.

STAT3 signaling in ovarian cancer: a potential therapeutic target.

Accumulating evidence has shown that Signal Transducer and Activator of Transcription 3 (STAT3) is thought to be a promising target for cancer therapy as STAT3 is frequently overexpressed in a wide range of cancer cells as well as clinical specimens, promoting tumor progression. It is widely accepted that STAT3 regulates a variety of cellular processes, such as tumor cell growth, survival, invasion, cancer stem cell-like characteristic, angiogenesis and drug-resistance. In this review, we focus on the role of STAT3 in tumorigenesis in ovarian cancer and discuss the existing inhibitors of STAT3 signaling that can be promisingly developed as the strategies for ovarian cancer therapy.

Pretreatment Plasma EBV-DNA Load Guides Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Cancer: A Meta-Analysis.

BACKGROUND: The efficacy of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal cancer (LA-NPC) is controversial. In this paper, we conduct a meta-analysis based on relevant studies to provide strong evidence for clinical strategies. MATERIALS AND METHODS: We searched the MEDLINE, Embase, Cochrane, PubMed, and Web of Science databases for studies that stratified patients based on a high or low plasma Epstein-Barr virus deoxyribonucleic acid (EBV-DNA) load before treatment and compared the clinical efficacy of IC+CCRT vs. CCRT alone in LA-NPC. We tested for heterogeneity of studies and conducted sensitivity analysis. Subgroup analysis was performed for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). RESULTS: Seven studies with a total of 5289 cases were finally included in the meta-analysis. The heterogeneity test revealed the homogeneity of OS (I 2 = 0.0%, p=0.794), PFS (I 2 = 0.0%, p=0.778), DMFS (I 2 = 0.0%, p=0.997), and LRFS (I 2 = 0.0%, p=0.697) in patients with EBV-DNA loads of ≥4000 copies/ml in both the IC+CCRT and CCRT groups. The results reveal that IC+CCRT significantly extended the OS (HR 0.70 [95% CI 0.58-0.83], p=0.000), PFS (HR 0.83 [95% CI 0.70-0.99], p=0.033), and DMFS (HR 0.79 [95% CI 0.69-0.9], p=0.000) of patients compared with the CCRT group, but there were no beneficial effects on LRFS (HR 1.07 [95% CI 0.80-1.42], p=0.647). The heterogeneity test found that there was no significant heterogeneity of PFS (I 2 = 0.0%, p=0.564), DMFS (I 2 = 0.0%, p=0.648), LRFS (I 2 = 22.3%, p=0.257), and OS (I 2 = 44.6%, p=0.164) in patients with EBV-DNA loads of <4000 copies/ml. The results show that IC+CCRT prolonged DMFS (HR 0.57 [95% CI 0.39-0.85], p=0.006) of patients without significant improvements in OS (HR 0.88 [95% CI 0.55-1.26], p=0.240), PFS (HR 0.98 [95% CI 0.74-1.31], p=0.908), and LRFS (HR 0.98 [95% CI 0.54-1.77], p=0.943). CONCLUSIONS: Pretreatment plasma EBV-DNA can be considered a promising effective marker for the use of IC in LA-NPC patients. The addition of IC could improve the OS and PFS of patients with EBV-DNA load ≥4000 copies/ml, but we saw no efficacy in patients with EBV-DNA load <4000 copies/ml. Moreover, regardless of the EBV-DNA load, IC could improve DMFS, but there was no effect on LRFS.

Platinum single-agent vs. platinum-based doublet agent concurrent chemoradiotherapy for locally advanced cervical cancer: A meta-analysis of randomized controlled trials.

OBJECTIVES: This study compared treatment outcomes and adverse events in patients with locally advanced cervical cancer undergoing radiotherapy (RT) with concurrent platinum-based doublet therapy vs. RT plus platinum single-agent therapy. The main outcomes were progression-free survival (PFS), overall survival (OS), and the occurrence of adverse events. METHODS: We comprehensively searched Medline, Embase, the Cochrane Library, China National Knowledge Web, Wanfang Database, and VIP database, and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) by using the fixed-effect or random-effect models. The primary endpoints were OS and PFS, reported as hazard ratios (HRs) and 95% confidence intervals (95% CIs). The meta-analysis was performed with RevMan 5.2. RESULTS: Seven randomized trials including 1503 patients were identified. The meta-analysis showed that, for locally advanced cervical cancer, concurrent RT with platinum-based doublet chemotherapy significantly improved the OS (HR 0.75, 95% CI 0.60-0.94, p = 0.01) and the PFS (HR 0.78, 95% CI 0.65-0.94，p = 0.01) compared to RT with cisplatin monotherapy. Grade 3 or 4 vomiting (related ratio [RR] = 3.19, 95% CI 1.85-5.49, p < 0.0001) and thrombocytopenia (RR = 2.75, 95% CI 1.39-5.44, p = 0.004) occurred more frequently in the polychemotherapy arm. The incidence of urinary system toxicity tended to be higher in the polychemotherapy arm (RR = 4.58, 95% CI 1.00-20.89, p = 0.05). CONCLUSIONS: Under the premise of good tolerance, RT plus platinum-based doublet therapy improves survival compared to RT plus platinum single-agent therapy in patients with locally advanced cervical cancer.

A novel peptide ligand RAP12 of LRP1 for glioma targeted drug delivery.

The receptor associated protein (RAP) is a 39 kDa chaperone protein, binding tightly to low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed in glioma, tumor neovasculature, vasculogenic mimicry (VM), the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Herein, we miniaturized the RAP protein into a short peptide RAP12 (EAKIEKHNHYQK) aiding by computer-aided peptide design technique. RAP12 contained the essential lysines at the positions 253 and 256. The binding affinity of RAP12 to LRP1 was theoretically and experimentally evaluated. In cellular level, RAP12 could effectively internalize into U87, HUVEC and bEnd.3 cells. When modified on the surface of PEG-PLA micelles (RAP12-PEG-PLA), RAP12 could effectively facilitate the penetration of micelles through the BBB/BBTB in vitro/vivo. Paclitaxel-loaded RAP12-PEG-PLA could remarkably inhibit the growth of glioma cells and the formation of tumor neovasculature and VM, significantly prolong the median survival time of nude mice bearing intracranial glioma in comparison to model mice treated with plain micelles or Taxol. These results suggested that the RAP12 held the potential for multifunctional glioma-targeted drug delivery.

SH3BP1-induced Rac-Wave2 pathway activation regulates cervical cancer cell migration, invasion, and chemoresistance to cisplatin.

Cervical cancer still remains the fourth most common cancer, affecting women worldwide with large geographic variations in cervical cancer incidence and mortality rates. SH3-domain binding protein-1 (SH3BP1) specifically inactivating Rac1 and its target Wave2 is required for cell motility, thus regarded as an essential regulator of cancer cell metastasis. However, the exact effects and molecular mechanisms of SH3BP1 in cervical cancer progression are still unknown. The present study is aimed to investigate the mechanism of SH3BP1 in regulation of cervical cancer cell metastasis and chemoresistance. In the present study, we demonstrated a high SH3BP1 expression in cervical cancer tissues; a higher SH3BP1 expression is also correlated with a shorter overall survival of patients with cervical cancer. Further, we revealed that SH3BP1 overexpression promoted the invasion, migration, and chemoresistance of cervical cancer cell through increasing Rac1 activity and Wave2 protein level. The promotive effect of SH3BP1 could be partially reversed by a Rac1 inhibitor, NSC 23766. In cisplatin-resistant cervical cancer tissues, SH3BP1, Rac1, and Wave2 mRNA expression was significantly up-regulated compared to that of the cisplatin-sensitive cervical cancer tissues. Taken together, SH3BP1/Rac1/Wave2 pathway may potentially act as an effective therapeutic target combined with traditional cisplatin-based chemotherapy for cervical cancer.

A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides.

Inhibition of gene expression by nucleic acids is a promising strategy in the treatment of ocular diseases. However, intraocular delivery of nucleic acids to the posterior ocular tissues remains a great challenge due to the presence of various biological barriers. To circumvent this problem, we established a novel penetratin (P) modified poly(amidoamine) dendrimer (D)/hyaluronic acid (H) complex to deliver antisense oligonucleotides (ASOs, O). Complexes (D/O, HD/O and PHD/O) were easily prepared and modification layers (hyaluronic acid and penetratin) were respectively absorbed on the surface via electrostatic interaction. Complexes with different outer layers were characterized as spherical particles with reversed charges. In vitro cellular uptake of ASOs in PHD/O complex was significantly increased than those in other formulations. In vivo studies were carried out after topical instillation of the complexes in the conjunctival sac of mice. Compared with D/O and HD/O, PHD/O exhibited much more distribution in the posterior segment of the eyes and prolonged retention time of ASOs in retina for more than 8h. Taken together, these results indicated that PHD/O complex possessed substantially improved ocular permeability and distribution in the posterior ocular tissues. This work provided a promising noninvasive intraocular delivery strategy for nucleic acids via topical administration.

Stapled RGD Peptide Enables Glioma-Targeted Drug Delivery by Overcoming Multiple Barriers.

Malignant glioma, the most frequent and aggressive central nervous system (CNS) tumor, severely threatens human health. One reason for its poor prognosis and short survival is the presence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), which restrict the penetration of therapeutics into the brain at different stages of glioma. Herein, inspired by the peptide stapling technique, we designed a cyclic RGD ligand via an all-hydrocarbon staple (stapled RGD, sRGD) to facilitate BBB penetration while retaining the capacity of BBTB penetration and targeting ability to glioma cells. As expected, sRGD-modified micelles were able to penetrate the in vitro BBB model while retaining the glioma targeted capability. The results of the in vivo imaging studies further revealed that this nanocarrier could not only efficiently transverse the intact BBB of normal mice, but also could specifically target glioma cells of intracranial glioma-bearing nude mice. Furthermore, Paclitaxel-loaded sRGD-modified micelles exhibited improved antiglioma efficacy in vitro and significantly prolonged survival time of glioma-bearing nude mice. Overall, this sRGD peptide showed potency for glioma-targeted drug delivery by overcoming multiple barriers.

Noninvasive delivery of oligonucleotide by penetratin-modified polyplexes to inhibit protein expression of intraocular tumor.

Our present study aimed to develop an antisense oligonucleotide (ASO) delivery system to achieve gene silencing in intraocular tumor via topical instillation. ASO specific for luciferase was chosen as model drug, polyamidoamine (PG5) was employed to condense ASO, and penetratin (Pene) was used to enhance cellular uptake. Nanoscale PG5/ASO/Pene polyplex was stabilized via noncovalent bonding. In vitro evaluations indicated that PG5/ASO/Pene exhibited improved cell-penetrating and gene silencing ability compared with naked ASO and PG5/ASO. Subcutaneous and orthotopic tumor models expressing luciferase were established in nude mice. After treated by PG5/ASO/Pene, immunohistochemical results of subcutaneous tumors showed significant inhibition of luciferase expression via peritumoral injection, and bioluminescence from orthotopic tumor was obviously weakened via topical instillation. To date, few works were successful in noninvasive treatment of intraocular diseases using antisense strategy, this penetratin-modified polyplex could be a promising vector to inhibit protein expression by effectively delivering ASOs into the eye.

Glioma-Targeted Drug Delivery Enabled by a Multifunctional Peptide.

The rapid proliferation of glioma relies on vigorous angiogenesis for the supply of essential nutrients; thus, a radical method of antiglioma therapy should include blocking tumor neovasculature formation. A phage display selected heptapeptide, the glioma-initiating cell peptide GICP, was previously reported as a ligand of VAV3 protein (a Rho GTPase guanine nucleotide exchange factor), which is overexpressed on glioma cells and tumor neovasculature. Therefore, GICP holds potential for the multifunctional targeting of glioma (tumor cells and neovasculature). We developed GICP-modified micelle-based paclitaxel delivery systems for antiglioma therapy in vitro and in vivo. GICP and GICP-modified PEG-PLA micelles (GICP-PEG-PLA) could be significantly taken up by U87MG cells, a human cell line derived from malignant gliomas and human umbilical vein endothelial cells (HUVECs). Furthermore, GICP-PEG-PLA micelles demonstrated enhanced penetration in a tumor spheroid model in vitro in comparison to unmodified micelles. In vivo, DiR-loaded GICP-PEG-PLA micelles exhibited superior accumulation in the tumor region by targeting neovasculature and glioma cells in nude mice bearing subcutaneous glioma. When loaded with paclitaxel, GICP-PEG-PLA micelles could more effectively suppress tumor growth and neovasculature formation than unmodified micelles in vivo. Our results indicated that GICP could serve as a promising multifunctional ligand for glioma targeting.