Mitochondria targeted biomimetic platform for chemo/photodynamic combination therapy against osteosarcoma.

Clinical treatment for osteosarcoma (OS) is still lacking effective means, and no significant progress in OS treatment have been made in recent years. Single chemotherapy has serious side effects and can produce drug resistance easily, resulting poor therapeutic effect. As a modern and non-invasive treatment form, photodynamic therapy (PDT) is widely used to treat diverse cancers. Chemotherapy in combination with PDT is a particularly efficient antitumor method that could overcome the defects of monotherapies. Since mitochondria is a key subcellular organelle involved in cell apoptosis regulation, targeting tumor cells mitochondria for drug delivery has become an important entry point for anti-tumor therapy. Herein, we rationally designed a core-shell structured biomimetic nanoplatform, i.e., D@SLNP@OSM-IR780, to achieve tumor homologous targeting and mitochondria targeted drug release for chemotherapy combined with PDT against OS. Upon 808 nm laser irradiation, D@SLNP@OSM-IR780 exhibited excellent photo-cytotoxicity in vitro. The excellent targeting effect of D@SLNP@OSM-IR780 in tumor tissues produced a tumor inhibition rate of 98.9% in vivo. We further indicated that synergistic chemo-photodynamic effect induced by D@SLNP@OSM-IR780 could activate mitochondria-mediated apoptosis pathway, along with host immune response and potential photothermal effect. On the whole, D@SLNP@OSM-IR780 is revealed to be a promising platform for OS targeted combination therapeutics.

Biomimetic lipid nanoparticles for homologous-targeting and enhanced photodynamic therapy against glioma.

Biomimetic nano-platforms have attracted extensive attention due to their good biocompatibility, low immunogenicity, and homologous targeting to lesions. In this study, glioma cell membranes are used to encapsulate indocyanine green (ICG) loaded nanoparticles (SLNP/ICG), termed as SLNP/ICG@M for targeted photodynamic therapy (PDT) against glioma. Cell membrane modification significantly enhances cellular uptake of SLNP/ICG@M in homologous glioma cells in vitro and tumor distribution in vivo. Furthermore, SLNP/ICG@M can stimulate glioma cells to generate plentiful reactive oxygen species (ROS) under NIR irradiation, finally producing excellent photo-cytotoxicity and the optimal tumor growth inhibition with a tumor suppression rate of 93.2%. We also confirm that SLNP/ICG@M combined with NIR irradiation could activate mitochondria mediated apoptosis pathway, and the increased proliferation of CD4+ T cells and CD8+ T cells accompanied by immune activation further enhances PDT effect of SLNP/ICG@M. Herein, SLNP/ICG@M is a promising biomimetic nano drug delivery system for glioma targeted PDT therapy.

Effect of axitinib regulating the pathological blood-brain barrier functional recovery for glioblastoma therapeutics.

AIMS: Dysfunction of the blood-brain barrier (BBB) is a prominent pathological feature of glioblastoma (GBM). Vascular endothelial growth factor (VEGF) is confirmed to be abnormally elevated in the pathogenesis of GBM, causing BBB pathological disruption, which further allows the leakage of neurotoxic blood-derived molecules into the central nervous system (CNS), interfering brain homeostasis and leading to poor patient outcome. Since BBB is an integral and pivotal part of the brain microenvironment, which strongly supports the occurrence and the pathological progression of GBM, here we have selected the VEGFR antagonist axitinib as a BBB functional regulator and hypothesized to regulate pathological BBB restoration for GBM effective treatment. METHODS: The pathological BBB cell model was constructed to investigate the timeliness and dose effect of axitinib regulating pathological BBB restoration. In order to investigate the efficacy and safety of axitinib regulating pathological BBB restoration for anti-GBM treatment, the orthotropic GBM-bearing mice model was established for in vivo study, and bioluminescent imaging was used to real-time and noninvasively monitor tumor growth response in vivo, and survival time was also recorded. RESULTS: Axitinib under non-cytotoxic dosage regulated pathological BBB restoration in a time-dependent mode, and multiple intervention of axitinib could realize a visible restoration of pathological BBB in vitro. Moreover, axitinib treatment restored pathological BBB in orthotropic GBM-bearing mice. We further confirmed that functional restoration of pathological BBB with axitinib had certain curative effect in prolonging median survival of orthotropic GBM-bearing mice at non-cytotoxic dosages in vivo. CONCLUSION: The mechanism of axitinib involved in BBB functional regulation in the treatment of GBM is first illuminated in this report; moreover, this is the first report first referring to regulating pathological BBB functional recovery for GBM effective therapeutics. Overall, the view of regulating pathological BBB functional recovery may offer a novel sight for other CNS diseases relating to BBB permeability effective therapeutics.

Regulation of pathological blood-brain barrier for intracranial enhanced drug delivery and anti-glioblastoma therapeutics.

The blood-brain barrier (BBB) is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system (CNS). During the occurrence and development of glioblastoma (GBM), BBB is pathologically destroyed with a marked increase in permeability. Due to the obstruction of the BBB, current strategies for GBM therapeutics still obtain a meager success rate and may lead to systemic toxicity. Moreover, chemotherapy could promote pathological BBB functional restoration, which results in significantly reduced intracerebral transport of therapeutic agents during multiple administrations of GBM and the eventual failure of GBM chemotherapy. The effective delivery of intracerebral drugs still faces severe challenges. However, strategies that regulate the pathological BBB to enhance the transport of therapeutic agents across the barrier may provide new opportunities for the effective and safe treatment of GBM. This article reviews the structure and function of BBB in physiological states, the mechanisms underlying BBB pathological fenestration during the development of GBM, and the therapeutic strategies of GBM based on BBB intervention and medicinal drugs transporting across the BBB.

siRNA and chemotherapeutic molecules entrapped into a redox-responsive platform for targeted synergistic combination therapy of glioma.

Vascular endothelial growth factor (VEGF) has been implicated as the key regulator of tumor neovascularization. RNAi interference plays a critical role on down-regulation of VEGF, while single VEGF inhibition could not completely suppress angiogenesis and tumor growth; the effect of siRNA is temporary. To improve glioma therapy efficacy, an angiopep-2 (Ap) modified redox-responsive glycolipid-like copolymer co-delivering siVEGF and paclitaxel (PTX), termed as Ap-CSssSA/P/R complexes, was developed in this study. Ap modification significantly enhanced the distribution of Ap-CSssSA in glioma cells both in vitro and in vivo. Ap-CSssSA/P/R complexes could simultaneously deliver siVEGF and PTX into tumor cells, exhibiting great superiority in glioma growth suppression via receptor-mediated targeting delivery and cell apoptosis, accompanied with an obvious inhibition of neovascularization induced by VEGF gene silencing. The present study indicated that the combination delivery of siVEGF and PTX via Ap-modified copolymeric micelles presented a promising and safe platform for glioma targeted therapeutics.

AKT activation by SC79 to transiently re-open pathological blood brain barrier for improved functionalized nanoparticles therapy of glioblastoma.

Glioblastoma (GBM) is one of the malignant tumors with high mortality, and the presence of the blood brain barrier (BBB) severely limits the penetration and tissue accumulation of therapeutic agents in the lesion of GBM. Active targeting nanotechnologies can achieve efficient drug delivery in the brain, while still have a very low success rate. Here we revealed a previously unexplored phenomenon that chemotherapy with active targeting nanotechnologies causes pathological BBB functional recovery through VEGF-PI3K-AKT signaling pathway inhibition, accompanied with up-regulated expression of Claudin-5 and Occludin. Seriously, pathological BBB functional recovery induces a significant decrease of intracerebral active targeting nanotechnologies transport during GBM multiple administration, leading to chemotherapy failure in GBM therapeutics. To address this issue, we chose AKT agonist SC79 to transiently re-open functional recovering pathological BBB for continuously intracerebral delivery of brain targeted nanotherapeutics, finally producing an observable anti-GBM effect in vivo, which may offer new sight for other CNS disease treatment.

A novel technique of using a miniature plate in combination with tension band wiring to treat comminuted patellar fractures.

Traditionally, tension band fixation has been used for treating simple fracture patterns; however, fixation remains a challenge, especially for comminuted fractures. We describe a new method of operation using a combination of a miniature plate with tension band wiring to treat comminuted patellar fractures. The aim of this technique is to transform complicate fractures into simple transverse fractures. As far as we know, no studies using a similar method have been found.The purpose of this study was to assess the effectiveness of a novel technique in which a miniature plate is used in combination with tension band wiring to treat comminuted patellar fractures.Between March 2013 and May 2015, 16 patients with closed, displaced, comminuted fractures of the patella were included in the present study. All subjects underwent fixation using a combination of a miniature plate with a tension band wire. Knee function and patient status were evaluated at 12 months using the Böstman knee score and Lysholm knee scale.The average follow-up period was 15.6 months (range, 12-20 months). At the 12-month follow-up, bone healing was satisfactory in all patients. The average postoperative Lysholm score was 91.6 ±â€Š1.4 (range, 84-97). The average postoperative Böstman scale score was 26.4 ±â€Š0.5 (range, 22-30), thereby indicating excellent results in 4 patients and good results in 12. No patients required reoperation.The results demonstrate that this new technique is an effective and safe treatment option for comminuted patella fractures, as it is associated with good clinical outcomes.

ABT-737 potentiates cisplatin-induced apoptosis in human osteosarcoma cells via the mitochondrial apoptotic pathway.

ABT-737 is a BH-3 mimetic that inhibits Bcl-2 and induces apoptosis of cancer cells, which has potential for anticancer therapies. Studies have shown that Bcl-2 expression in human osteosarcoma (OS) cells plays a significant role in tumor progression; however, its effects on OS cell apoptosis are still unknown. Therefore, we examined whether ABT-737 was effective in eliminating human U-2OS cells, either alone or in combination with the chemotherapy drug cisplatin [cis-diamminedichloroplatinum (II); DDP]. Furthermore, we studied the molecular mechanisms of ABT-737 in combination with DDP to induce apoptosis. To analyze the role of ABT-737 and/or DDP on osteosarcoma progression, CCK-8 viability assay, flow cytometry, Hoechst 33258 staining, and western blots were performed. Combined use of ABT-737 and DDP synergistically suppressed cell viability and induced apoptosis in human U-2OS cells when compared with either compound treated alone at low doses. We found that the combination of ABT-737 and DDP upregulated the expression of the pro-apoptotic protein Bax and downregulated the expression of the pro-survival protein Bcl-2, resulting in a change in the Bax/Bcl-2 ratio, release of cytochrome c, and activation of the mitochondrial apoptotic pathway, which resulted in caspase-9 and caspase-3 activation and PARP cleavage. Our results demonstrated that ABT-737 alone has a nominal influence on human U-2OS cells when treated within the clinically administered range, but when combined with DDP, it can inhibit the proliferation of human U-2OS cells by inducing apoptosis via the mitochondrial apoptotic pathway.

Mucinous tumor arising in a giant sacrococcygeal teratoma: A rare case report.

RATIONALE: Teratomas, which most frequently affect adult females, are the most common type of germ cell tumor, it always comprises derivatives of at least 2 germ layers. The most common site of primary teratomas is the ovary. Sacrococcygeal teratomas (SCTs), which are exceedingly rare in adults, are generally found in newborns or children. PATIENT CONCERNS: A 39-year-old woman presented to our clinic with a 1-year history of gradually aggravated difficulty in micturition and defecation, and a tumor in her right buttock present since birth. Appropriate preoperative examinations showed a large (15.6 cm × 12.2 cm × 30.0 cm) multicystic SCT. DIAGNOSES: Histologic examination confirmed a mucinous tumor arising in a giant SCT. INTERVENTIONS: Abdominoperineal rectal resection was performed. OUTCOMES: The patient recovered well and was discharged on day 33 of admission. LESSONS: We report the first case of a mucinous tumor arising in an SCT, in which the teratoma presented mature tissue elements derived only from the endodermal germ layer (keratinous debris).