ABSTRACT
Due to a unique cortical venous drainage pattern without sinus drainage, ethmoidal dural arteriovenous fistula (DAVF) are uncommon cerebral vascular lesions that carry a high risk of brain bleeding and neurologic deficit. Surgical intervention has been found to have a lower complication rate and a more satisfactory obliteration rate than endovascular treatment among the various DAVF treatment options. The supraorbital keyhole subfrontal approach is one of the least invasive and appropriate surgical techniques for addressing the anterior fossa vascular lesion in eDAVFs. We describe two men, ages 60 and 71, who underwent this surgical intervention to treat asymptomatic Cognard type IV eDAVFs. Complete obliteration with a detached fistulous point and skeletonization was accomplished with the aid of intraoperative neuronavigation. Thus, we suggest that a suitable surgical method for the treatment of eDAVFs would be to use a supraorbital keyhole subfrontal approach.
Subject(s)
Central Nervous System Vascular Malformations , Humans , Male , Middle Aged , Central Nervous System Vascular Malformations/surgery , Central Nervous System Vascular Malformations/diagnostic imaging , Aged , Treatment OutcomeABSTRACT
Herein, we fabricated gold surface-coated iron titanium core-shell (FeTi@Au) nanoparticles (NPs) with conjugation of angiopep-2 (ANG) (FeTi@Au-ANG) NPs for targeted delivery and improved NPs penetration by receptor-mediated endocytosis to achieve hyperthermic treatment of gliomas. The synthesized "core-shell" FeTi@Au-ANG NPs exhibited spherical in shape with around 16 nm particle size and increased temperature upon alternating magnetic field (AMF) stimulation, rendering them effective for localized hyperthermic therapy of cancer cells. Effective targeted delivery of FeTi@Au-ANG NPs was demonstrated in vitro by improved transport and cellular uptake, and increased apoptosis in glioma cells (C6) compared with normal fibroblast cells (L929). FeTi@Au-ANG NPs exhibited higher deposition in brain tissues and a superior therapeutic effect in an orthotopic intracranial xenograft mouse model. Taken together, our data indicate that FeTi@Au-ANG NPs hold significant promise as a targeted delivery strategy for glioma treatment using hyperthermia.
Subject(s)
Glioma , Hyperthermia, Induced , Nanoparticles , Humans , Mice , Animals , Cell Line, Tumor , Glioma/drug therapy , Gold/therapeutic useABSTRACT
The poor permeability of therapeutic agents across the blood-brain barrier and blood-tumor barrier is a significant barrier in glioma treatment. Low-density lipoprotein receptor-related protein (LRP-1) recognises a dual-targeting ligand, angiopep-2, which is overexpressed in the BBB and gliomas. Here, we have synthesized Ti@FeAu core-shell nanoparticles conjugated with angiopep-2 (Ti@FeAu-Ang nanoparticles) to target glioma cells and treat brain cancer via hyperthermia produced by a magnetic field. Our results confirmed that Ti@FeAu core-shell nanoparticles were superparamagnetic, improved the negative contrast effect on glioma, and exhibited a temperature elevation of 12° C upon magnetic stimulation, which implies potential applications in magnetic resonance imaging (MRI) and hyperthermia-based cancer therapy. Angiopep-2-decorated nanoparticles exhibited higher cellular uptake by C6 glioma cells than by L929 fibroblasts, demonstrating selective glioma targeting and improved cytotoxicity up to 85% owing to hyperthermia produced by a magnetic field. The in vivo findings demonstrated that intravenous injection of Ti@FeAu-Ang nanoparticles exhibited a 10-fold decrement in tumor volume compared to the control group. Furthermore, immunohistochemical analysis of Ti@FeAu-Ang nanoparticles showed that coagulative necrosis of tumor tissues and preliminary safety analysis highlighted no toxicity to the haematological system, after Ti@FeAu-Ang nanoparticle-induced hyperthermia treatment.
Subject(s)
Brain Neoplasms , Glioma , Magnetite Nanoparticles , Nanoparticles , Alloys , Blood-Brain Barrier/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/therapy , Cell Line, Tumor , Diagnostic Imaging , Drug Delivery Systems/methods , Glioma/drug therapy , Glioma/therapy , Humans , Ligands , Lipoproteins, LDL , Peptides , Theranostic Nanomedicine , Titanium/pharmacologyABSTRACT
Malignant gliomas (MGs) are the most common and devastating primary brain tumor. At present, surgical interventions, radiotherapy, and chemotherapy are only marginally effective in prolonging the life expectancy of patients with MGs. Inherent heterogeneity, aggressive invasion and infiltration, intact physical barriers, and the numerous mechanisms underlying chemotherapy and radiotherapy resistance contribute to the poor prognosis for patients with MGs. Various studies have investigated methods to overcome these obstacles in MG treatment. In this review, we address difficulties in MG treatment and focus on promising polymeric local drug delivery systems. In contrast to most local delivery systems, which are directly implanted into the residual cavity after intratumoral injection or the surgical removal of a tumor, some rapidly developing and promising nanotechnological methods-including surface-decorated nanoparticles, magnetic nanoparticles, and focused ultrasound assist transport-are administered through (systemic) intravascular injection. We also discuss further synergistic and multimodal strategies for heightening therapeutic efficacy. Finally, we outline the challenges and therapeutic potential of these polymeric drug delivery systems.
Subject(s)
Drug Carriers , Glioma/drug therapy , Polymers , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Combined Modality Therapy , Drug Carriers/chemistry , Humans , Polymers/chemistryABSTRACT
BACKGROUND: Postoperative tissue adhesion is a major concern for most surgeons and is a nearly unpreventable complication after abdominal or pelvic surgeries. This study explored the use of sandwich-structured antimicrobial agents, analgesics, and human epidermal growth factor (hEGF)-incorporated anti-adhesive poly(lactic-co-glycolic acid) nanofibrous membranes for surgical wounds. MATERIALS AND METHODS: Electrospinning and co-axial electrospinning techniques were utilized in fabricating the membranes. After spinning, the properties of the prepared membranes were assessed. Additionally, high-performance liquid chromatography and enzyme-linked immunosorbent assays were utilized in assessing the in vitro and in vivo liberation profiles of the pharmaceuticals and the hEGF from the membranes. RESULTS: The measured data suggest that the degradable anti-adhesive membranes discharged high levels of vancomycin/ceftazidime, ketorolac, and hEGF in vitro for more than 30, 24, and 27 days, respectively. The in vivo assessment in a rat laparotomy model indicated no adhesion in the peritoneal cavity at 14 days post-operation, demonstrating the anti-adhesive capability of the sandwich-structured nanofibrous membranes. The nanofibers also released effective levels of vancomycin, ceftazidime, and ketorolac for more than 28 days in vivo. Histological examination revealed no adverse effects. CONCLUSION: The outcomes of this study implied that the anti-adhesive nanofibers with sustained release of antimicrobial agents, analgesics, and growth factors might offer postoperative pain relief and infection control, as well as promote postoperative healing of surgical wounds.
Subject(s)
Analgesics/pharmacology , Anti-Infective Agents/pharmacology , EGF Family of Proteins/metabolism , Membranes, Artificial , Nanofibers/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Adhesiveness/drug effects , Analgesics/chemistry , Animals , Anti-Infective Agents/chemistry , Humans , Rats , Surgical Wound/physiopathology , Wound Healing/drug effectsABSTRACT
Glioblastoma multiforme (GBM) has remained one of the most lethal and challenging cancers to treat. Previous studies have shown encouraging results when irinotecan was used in combination with temozolomide (TMZ) for treating GBM. However, irinotecan has a narrow therapeutic index: a slight dose increase in irinotecan can induce toxicities that outweigh its therapeutic benefits. SN-38 is the active metabolite of irinotecan that accounts for both its anti-tumor efficacy and toxicity. In our previous paper, we showed that SN-38 embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs) provides an efficient delivery and sustained release of SN-38 from SMPs in the brain tissues of rats. These properties of SMPs give them potential for therapeutic application due to their high efficacy and low toxicity. In this study, we tested the anti-tumor activity of SMP-based interstitial chemotherapy combined with TMZ using TMZ-resistant human glioblastoma cell line-derived xenograft models. Our data suggest that treatment in which SMPs are combined with TMZ reduces tumor growth and extends survival in mice bearing xenograft tumors derived from both TMZ-resistant and TMZ-sensitive human glioblastoma cell lines. Our findings demonstrate that combining SMPs with TMZ may have potential as a promising strategy for the treatment of GBM.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Glioblastoma/drug therapy , Irinotecan/pharmacology , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Temozolomide/pharmacology , Animals , Apoptosis/drug effects , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Delivery Systems , Drug Liberation , Glioblastoma/mortality , Glioblastoma/pathology , Humans , Irinotecan/adverse effects , Mice , Microplastics/chemistry , Microscopy, Electron, Scanning , Rats , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors. Intracranial GBM metastases to the spine are rarely detected clinically. Secondary gliosarcomas after treatment of primary GBM are rarely described. CASE PRESENTATION: Herein, we report the case of a 53-year-old woman who presented to our emergency room with progressive headache and weakness on the left side. Plain computed tomography and contrast magnetic resonance imaging of the brain revealed an approximately 6.8 cm × 4.5 cm right temporoparietooccipital intraaxial cystic tumor with surrounding diffuse perifocal edema that caused midline shift toward the left. Emergency craniotomy was performed to remove the tumor, and pathological examination revealed GBM. The patient received proton beam therapy, Gliadel implantation, and oral temozolomide chemotherapy as well as targeted therapy with bevacizumab. Approximately 15 months after diagnosis, she underwent surgical resection of the right temporal recurrent tumor and was newly diagnosed as having a metastatic spinal tumor. Pathologically, the right temporal and metastatic spinal tumors were gliosarcoma and GBM, respectively. CONCLUSIONS: Concurrent spinal metastasis and gliosarcomatous transformation, which are two types of GBM complications, are rare. To our knowledge, this is the first report of a case of recurrent GBM with gliosarcoma after proton bean therapy.
Subject(s)
Brain Neoplasms/pathology , Brain/pathology , Glioblastoma/secondary , Gliosarcoma/pathology , Neoplasm Recurrence, Local/pathology , Spinal Neoplasms/secondary , Antineoplastic Agents, Alkylating/therapeutic use , Brain/diagnostic imaging , Brain/surgery , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/therapy , Craniotomy , Fatal Outcome , Female , Glioblastoma/diagnostic imaging , Glioblastoma/therapy , Humans , Magnetic Resonance Imaging , Middle Aged , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/therapy , Proton Therapy , Spinal Neoplasms/diagnostic imaging , Spinal Neoplasms/surgery , Temozolomide/therapeutic use , Tomography, X-Ray ComputedABSTRACT
Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups-group A (n = 13; stereotactically injected pure PLGA microparticles), group B (n = 12; stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13; stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG.
ABSTRACT
We successfully synthesized a strontium-doped tricalcium silicate (SrxCa3-xSiO5, Srâ¯=â¯0 to 2â¯mol%) bone cement using the sol-gel process. The material properties including crystallinity, setting time, mechanical strength, and hydration products were characterized. Release of ions and pH values of simulated body fluid soaked with the bone cement were measured. In vitro biocompatibility of different concentrations of the material was evaluated by the viability of L929 cells. The setting times of as-prepared slurries were all <70â¯min. Doping with 0.5â¯mol% Sr reduced the final setting time by 20â¯min. After 14â¯days curing, 0.25â¯mol% Sr-doped SrxCa3-xSiO5 possessed the highest compressive strength of 45â¯MPa among all the Sr-doped groups with no statistical difference to Ca3SiO5. The bioactivity of the materials was confirmed with the formation of an apatite layer on the surface of the materials after immersion in simulated body fluid. In addition, the proliferation of L929 cells exposed to 1â¯mol% Sr was significantly promoted as compared to no Sr doping. SrxCa3-xSiO5 is a novel and advanced material that has the potential to serve as a bone cement in bone restoration with appropriate mechanical strength and favorable biocompatibility.
Subject(s)
Bone Cements , Calcium Compounds , Cell Proliferation/drug effects , Materials Testing , Silicates , Strontium , Animals , Bone Cements/chemical synthesis , Bone Cements/chemistry , Bone Cements/pharmacology , Calcium Compounds/chemical synthesis , Calcium Compounds/chemistry , Calcium Compounds/pharmacology , Cell Line , Mice , Phase Transition , Silicates/chemical synthesis , Silicates/chemistry , Silicates/pharmacology , Strontium/chemistry , Strontium/pharmacologyABSTRACT
Brain abscesses are emergent and life-threating despite advances in modern neurosurgical techniques and antibiotics. The present study explores the efficacy of vancomycin embedded to 50:50 poly(lactic-co-glycolide acid) (PLGA) microparticles in the treatment of brain abscess. The vancomycin embedded microparticles (VMPs) were stereotactically introduced into the cerebral parenchyma in Staphylococcus aureus bacteria- induced brain abscess-bearing rats. Experimental rats were divided into three groups: group A (n = 13; no treatment), group B (n = 14; daily vancomycin injection (5 mg intraperitoneally), and group C (n = 12; stereotactic introduction of VMPs into the abscess cavity). Group C exhibited no inflammatory response and significantly increased survival and reduced mean abscess volumes (p <0.001) at the eighth week, compared with other groups. Vancomycin delivery via a biodegradable PLGA vehicle can easily attain Area Under the Curve (AUC)/minimum inhibitory concentration (MIC) ratios of ≥400, and strengthens the therapeutic efficacy of antibiotics without provoking any potential toxicity. Biodegradable VMPs are a safe and sustainable drug delivery vehicle for the treatment of brain abscess.
ABSTRACT
BACKGROUND: Malignant gliomas (MGs) are highly chemotherapy-resistant. Temozolomide (TMZ) and carmustine (BiCNU) are alkylating agents clinically used for treating MGs. However, their effectiveness is restrained by overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in tumors. O6-benzylguanine (O6-BG) is a nonreversible inhibitor of MGMT, it promotes the cytotoxicity of alkylating chemotherapy. The authors have developed a hybrid-structured nanofibrous membrane (HSNM) that sequentially delivers high concentrations of O6-BG, BiCNU, and TMZ in an attempt to provide an alternative to the current therapeutic options for MGs. METHODS: The HSNMs were implanted onto the cerebral surface of pathogen-free rats following surgical craniectomy, while the in vivo release behaviors of O6-BG, TMZ, and BiCNU from the HSNMs were explored. Subsequently, the HSNMs were surgically implanted onto the brain surface of two types of tumor-bearing rats. The survival rate, tumor volume, malignancy of tumor, and apoptotic cell death were evaluated and compared with other treatment regimens. RESULTS: The biodegradable HSNMs sequentially and sustainably delivered high concentrations of O6-BG, BiCNU, and TMZ for more than 14 weeks. The tumor-bearing rats treated with HSNMs demonstrated therapeutic advantages in terms of retarded and restricted tumor growth, prolonged survival time, and attenuated malignancy. CONCLUSION: The results demonstrated that O6-BG potentiates the effects of interstitially transported BiCNU and TMZ. Therefore, O6-BG may be required for alkylating agents to offer maximum therapeutic benefits for the treatment of MGMT-expressing tumors. In addition, the HSNM-supported chemoprotective gene therapy enhanced chemotherapy tolerance and efficacy. It can, therefore, potentially provide an improved therapeutic alternative for MGs.
ABSTRACT
Background: This study exploited sheath-core-structured lidocaine/human EGF (hEGF)-loaded anti-adhesive poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibrous films for surgical wounds via a co-axial electrospinning technique. Materials and methods: After spinning, the properties of the co-axially spun membranes were characterized by scanning electron microscopy, laser-scanning confocal microscopy, Fourier Transform Infrared spectrometry, water contact angle measurements, and tensile tests. Furthermore, a HPLC analysis and an ELISA evaluated the in vitro and in vivo release curves of lidocaine and hEGF from the films. Results: PLGA anti-adhesion nanofibers eluted high levels of lidocaine and hEGF for over 32 and 27 days, respectively, in vitro. The in vivo evaluation of post-surgery recovery in a rat model demonstrated that no adhesion was noticed in tissues at 2 weeks after surgery illustrating the anti-adhesive performance of the sheath-core-structured nanofibers. Nanofibrous films effectively released lidocaine and hEGF for >2 weeks in vivo. In addition, rats implanted with the lidocaine/hEGF nanofibrous membranes exhibited greater activities than the control demonstrating the pain relief efficacy of the films. Conclusion: The empirical outcomes suggested that the anti-adhesive nanofibrous films with extended release of lidocaine and hEGF offer post-operative pain relief and wound healing.
Subject(s)
Adhesives/therapeutic use , Epidermal Growth Factor/therapeutic use , Nanofibers/chemistry , Pain/drug therapy , Surgical Wound/drug therapy , Wound Healing/drug effects , Adhesives/pharmacology , Anesthetics, Local/pharmacology , Animals , Cell Survival/drug effects , Drug Liberation , Epidermal Growth Factor/pharmacology , Humans , Lidocaine/pharmacology , Lidocaine/therapeutic use , Male , Nanofibers/ultrastructure , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Surgical Wound/pathologyABSTRACT
In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood-brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24 h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.
Subject(s)
Apoptosis/drug effects , Autophagy/drug effects , Biphenyl Compounds/pharmacology , Lignans/pharmacology , Neuroblastoma/genetics , Neuroblastoma/pathology , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Suppressor Protein p53/metabolism , Caspase 3/genetics , Caspase 3/metabolism , Cell Survival/drug effects , Humans , Time Factors , Tumor Cells, CulturedABSTRACT
Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small-molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase-3/7-activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1-CDK1 and cyclin A-CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent-G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1-mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , G2 Phase Cell Cycle Checkpoints/drug effects , Medulloblastoma/metabolism , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Biomarkers , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinases/metabolism , Dose-Response Relationship, Drug , G2 Phase Cell Cycle Checkpoints/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Medulloblastoma/genetics , Protein Processing, Post-TranslationalABSTRACT
Chemotherapy is ineffective for treating malignant glioma (MG) because of the low therapeutic levels of pharmaceuticals in tumour tissues and the well-known tumour resistance. The resistance to alkylators is modulated by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT). O6-benzylguanine (O6-BG) can irreversibly inactivate AGT by competing with O6-methylguanine and has been confirmed to increase the therapeutic activity of alkylators. We developed hybrid-structured poly[(d,l)-lactide-co-glycolide] nanofibrous membranes (HSNMs) that enable the sequential and sustained release of O6-BG and two alkylators (carmustine and temozolomide [TMZ]). HSNMs were surgically instilled into the cerebral cavity of pathogen-free rats and F98 glioma-bearing rats. The release behaviours of loaded drugs were quantified by using high-performance liquid chromatography. The treatment results were compared with the rats treated with intraperitoneal injection of O6-BG combined with surgical implantation of carmustine wafer and oral TMZ. The HSNMs revealed a sequential drug release behaviour with the elution of high drug concentrations of O6-BG in the early phase, followed by high levels of two alkylators. All drug concentrations remained high for over 14 weeks. Tumour growth was slower and the mean survival time was significantly prolonged in the HSNM-treated group. Biodegradable HSNMs can enhance therapeutic efficacy and prevent toxic systemic effects.
Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Genetic Therapy , Glioma/pathology , Glioma/therapy , Nanofibers/chemistry , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Liberation , Glioma/drug therapy , Glioma/genetics , Magnetic Resonance Imaging , Male , Rats , Survival Analysis , Tumor Burden/drug effectsABSTRACT
BACKGROUND: Endovascular repair for mycotic aortic aneurysm (MAA) is a less invasive alternative to open surgery, although the placement of a stent graft in an infected environment remains controversial. In this study, we developed hybrid biodegradable, vancomycin-eluting, nanofiber-loaded endovascular prostheses and evaluated antibiotic release from the endovascular prostheses both in vitro and in vivo. METHODS: Poly(D,L)-lactide-co-glycolide and vancomycin were dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. This solution was electrospun into nanofibrous tubes, which were mounted onto commercial vascular stents and endovascular aortic stent grafts. In vitro antibiotic release from the nanofibers was characterized using an elution method and high-performance liquid chromatography. Antibiotic release from the hybrid stent graft was analyzed in a three-dimensional-printed model of a circulating MAA. The in vivo drug release characteristics were examined by implanting the antibiotic-eluting stents in the abdominal aorta of New Zealand white rabbits (n = 15). RESULTS: The in vitro study demonstrated that the biodegradable nanofibers and the nanofiber-loaded stent graft provided sustained release of high concentrations of vancomycin for up to 30 days. The in vivo study showed that the nanofiber-loaded stent exhibited excellent biocompatibility and released high concentrations of vancomycin into the local aortic wall for 8 weeks. CONCLUSIONS: The proposed biodegradable vancomycin-eluting nanofibers significantly contribute to the achievement of local and sustainable delivery of antibiotics to the aneurysm sac and the aortic wall, and these nanofibers may have therapeutic applications for MAAs.
Subject(s)
Absorbable Implants , Aneurysm, Infected/surgery , Anti-Bacterial Agents/administration & dosage , Aorta, Abdominal/surgery , Aortic Aneurysm/surgery , Blood Vessel Prosthesis Implantation/instrumentation , Blood Vessel Prosthesis , Endovascular Procedures/instrumentation , Lactic Acid/chemistry , Nanofibers , Polyglycolic Acid/chemistry , Vancomycin/administration & dosage , Aneurysm, Infected/diagnostic imaging , Aneurysm, Infected/microbiology , Animals , Anti-Bacterial Agents/pharmacokinetics , Aorta, Abdominal/metabolism , Aortic Aneurysm/diagnostic imaging , Aortic Aneurysm/microbiology , Aortography/methods , Computed Tomography Angiography , Delayed-Action Preparations , Drug Implants , Drug Liberation , Humans , Male , Models, Anatomic , Models, Animal , Models, Cardiovascular , Polylactic Acid-Polyglycolic Acid Copolymer , Printing, Three-Dimensional , Prosthesis Design , Rabbits , Vancomycin/pharmacokineticsABSTRACT
Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromatography. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Brain/drug effects , Drug Delivery Systems , Membranes, Artificial , Nanofibers/chemistry , Animals , Brain/pathology , Drug Liberation , Glial Fibrillary Acidic Protein/metabolism , Humans , Immunohistochemistry , Rats, Wistar , Time FactorsABSTRACT
BACKGROUND: Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity. METHODS: We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit. RESULTS: MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors. CONCLUSIONS: These results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells.
Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cerebellar Neoplasms/drug therapy , Medulloblastoma/drug therapy , Neoplastic Stem Cells/drug effects , Antineoplastic Agents/administration & dosage , Autophagy/drug effects , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Cell Survival , Cisplatin/therapeutic use , Drug Synergism , Drug Therapy, Combination , Humans , Oligopeptides/therapeutic use , Thiazoles/therapeutic use , Vincristine/therapeutic useABSTRACT
Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Glioma/drug therapy , Nanofibers/statistics & numerical data , Animals , Bibenzyls/metabolism , Brain/pathology , Brain/surgery , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Cisplatin/therapeutic use , Disease Models, Animal , Drug Delivery Systems , Ethylnitrosourea/analogs & derivatives , Ethylnitrosourea/therapeutic use , Humans , Irinotecan , Lactic Acid/chemistry , Male , Nanofibers/chemistry , Neurosurgical Procedures , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , Rats, Wistar , Tumor Burden/drug effectsABSTRACT
Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma.