scholarly journals Multi-responsive nanofibers composite gel for local drug delivery to inhibit recurrence of glioma after operation

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yufu Zhu ◽  
Jun Jia ◽  
Gang Zhao ◽  
Xuyang Huang ◽  
Lansheng Wang ◽  
...  
Keyword(s):  
Malignant Gliomas ◽  
Postoperative Recurrence ◽  
Local Drug Delivery ◽  
Recurrent Glioma ◽  
Mixed Solution ◽  
Composite Gel ◽  
Poly Propylene ◽  
Responsive Hydrogels

Abstract Background The postoperative recurrence of malignant gliomas has presented a clinical conundrum currently. Worse, there is no standard treatment for these recurrent tumours. Therefore, novel promising methods of clinical treatment are urgently needed. Methods In this study, we synthesized reactive oxygen species (ROS)-triggered poly(propylene sulfide)60 (PPS60) mixed with matrix metalloproteinases (MMPs)-responsive triglycerol monostearate (T) lipids and TMZ. The mixed solution could self-assemble at 50 ℃ to generate hydrogels with MMPs- and ROS-responsiveness. We explored whether the T/PPS + TMZ hydrogel could achieve the MMP- and ROS-responsive delivery of TMZ and exert anti-glioma regrowth effects in vitro and in vivo. These results demonstrated that the T/PPS + TMZ hydrogel significantly improved the curative effect of TMZ to inhibit postsurgical recurrent glioma. Results The results confirmed the responsive release of TMZ encapsulated in the T/PPS + TMZ hydrogel, and the hydrogel showed excellent performance against glioma in an incomplete glioma operation model, which indicated that the T/PPS + TMZ hydrogel effectively inhibited the growth of recurrent glioma. Conclusion In summary, we successfully developed injectable MMPs- and ROS-responsive hydrogels that could achieve the sustained release of TMZ in the surgical cavity to inhibit local recurrent glioma after surgery. Graphic abstract

Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

2020 ◽  
Vol 26 ◽  
Author(s):  
John Chen ◽  
Andrew Martin ◽  
Warren H. Finlay
Keyword(s):  
Drug Delivery ◽  
In Silico ◽  
Local Drug Delivery ◽  
In Vivo Studies ◽  
Intranasal Drug Delivery ◽  
Nasal Sprays ◽  
In Silico Studies ◽  
Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

scholarly journals EXTH-70. ENHANCEMENT OF ANTITUMOR ACTIVITY BY USING 5-ALA–MEDIATED SONODYNAMIC THERAPY TO INDUCE APOPTOSIS AND NECROSIS IN A MOUSE GLIOMA MODEL

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Satoshi Suehiro ◽  
Takanori Ohnishi ◽  
Akihiro Inoue ◽  
Daisuke Yamashita ◽  
Masahiro Nishikawa ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
High Intensity Focused Ultrasound ◽  
Control Group ◽  
Normal Brain ◽  
Sonodynamic Therapy ◽  
Cytotoxic Effects

Abstract OBJECTIVE High invasiveness of malignant gliomas frequently causes local tumor recurrence. To control such recurrence, novel therapies targeted toward infiltrating glioma cells are required. Here, we examined cytotoxic effects of sonodynamic therapy (SDT) combined with a sonosensitizer, 5-aminolevulinic acid (5-ALA), on malignant gliomas both in vitro and in vivo. METHODS In vitro cytotoxicity of 5-ALA-SDT was evaluated in U87 and U251 glioma cells and in U251Oct-3/4 glioma stemlike cells. Treatment-related apoptosis was analyzed using flow cytometry. Intracellular reactive oxygen species (ROS) were measured and the role of ROS in treatment-related cytotoxicity was examined. Effects of 5-ALA-SDT with high-intensity focused ultrasound (HIFU) on tumor growth, survival of glioma-transplanted mice, and histological features of the mouse brains were investigated. RESULTS The 5-ALA-SDT inhibited cell growth and changed cell morphology. Flow cytometric analysis indicated that 5-ALA-SDT induced apoptotic cell death. The 5-ALA-SDT generated higher ROS than in the control group, and inhibition of ROS generation completely eliminated the cytotoxic effects of 5-ALA-SDT. In the in vivo study, 5-ALA-SDT with HIFU greatly prolonged survival of the tumor-bearing mice compared with that of the control group (p < 0.05). Histologically, 5-ALA-SDT produced mainly necrosis of the tumor tissue in the focus area and induced apoptosis of the tumor cells in the perifocus area around the target of the HIFU-irradiated field. Normal brain tissues around the ultrasonic irradiation field of HIFU remained intact. CONCLUSIONS The 5-ALA-SDT was cytotoxic toward malignant gliomas. Generation of ROS by the SDT was thought to promote apoptosis of glioma cells. The 5-ALA-SDT with HIFU induced tumor necrosis in the focus area and apoptosis in the perifocus area of the HIFU-irradiated field. These results suggest that 5-ALA-SDT with HIFU may present a less invasive and tumor-specific therapy, not only for a tumor mass but also for infiltrating tumor cells in malignant gliomas.

scholarly journals Astrocytes derived from p53-deficient mice provide a multistep in vitro model for development of malignant gliomas.

1995 ◽  
Vol 15 (8) ◽  
pp. 4249-4259 ◽  
Author(s):  
A M Yahanda ◽  
J M Bruner ◽  
L A Donehower ◽  
R S Morrison
Keyword(s):  
Genomic Instability ◽  
Malignant Transformation ◽  
Nude Mice ◽  
Malignant Gliomas ◽  
Early Event ◽  
Wild Type ◽  
Early Passage ◽  
Wild Type P53

Loss or mutation of p53 is thought to be an early event in the malignant transformation of many human astrocytic tumors. To better understand the role of p53 in their growth and transformation, we developed a model employing cultured neonatal astrocytes derived from mice deficient in one (p53 +/-) or both (p53 -/-) p53 alleles, comparing them with wild-type (p53 +/+) cells. Studies of in vitro and in vivo growth and transformation were performed, and flow cytometry and karyotyping were used to correlate changes in growth with genomic instability. Early-passage (EP) p53 -/- astrocytes achieved higher saturation densities and had more rapid growth than EP p53 +/- and +/+ cells. The EP p53 -/- cells were not transformed, as they were unable to grow in serum-free medium or in nude mice. With continued passaging, p53 -/- cells exhibited a multistep progression to a transformed phenotype. Late-passage p53 -/- cells achieved saturation densities 50 times higher than those of p53 +/+ cells and formed large, well-vascularized tumors in nude mice. p53 +/- astrocytes exhibited early loss of the remaining wild-type p53 allele and then evolved in a manner phenotypically similar to p53 -/- astrocytes. In marked contrast, astrocytes retaining both wild-type p53 alleles never exhibited a transformed phenotype and usually senesced after 7 to 10 passages. Dramatic alterations in ploidy and karyotype occurred and were restricted to cells deficient in wild-type p53 following repeated passaging. The results of these studies suggest that loss of wild-type p53 function promotes genomic instability, accelerated growth, and malignant transformation in astrocytes.

scholarly journals Yb3+-containing chitosan hydrogels induce B-16 melanoma cell anoikis via a Fak-dependent pathway

2019 ◽  
Vol 8 (1) ◽  
pp. 645-660 ◽  
Author(s):  
Yu Miao ◽  
Jiawei Lu ◽  
Junhui Yin ◽  
Changchun Zhou ◽  
Yaping Guo ◽  
...  
Keyword(s):  
Acetic Acid Solution ◽  
Tumor Model ◽  
In Vivo Studies ◽  
High Recurrence Rate ◽  
Mixed Solution ◽  
Chitosan Hydrogel ◽  
Chitosan Hydrogels ◽  
Dermal Cells

AbstractMelanoma is the most lethal dermal tumor, and a high recurrence rate and skin defects are two main serious problems. An antimelanoma material,which effectively inhibits tumor recurrence and possesses excellent biocompatibility, is urgently needed to treat melanoma. In this study, we developed a novel antitumor Yb3+ [Yb(NO3)3]containing chitosan hydrogel (Yb-CS hydrogel) by dissolving Yb(NO3)3 and chitosan in acetic acid solution and forming composite hydrogels by a freeze-drying process after adding NaOH to the mixed solution. In vitro studies demonstrated that the Yb3+ produces effect of inducing cell death in Yb-CS hydrogel. Moreover, we found that the Yb-CS hydrogel inhibited a focal adhesion kinase (FAK)-dependent signaling pathway and induced B-16 cell anoikis. However, the Yb-CS hydrogel was less effective on L929 normal mouse dermal cells. In vivo studies showed that the Yb-CS hydrogel inhibited the recurrence of melanoma in a mouse bare xenograft tumor model. We concluded that the Yb-CS hydrogel could potentially be used in the antimelanoma field, especially in the inhibition of melanoma recurrence.

Dendrimeric poly(propylene-imines) as effective delivery agents for DNAzymes: Toxicity, in vitro transfection and in vivo delivery

2006 ◽  
Vol 116 (2) ◽  
pp. e26-e28 ◽  
Author(s):  
F. Tack ◽  
A. Bakker ◽  
S. Maes ◽  
N. Dekeyser ◽  
M. Bruining ◽  
...  
Keyword(s):  
Effective Delivery ◽  
Poly Propylene ◽  
Toxicity In Vitro ◽  
In Vitro Transfection ◽  
In Vivo Delivery

scholarly journals Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e66825 ◽  
Author(s):  
Henry Ogbomo ◽  
Franz J. Zemp ◽  
Xueqing Lun ◽  
Jiqing Zhang ◽  
Danuta Stack ◽  
...  
Keyword(s):  
Virus Infection ◽  
Malignant Gliomas ◽  
Myxoma Virus

scholarly journals Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models

2014 ◽  
Vol 120 (4) ◽  
pp. 854-863 ◽  
Author(s):  
Kaleb Yohay ◽  
Betty Tyler ◽  
Kyle D. Weaver ◽  
Andrea C. Pardo ◽  
Dan Gincel ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Malignant Gliomas ◽  
In Vitro Assays ◽  
Systemic Delivery ◽  
Organotypic Cultures ◽  
9L Gliosarcoma ◽  
Rat Glioma ◽  
F98 Glioma

Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. Conclusions Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

scholarly journals Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy

2014 ◽  
Vol 37 (6) ◽  
pp. E12 ◽  
Author(s):  
Encouse B. Golden ◽  
Hee-Yeon Cho ◽  
Ardeshir Jahanian ◽  
Florence M. Hofman ◽  
Stan G. Louie ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
In Vivo Model ◽  
Autophagosome Formation ◽  
Individual Drug ◽  
In Vivo Experiments ◽  
Associated Proteins

Object In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen. Methods Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ. Results Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD-153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors. Conclusions Taken together, these results demonstrate that CQ blocks autophagy and triggers endoplasmic reticulum stress, thereby increasing the chemosensitivity of glioma cells to TMZ.

MR Imaging in Cerebral Gliomas

1994 ◽  
Vol 35 (5) ◽  
pp. 495-505 ◽  
Author(s):  
M. Tovi ◽  
M. Hartman ◽  
A. Lilja ◽  
A. Ericsson
Keyword(s):  
Mr Imaging ◽  
Malignant Gliomas ◽  
Close Correlation ◽  
Whole Brain ◽  
Tumour Spread ◽  
Cerebral Gliomas ◽  
Degree Of Malignancy ◽  
Periventricular Hyperintensity

A comparative analysis between MR examinations and histopathologic whole-brain sections regarding tumour components was performed in 5 brain specimens from patients with malignant glial brain tumours. All cases were examined with MR imaging in vitro and in 2 cases a close comparison with the MR examinations in vivo was also possible. The most homogeneous hypercellular area in malignant gliomas, giving the highest tumour grade, was not visualised on MR imaging as an isolated entity, either in vitro or in vivo. The most conspicuous tumour component, reflecting the heterogeneity of malignant gliomas, was necrosis. This feature was best depicted in the T2WI. In 4 of 5 cases, distant tumour spread of benign-looking tumour cells was found in areas visualised as normal on T2WI, outside the margins of the peritumoural oedema. In 2 cases, estimation of water content was performed immunohistochemically and a close correlation was found in each case between peritumoural and periventricular hyperintensity on T2WI and areas of pallor on the haematoxylin-eosin-stained whole-brain sections. These areas corresponded to microscopical oedema. MR imaging reflects underlying heterogeneous histopathology in malignant gliomas. The degree of malignancy of the lesion as a whole can thus be assessed by MR imaging. However, the method does not allow malignant gliomas to be correctly delineated.

scholarly journals Local Delivery of Minocycline and Vorinostat Act Synergistically to Inhibit Recurrence of Gliomas

2020 ◽  
Author(s):  
Gang Zhao ◽  
Jun Jia ◽  
Lansheng Wang ◽  
Yongkang Zhang ◽  
Han Yang ◽  
...  
Keyword(s):  
High Performance ◽  
Postoperative Recurrence ◽  
The Cancer Genome Atlas ◽  
The Public ◽  
Continuous Release ◽  
Clinical Consequences ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background:Postoperative recurrence is the main reason of poor clinical consequences in glioma patients, so preventing recurrence of tumors is crucial in management of gliomas. Methods:In this study, the expression of matrix metalloproteinases (MMPs)in tissues from normal were detected by using RNA-seq analysis.Glioma cases from the public databases (The Cancer Genome Atlas (TCGA), The Chinese Glioma Genome Atlas(CGGA), Betastasis) were included in this study.The hydrogelcontains minocycline (Mino) and vorinostat (Vor)(G/Mino + Vor) was formed under 365 nm when photoinitiator was added in. High Performance Liquid Chromatography (HPLC) assay was used to assessed the release of drugs in G/Mino + Vor hydrogel. MTT assay was used to explore the biosecurity of GelMA. Immunohistochemistry assay, ELISA assay, Tunel assay were used to demonstrate the antitumor effect of G/Mino + Vor hydrogel.Results:We developed G/Mino + Vor hydrogel successfully. Thenthe experiment in vitro and in vivo confirmed MMPs-responsive delivery of minocycline and vorinostat in hydrogel and the anti-glioma effect on incomplete tumor operation model, which indicated that G/Mino + Vor hydrogel effectively inhibited the recurrence of glioma after surgery.Conclusions: In summary, G/Mino + Vor hydrogel could continuous release minocycline and vorinostat in surgical cavity for inhibiting local recurrence of glioma after operation.

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