Enhanced Anti-Tumor Activity in Mice with Temozolomide-Resistant Human Glioblastoma Cell Line-Derived Xenograft Using SN-38-Incorporated Polymeric Microparticle.

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.

Sustained local delivery of high-concentration vancomycin from a hybrid biodegradable, antibiotic-eluting, nanofiber-loaded endovascular prosthesis for treatment of mycotic aortic aneurysms.

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.

Angiopep-2-decorated titanium-alloy core-shell magnetic nanoparticles for nanotheranostics and medical imaging.

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.

Role of Polymeric Local Drug Delivery in Multimodal Treatment of Malignant Glioma: A Review.

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.

Assessment of Antimicrobial Agents, Analgesics, and Epidermal Growth Factors-Embedded Anti-Adhesive Poly(Lactic-Co-Glycolic Acid) Nanofibrous Membranes: In vitro and in vivo Studies.

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.

Study on strontium doped tricalcium silicate synthesized through sol-gel process.

We successfully synthesized a strontium-doped tricalcium silicate (SrxCa3-xSiO5, Sr = 0 to 2 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 <70 min. Doping with 0.5 mol% Sr reduced the final setting time by 20 min. After 14 days curing, 0.25 mol% Sr-doped SrxCa3-xSiO5 possessed the highest compressive strength of 45 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 1 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.

Anesthetics and human epidermal growth factor incorporated into anti-adhesive nanofibers provide sustained pain relief and promote healing of surgical wounds.

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.

Percutaneous polymethylmethacrylate vertebroplasty in the treatment of pain induced by metastatic spine tumor.

BACKGROUND: Metastases to the spine are a common problem in the large oncology center and represent a challenging problem in oncology practice. Patients with osteolytic metastases often experience intractable local and/or radicular pain. Therapeutic intervention can alleviate pain, preserve or improve neurologic function, achieve mechanical stability, and improve quality of life. Percutaneous polymethylmethacrylate vertebroplasty is an effective and relatively easy method of relieving patients' pain. METHOD: Between January 2002 and December 2006, 57 patients (78 vertebrae) with spinal metastatic tumor treated with PMMA vertebroplasty were enrolled in this study. The main indication for treatment was pain. RESULT: The mean value of VAS was 8.1+/-0.67 preoperatively, and it significantly decreased to 3.8+/-1.9 (1-8, P<.015) 1 day after vertebroplasty. The mean VAS value 6 months after vertebroplasty was 2.8+/-2.0 (P<.001). The mean amounts of preoperative nonnarcotic analgesic and narcotic analgesic were 1.98+/-1.4 and 1.19+/-0.73, respectively. Postoperatively, the mean amounts of nonnarcotic and narcotic analgesic decreased to 1.35+/-0.70 (P<.05) and 0.65+/-0.53 (P<.05). A statistically significant reduction of nonnarcotic analgesic use was noticed in our study. CONCLUSIONS: Percutaneous vertebroplasty is a minimally invasive procedure that offers a remarkable advantage of effective and immediate pain relief with few complications.

Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes.

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.

Advanced interstitial chemotherapy for treating malignant glioma.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most prevalent primary neoplasm of the brain. Moreover, the prognosis of patients with GBM has been poor, with almost uniform progressive neurological impairment and rapid death. Despite the availability of multimodal treatments through surgery, focal radiation, and chemotherapy, no major progress has been reported until recently. Area covered: The development of interstitial biodegradable carmustine wafers (Gliadel) for treating selected patients with malignant gliomas has resulted in marginal survival benefits in such patients (only approximately 2 months longer than that of those who did not receive the treatment). Therefore, this study summarizes several recent representative studies, presents emerging studies, and highlights the directions for additional developments in this area. An overview of the current knowledge of preclinical developments, efficacy and safety observed in clinical trials and practice following drug approval, and future avenues of research is imperative. Expert opinion: Studies are being conducted to improve the efficacy of interstitial chemotherapy by using nanobiotechnology and polymeric material science in addition to different chemotherapeutic, antiangiogenesic, and gene therapy agents and growth factors. Nanocarrier-based noninvasive techniques may have considerable potential to enhance the efficacy of GBM treatment.

Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes.

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.

Nanofibers used for the delivery of analgesics.

Nanofibers are extremely advantageous for drug delivery because of their high surface area-to-volume ratios, high porosities and 3D open porous structures. Local delivery of analgesics by using nanofibers allows site-specificity and requires a lower overall drug dosage with lower adverse side effects. Different analgesics have been loaded onto various nanofibers, including those that are natural, synthetic and copolymer, for various medical applications. Analgesics can also be singly or coaxially loaded onto nanofibers to enhance clinical applications. In particular, analgesic-eluting nanofibers provide additional benefits to preventing wound adhesion and scar formation. This paper reviews current research and breakthrough discoveries on the innovative application of analgesic-loaded nanofibers that will alter the clinical therapy of pain.

Biodegradable vancomycin-eluting poly[(d,l)-lactide-co-glycolide] nanofibres for the treatment of postoperative central nervous system infection.

The incidence of postoperative central nervous system infection (PCNSI) is higher than 5%-7%. Successful management of PCNSI requires a combined therapy of surgical debridement and long-term antibiotic treatment. In this study, Duraform soaked in a prepared bacterial solution was placed on the brain surface of rats to induce PCNSI. Virgin poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibrous membranes (vehicle-control group) and vancomycin-eluting PLGA membranes (vancomycin-nanofibres group) were implanted. The wound conditions were observed and serial brain MRI and pathology examinations were performed regularly. PCNSI was consistently induced in a single, simple step. In the vehicle-control group, most rats died within 1 week, and the survival rate was low (odds ratio = 0.0357, 95% confidence interval = 0.0057-0.2254). The wounds and affected cerebral tissues necrosed with purulence and increased in mass from the resulting PCNSI volumes. Initially, the mean PCNSI volumes showed no significant difference between the two groups. The PCNSI volume in the rats in the vancomycin-nanofibres group significantly decreased (P < 0.01), and the wound appearance was excellent. Pathologic examinations revealed that the necrosis and leukocyte infiltration area decreased considerably. The experimental results suggest that vancomycin-eluting PLGA nanofibres are favourable candidates for treating PCNSI after surgical debridement.

Biodegradable poly([D,L]-lactide-co-glycolide) nanofibers for the sustainable delivery of lidocaine into the epidural space after laminectomy.

AIM: We developed biodegradable, lidocaine-embedded poly([D,L]-lactide-co-glycolide) nanofibers for epidural analgesia to reduce the severe pain in rats after laminectomies. MATERIALS & METHODS: Nanofibers were prepared by an electrospinning process and were introduced into the epidural space of rats after laminectomy. The lidocaine concentration, postoperative bodyweight change and amount of food/water intake were monitored to evaluate the analgesic effectiveness of the drug-eluting nanofibers. RESULTS: It was demonstrated that the nanofibers provided a sustained release of lidocaine for more than 2 weeks, and the local pharmaceutical concentration was much higher than the concentration in plasma. Rats that received laminectomies without nanofibers exhibited the greatest bodyweight reduction. The food/water intake and activity performance were significantly higher in rats receiving laminectomies with nanofibers than in rats without nanofibers. CONCLUSION: The results of this study suggest that the lidocaine-loaded nanofibers can provide an easy, practical and safe means of achieving effective postlaminectomy analgesia.

Sustainable release of carmustine from biodegradable poly[((D,L))-lactide-co-glycolide] nanofibrous membranes in the cerebral cavity: in vitro and in vivo studies.

OBJECTIVE: Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. The only interstitial chemotherapy pharmaceutical approved to date for GBM treatment is the Gliadel® wafer. Despite the safety and efficacy of this approach that have been demonstrated in patients undergoing resection of both newly diagnosed and recurrent malignant gliomas, the wafer provides an effective release of the anticancer 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for only 5 days. METHODS: In this study, the authors developed biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes via electrospinning that provided a sustained release of BCNU. An elution method and a HPLC assay were employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the electrospun membranes. RESULTS: The experimental results show that the biodegradable, nanofibrous membranes released high concentrations of BCNU for more than 6 weeks in the cerebral cavity of rats. Furthermore, the membranes can better conform to the geometry of the brain tissue and can cover more completely the tissue after the removal of tumors, achieving better drug transport without interfering with the normal function of the brain. Histological examination showed no obvious inflammation reactions of the brain tissues. CONCLUSION: Adopting the electrospinning technique will help in manufacturing biodegradable, nanofibrous membranes for the long-term deliveries of various anticancer drugs in the cerebral cavity, which will further enhance the therapeutic efficacy of GBM treatment.

Biodegradable drug-eluting poly[lactic-co-glycol acid] nanofibers for the sustainable delivery of vancomycin to brain tissue: in vitro and in vivo studies.

Successful treatment of a brain infection requires aspiration of the pus or excision of the abscess, followed by long-term (usually 4-8 weeks) parenteral antibiotic treatment. Local antibiotic delivery using biodegradable drug-impregnated carriers is effective in treating postoperative infections, thereby reducing the toxicity associated with parenteral antibiotic treatment and the expense involved with long-term hospitalization. We have developed vancomycin-loaded, biodegradable poly[lactic-co-glycol acid] nanofibrous membranes for the sustainable delivery of vancomycin to the brain tissue of rats by using the electrospinning technique. A high-performance liquid chromatography assay was employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the membranes. The experimental results suggested that the biodegradable nanofibers can release high concentrations of vancomycin for more than 8 weeks in the cerebral cavity of rats. Furthermore, the membranes can cover the wall of the cavity after the removal of abscess more completely and achieve better drug delivery without inducing adverse mass effects in the brain. Histological examination also showed no inflammation reaction of the brain tissues. By adopting the biodegradable, nanofibrous drug-eluting membranes, we will be able to achieve long-term deliveries of various antibiotics in the cerebral cavity to enhance the therapeutic efficacy of cerebral infections.