Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo

2011 ◽  
Vol 114 (3) ◽  
pp. 689-694 ◽  
Author(s):  
Weijun Wang ◽  
Alex Ghandi ◽  
Leonard Liebes ◽  
Stan G. Louie ◽  
Florence M. Hofman ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Survival Time ◽  
Topoisomerase I ◽  
Malignant Gliomas ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Systemic Delivery ◽  
Series Of Experiments

Object Irinotecan (CPT-11), a topoisomerase I inhibitor, is a cytotoxic agent with activity against malignant gliomas and other tumors. After systemic delivery, CPT-11 is converted to its active metabolite, SN-38, which displays significantly higher cytotoxic potency. However, the achievement of therapeutically effective plasma levels of CPT-11 and SN-38 is seriously complicated by variables that affect drug metabolism in the liver. Thus the capacity of CPT-11 to be converted to the active SN38 intratumorally in gliomas was addressed. Methods For in vitro studies, 2 glioma cell lines, U87 and U251, were tested to determine the cytotoxic effects of CPT-11 and SN-38 in a dose-dependent manner. In vivo studies were performed by implanting U87 intracranially into athymic/nude mice. For a period of 2 weeks, SN-38, CPT-11, or vehicle was administered intratumorally by means of an osmotic minipump. One series of experiments measured the presence of SN-38 or CPT-11 in the tumor and surrounding brain tissues after 2 weeks' exposure to the drug. In a second series of experiments, after 2 weeks' exposure to the drug, the animals were maintained, in the absence of drug, until death. The survival curves were then calculated. Results The results show that the animals that had CPT-11 delivered intratumorally by the minipump expressed SN-38 in vivo. Furthermore, both CPT-11 and SN-38 accumulated at higher levels in tumor tissues compared with uninvolved brain. Intratumoral delivery of CPT-11 or SN-38 extended the average survival time of tumor-bearing animals from 22 days to 46 and 65 days, respectively. Conclusions These results demonstrate that intratumorally administered CPT-11 can be effectively converted to SN-38 and this method of drug delivery is effective in extending the survival time of animals bearing malignant gliomas.

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 Modulatory Effects of Osthole on Lipopolysaccharides-Induced Inflammation in Caco-2 Cell Monolayer and Co-Cultures with THP-1 and THP-1-Derived Macrophages

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 123
Author(s):  
Natalia K. Kordulewska ◽  
Justyna Topa ◽  
Małgorzata Tańska ◽  
Anna Cieślińska ◽  
Ewa Fiedorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Reaction ◽  
Wide Spectrum ◽  
Cell Monolayer ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tnf Α

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150–450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied (p < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 (p < 0.01) and 300 ng/μL for NF-κB (p < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Self-assembled drug delivery systems. Part 6: In vitro/in vivo studies of anticancer N-octadecanoyl gemcitabine nanoassemblies

2012 ◽  
Vol 430 (1-2) ◽  
pp. 276-281 ◽  
Author(s):  
Yiguang Jin ◽  
Yanju Lian ◽  
Lina Du ◽  
Shuangmiao Wang ◽  
Chang Su ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
In Vivo Studies ◽  
Self Assembled

Novel Self-Micro Emulsifying Drug Delivery System for safe intra muscular delivery with improved pharmacodynamics and pharmacokinetics

2021 ◽  
Vol 18 ◽  
Author(s):  
Subheet Kumar Jain ◽  
Neha Panchal ◽  
Amrinder Singh ◽  
Shubham Thakur ◽  
Navid Reza Shahtaghi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Inflammatory Diseases ◽  
Diclofenac Sodium ◽  
Physical Stability ◽  
In Vivo Studies ◽  
High Concentration

Background: Diclofenac sodium (DS) injection is widely used in the management of acute or chronic pain and inflammatory diseases. It incorporates 20 % w/v Transcutol-P as a solubilizer to make the stable injectable formulation. However, the use of Transcutol-P in high concentration leads to adverse effects such as severe nephrotoxicity, etc. Some advancements resulted in the formulation of an aqueous based injectable but that too used benzyl alcohol reported to be toxic for human use. Objective: To develop an injectable self-micro emulsifying drug delivery system (SMEDDS) as a novel carrier of DS for prompt release with better safety and efficacy. Methods: A solubility study was performed with different surfactants and co-surfactants. The conventional stirring method was employed for the formulation of SMEDDS. Detailed in vitro characterization was done for different quality control parameters. In vivo studies were performed using Wistar rats for pharmacokinetic evaluation, toxicological analysis, and analgesic activity. Results: The optimized formulation exhibited good physical stability, ideal globule size (156±0.4 nm), quick release, better therapeutics, and safety, increase in LD50 (221.9 mg/kg) to that of the commercial counterpart (109.9 mg/kg). Further, pre-treatment with optimized formulation reduced the carrageenan-induced rat paw oedema by 88±1.2 % after 4 h, compared to 77±1.6 % inhibition with commercial DS formulation. Moreover, optimized formulation significantly (p<0.05) inhibited the pain sensation in the acetic-acid induced writhing test in mice compared to its commercial equivalent with a better pharmacokinetic profile. Conclusion: The above findings confirmed that liquid SMEDDS could be a successful carrier for the safe and effective delivery of DS

Polymeric/Inorganic Multifunctional Nanoparticles for Simultaneous Drug Delivery and Visualization

2010 ◽  
Vol 1257 ◽  
Author(s):  
Andrea Fornara ◽  
Alberto Recalenda ◽  
Jian Qin ◽  
Abhilash Sugunan ◽  
Fei Ye ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fluorescence Microscopy ◽  
Contrast Agents ◽  
Gold Nanorods ◽  
In Vitro Cytotoxicity ◽  
In Vivo Studies ◽  
Multifunctional Nanoparticles ◽  
Cytotoxicity Studies

AbstractNanoparticles consisting of different biocompatible materials are attracting a lot of interest in the biomedical area as useful tools for drug delivery, photo-therapy and contrast enhancement agents in MRI, fluorescence and confocal microscopy. This work mainly focuses on the synthesis of polymeric/inorganic multifunctional nanoparticles (PIMN) based on biocompatible di-block copolymer poly(L,L-lactide-co-ethylene glycol) (PLLA-PEG) via an emulsion-evaporation method. Besides containing a hydrophobic drug (Indomethacin), these polymeric nanoparticles incorporate different visualization agents such as superparamagnetic iron oxide nanoparticles (SPION) and fluorescent Quantum Dots (QDs) that are used as contrast agents for Magnetic Resonance Imaging (MRI) and fluorescence microscopy together. Gold Nanorods are also incorporated in such nanostructures to allow simultaneous visualization and photodynamic therapy. MRI studies are performed with different loading of SPION into PIMN, showing an enhancement in T2 contrast superior to commercial contrast agents. Core-shell QDs absorption and emission spectra are recorded before and after their loading into PIMN. With these polymeric/inorganic multifunctional nanoparticles, both MRI visualization and confocal fluorescence microscopy studies can be performed. Gold nanorods are also synthesized and incorporated into PIMN without changing their longitudinal absorption peak usable for lased excitation and phototherapy. In-vitro cytotoxicity studies have also been performed to confirm the low cytotoxicity of PIMN for further in-vivo studies.

Characterization of patient-derived bone marrow human mesenchymal stem cells as oncolytic virus carriers for the treatment of glioblastoma

2021 ◽  
pp. 1-11
Author(s):  
Yuzaburo Shimizu ◽  
Joy Gumin ◽  
Feng Gao ◽  
Anwar Hossain ◽  
Elizabeth J. Shpall ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Human Mesenchymal Stem Cells ◽  
Oncolytic Viruses ◽  
In Vivo Studies ◽  
Systemic Delivery ◽  
Previously Treated

OBJECTIVE Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow–derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed to marrow-toxic chemotherapy. METHODS The authors enrolled 5 consecutive patients who had been treated with radiation therapy and chemotherapy. BM aspirates were obtained from the iliac crest and were cultured to obtain BM-hMSCs. RESULTS The patient-derived BM-hMSCs (PD-BM-hMSCs) had a morphology similar to that of healthy donor–derived BM-hMSCs (HD-BM-hMSCs). Flow cytometry revealed that all 5 cell lines expressed canonical MSC surface markers. Importantly, these cultures could be made to differentiate into osteocytes, adipocytes, and chondrocytes. In all cases, the PD-BM-hMSCs homed to intracranial glioma xenografts in mice after intracarotid delivery as effectively as HD-BM-hMSCs. The PD-BM-hMSCs loaded with Delta-24-RGD (PD-BM-MSC-D24) effectively eradicated human gliomas in vitro. In in vivo studies, intravascular administration of PD-BM-MSC-D24 increased the survival of mice harboring U87MG gliomas. CONCLUSIONS The authors conclude that BM-hMSCs can be acquired from patients previously treated with marrow-toxic chemotherapy and that these PD-BM-hMSCs are effective carriers for oncolytic viruses.

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.

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