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Carlisle, Grant, Austin Fowler, Joel Soma, Lester Drewes et Bret Friday. « SCIDOT-29. EVALUATING THE FEASIBILITY OF INTRANASAL FLT DELIVERY FOR PET IMAGING OF PRIMARY BRAIN TUMORS ». Neuro-Oncology 21, Supplement_6 (novembre 2019) : vi277. http://dx.doi.org/10.1093/neuonc/noz175.1165.
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Abstract INTRODUCTION Glioblastoma (GBM) is an aggressive primary brain tumor with a dismal prognosis. Overall survival rates have been correlated to initial tumor resection making improved imaging techniques necessary for improved patient outcomes. Functional imaging with fluorothymidine (FLT) has been limited due to inefficient transfer through the blood-brain-barrier. In this experiment, we strived to test the efficacy of tritium-labeled-FLT (3H-FLT) delivery to brain tissue through intranasal (IN) versus intravenous (IV) administration in a rat model. METHODS Adult rats (Sprague Dawley, 180-200g) received 3H-FLT through either an IN or IV delivery method. At 5, 20, and 60 minutes, concentrations of 3H-FLT were measured in 16 brain regions as well as blood and non-target organs via isotope quantitation using scintillation detection. Pharmacokinetic parameters were calculated. RESULTS Intranasal olfactory bulb concentrations of 3H-FLT trended higher compared to IV olfactory bulb. All other brain region concentrations were insignificantly different. Kp (brain-blood ratio) values mimicked this trend. Secondary calculations were performed to evaluate intranasal CNS drug targeting. Initial trends showed a more effective IN drug penetration to the olfactory bulb, spinal cord, and hippocampus. Drug targeting efficiency (DTE%) was found to be highest in the olfactory bulb at 212%, but all other brain regions were greater than 100% suggesting more efficient drug targeting with intranasal administration. Nose-to-brain direct transport percentage (DTP%), and comparative brain bioavailability (B%) showed similar trends. Non-target tissues including heart, lung, adipose and skeletal muscle were collected in the 5- and 60-minute trials and found to be significantly higher than all brain concentrations. CONCLUSION Drug delivery calculations suggest increased efficacy with IN administration of FLT to all brain regions compared to IV administration. However, additional optimization is likely necessary to improve PET imaging of primary brain tumors using IN delivery due to the relatively small differences observed.
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Bonthagarala, Brahmaiah, Shabana P., Abbaraju Lakshmi Harini et Varun Dasari. « Nasal Drug Delivery : A Potential Route for Brain Targetting ». International Journal of Advances in Scientific Research 1, no 2 (1 avril 2015) : 65. http://dx.doi.org/10.7439/ijasr.v1i2.1782.
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Present review highlights the potential of nasal mucosa as an administration route for targeting the centralnervous system, the brain. Targeted drug delivery seeks to concentrate the medication in the tissues ofinterest while reducing the relative concentration of medication in the remaining tissues. Thus improvingefficacy of the drug and reducing side effects. The nasal mucosa when compared to other mucousmembranes is easily accessible and provides a practical entrance portal for small and large molecules.Intranasal administration offers rapid onset of action, no first-pass effect, no gastrointestinal degradationor lung toxicity and non-invasiveness application and also improves bioavailability. It is thought thatolfactory route of drug transport, by pass the blood-brain barrier and allows the direct transport of drugfrom the nose to the brain. This review provides an overview of strategies to improve the drug delivery tobrain via nasal mucosa and recent advances in this field.
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Verry, Camille, Sandrine Dufort, Benjamin Lemasson, Sylvie Grand, Johan Pietras, Irène Troprès, Yannick Crémillieux et al. « Targeting brain metastases with ultrasmall theranostic nanoparticles, a first-in-human trial from an MRI perspective ». Science Advances 6, no 29 (juillet 2020) : eaay5279. http://dx.doi.org/10.1126/sciadv.aay5279.
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The use of radiosensitizing nanoparticles with both imaging and therapeutic properties on the same nano-object is regarded as a major and promising approach to improve the effectiveness of radiotherapy. Here, we report the MRI findings of a phase 1 clinical trial with a single intravenous administration of Gd-based AGuIX nanoparticles, conducted in 15 patients with four types of brain metastases (melanoma, lung, colon, and breast). The nanoparticles were found to accumulate and to increase image contrast in all types of brain metastases with MRI enhancements equivalent to that of a clinically used contrast agent. The presence of nanoparticles in metastases was monitored and quantified with MRI and was noticed up to 1 week after their administration. To take advantage of the radiosensitizing property of the nanoparticles, patients underwent radiotherapy sessions following their administration. This protocol has been extended to a multicentric phase 2 clinical trial including 100 patients.
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Nakayama, Shingo, Mamoru Sasaki, Shojiroh Morinaga et Naoto Minematsu. « Nonsmall Cell Lung Carcinoma with Giant Cell Features Expressing Programmed Death-Ligand 1 : A Report of a Patient Successfully Treated with Pembrolizumab ». Case Reports in Oncological Medicine 2018 (2018) : 1–4. http://dx.doi.org/10.1155/2018/5863015.
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Giant cell carcinoma, a rare variant of nonsmall cell lung carcinoma (NSCLC), is characterized by aggressive progression and poor response to conventional chemotherapy. This report is the first to describe a patient with NSCLC and giant cell features who was successfully treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). A 69-year-old woman was diagnosed with NSCLC with multiple brain metastases. Histological evaluation of lung biopsy specimens revealed proliferation of pleomorphic giant tumor cells with poor cohesiveness, findings consistent with giant cell carcinoma. Immunostaining showed that a high proportion of the tumor cells were positive for expression of programmed death-ligand 1 (PD-L1). The patient received stereotactic radiotherapy for the brain metastases, followed by administration of pembrolizumab. Treatment with pembrolizumab resulted in the rapid regression of the primary lung nodule, with the progression-free period maintained for at least four treatment cycles. Immunotherapy targeting PD-1/PD-L1 may be an option for patients with PD-L1-positive NSCLC with giant cell features.
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Moholkar, Disha Nagesh, Raghuram Kandimalla, Farrukh Aqil et Ramesh Gupta. « Abstract 372 : Biodistribution and tumor targeting of exosomes using mouse models ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 372. http://dx.doi.org/10.1158/1538-7445.am2022-372.
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Abstract Biodistribution studies are relevant models for understanding the fundamental preclinical information of the distribution of drugs to the potential target organs, which provide insight on which on-target or off-target effects might be expected. One of our research focuses is the study of uptake and distribution of bovine milk- and colostrum-derived exosomes, functionalized exosomes and exosomes in polyethyleneimine (PEI) matrix (EPM) using near-infrared fluorescent dye in rodents. Previously, when DiR dye was loaded onto milk exosomes, biodistribution studies showed that route of administration had a significant influence on the tissue distribution with somewhat uniform biodistribution with oral gavage while predominated liver accumulation with the i.v. route. In this study, we show biodistribution of colostrum exosomes, EPM and tumor targeting by attaching tumor targeting ligand, folic acid (FA). We studied the biodistribution of these formulations using exosomes labeled with Alexa Fluor 750 (AF750) in wild-type mice and subcutaneous lung tumor-bearing mice. In various studies we tested: i) biodistribution of exosomes vs EPM, ii) effect of different administration routes such as intravenous (i.v.), oral (p.o.), subcutaneous (s.c.), intranasal (i.n.) and intramuscular (i.m.) on biodistribution, and iii) tumor targeting using FA-functionalized exosomes and EPM. Uniform tissue distribution was observed upon oral administration of exosomes while predominant hepatic accumulation was observed with i.v. administration. The i.n. route resulted in pre-dominant accumulation in lung, whereas i.m. and s.c. delivery had almost similar distribution as observed with i.v. route. The distribution of exosomes and EPM matrix was largely similar. We observed that the fluorescent signals from AF750-labeled FA-Exo and FA-EPM treatment revealed higher tumor accumulation of exosomes as compared to non-functionalized exosomes and EPM, respectively due to overexpression of folate receptors. Time-dependent distribution showed accumulation of EPM in tumors at later time point. The EPM formulations could be detected at the sites otherwise difficult to target such as brain and lymph nodes after systemic administration, thus indicating suitability of these formulations to cross physiological barriers. To validate the therapeutic potential, FA-EPM was loaded with 15 μg siKRAS and injected intravenously to orthotopic A549 lung tumor-bearing mice. Significant reduction in tumor volume (67%; p <0.001) and tumor weight (76%; p <0.001) was observed which corroborated the significant knockdown of KRAS protein (p <0.01). Thus, this novel approach can be used as a nano ‘platform’ for drug delivery due to its increased circulating half-life, high uptake by target cells, and ability to load a diverse range of pharmaceutical therapeutics including biologics such as siRNA. (Supported from Duggan Endowment and 3P biotechnologies, Inc.) Citation Format: Disha Nagesh Moholkar, Raghuram Kandimalla, Farrukh Aqil, Ramesh Gupta. Biodistribution and tumor targeting of exosomes using mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 372.
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Rezaei Aghdam, Hakimeh, Ahmad Bitarafan Rajabi, Seyed Esmaeil Sadat Ebrahimi, Davood Beiki, Khosrou Abdi, Seyed Shahaboddin Mousavi Motlagh, Banafsheh Kiani Dehkordi, Amir Darbandi Azar et Mehdi Shafiee Ardestani. « 18F-FDG MicroPET and MRI Targeting Breast Cancer Mouse Model with Designed Synthesis Nanoparticles ». Journal of Nanomaterials 2022 (2 juin 2022) : 1–9. http://dx.doi.org/10.1155/2022/5737835.
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The first aim of this study was the development of real-time, quantitative, and noninvasive visual observation that necessitates different noninvasive multimodal imaging methods. Second, the design of a high-sensitivity imaging free-ligand green chemistry nanoprobe is a critical diagnosis of breast cancer mouse models. The gadolinium-based nanoparticles as box-Behnken design (BBD) experiment are synthesized. A small biomolecule L-glutamine is attached to its surface nanoparticles as a template. Large surface-area-to-volume ratios of nanoparticles enhance the capacity for interactions with biomolecules and present more sites for conjugation. G. 2-Deoxy-2[18F]fluoro-D-glucose ([18F]F-FDG) is a quantitative and sensitive tracking instrument in Positron Emission Tomography (PET), also applicable for the in vivo and in vitro characterization of L-glutamine SiGdNPs. Optical imaging was done for 4T1 breast cancer tumor-induced mice. 18F-NP uptake values were significantly higher in primary breast cancer and brain tumors than [18F]F-FDG in PET at 30 min, injected (20 μl/g) via the tail vein with about 300 μCi of 18F-FDG loading. After 15 min of the administration of injection (26 μl/g), the first passed the lung intravenously without any injury to the lung showing promising T1-T2 MRI contrast properties. We receive these by application of a variety of imaging modalities, especially microPET and MRI.
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Alonso, Mario, Emilia Barcia, Juan-Francisco González, Consuelo Montejo, Luis García-García, Mónica-Carolina Villa-Hermosilla, Sofía Negro, Ana-Isabel Fraguas-Sánchez et Ana Fernández-Carballido. « Functionalization of Morin-Loaded PLGA Nanoparticles with Phenylalanine Dipeptide Targeting the Brain ». Pharmaceutics 14, no 11 (31 octobre 2022) : 2348. http://dx.doi.org/10.3390/pharmaceutics14112348.
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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, with its incidence constantly increasing. To date, there is no cure for the disease, with a need for new and effective treatments. Morin hydrate (MH) is a naturally occurring flavonoid of the Moraceae family with antioxidant and anti-inflammatory properties; however, the blood–brain barrier (BBB) prevents this flavonoid from reaching the CNS when aiming to potentially treat AD. Seeking to use the LAT-1 transporter present in the BBB, a nanoparticle (NPs) formulation loaded with MH and functionalized with phenylalanine-phenylalanine dipeptide was developed (NPphe-MH) and compared to non-functionalized NPs (NP-MH). In addition, two formulations were prepared using rhodamine B (Rh-B) as a fluorescent dye (NPphe-Rh and NP-Rh) to study their biodistribution and ability to cross the BBB. Functionalization of PLGA NPs resulted in high encapsulation efficiencies for both MH and Rh-B. Studies conducted in Wistar rats showed that the presence of phenylalanine dipeptide in the NPs modified their biodistribution profiles, making them more attractive for both liver and lungs, whereas non-functionalized NPs were predominantly distributed to the spleen. Formulation NPphe-Rh remained in the brain for at least 2 h after administration.
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Priyadarshani G Patil, Sampada V Marodkar, Sachin J Dighade, Prajakta N Dongare et Bhagyashri A Borade. « Innovative approach for nasal drug delivery system for brain target ». GSC Advanced Research and Reviews 9, no 3 (30 décembre 2021) : 093–106. http://dx.doi.org/10.30574/gscarr.2021.9.3.0296.
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The goal of brain drug targeting technology is the delivery of therapeutics across the blood brain barrier (BBB), including the human BBB. Nose to brain drug delivery has received a great deal of attention as a non- invasive, convenient and reliable drug delivery system. For the systemic and targetedadministration of drug. The various drug deliveries through some drug transport pathways, Factor influencing nasal drug absorption, formulation strategies nose to brain, colloidal carriers in nose to brain drug delivery system and nasal delivery systems. Physiological barriers (BBB) that restricts the delivery of drug to CNS. Thus intranasal route has attracted a wide attention of convenient, non-invasive, reliable, and safe route to achieve faster and higher level of drug in the brain through olfactory region by passing blood brain barrier. Intranasal administration rapid onset of action, no first –pass effect , no gastrointestinal degradation lungs toxicity and non-invasiveness application and also improves bioavailability.
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Hasanovic, Anida, et Isabelle Mus-Veteau. « Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency ». Cells 7, no 8 (14 août 2018) : 107. http://dx.doi.org/10.3390/cells7080107.
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One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. Recent studies showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries have identified several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. In vivo proof of concept has been performed in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers.
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Epenetos, A. A., C. Kousparou et S. Stylianou. « Inhibition of Notch and tumor regression ». Journal of Clinical Oncology 27, no 15_suppl (20 mai 2009) : e14623-e14623. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14623.
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e14623 Background: Notch signaling is an evolutionary-conserved pathway in vertebrates and invertebrates which is involved many developmental processes, including cell fate decisions, apoptosis, proliferation, and stem-cell self renewal. There is increasing evidence that the same molecular pathways regulating the self renewal of stem cells are also being employed in cancer progression. The Notch signal transduction pathway has been implicated in the self-renewal of stem cells in hematopoietic, skin, neural, germ and breast tissue. Increasing evidence suggests that the Notch signaling pathway is frequently up regulated in many forms of cancer including acute T-cell lymphoblastic leukemia, cervical, prostate, lung, breast and others. Thus,inhibition of the pathway could provide a novel treatment of cancer and cancer stem cells. Methods: We have genetically engineered a fusion protein, consisting of the Drosophila transcription factor Antennapedia (ANTP) and with the truncated version of Mastermind-like (MAML) that behaves in a dominant negative (DN) fashion and inhibits Notch activation (ANTP/DN MAML, TR4). This novel fusion protein has been tested for its ability to target tumor cells in vitro and in vivo. Results: Our data show that ANTP/DN MAML fusion protein, TR4 contains signals for proper cell targeting, internalization and nuclear transport. Furthermore, TR4 inhibits human mammary and colon xenograft tumor growth and metastases in immuno deficient mice.TR4 presence and activity was also detected in the brains of treated animals demonstrating that TR4 can cross the blood-brain barrier and potentially eliminate brain tumors and metastases, unlike other anticancer drugs and biological such as monoclonal antibodies that cannot cross the blood brain barrier. TR4 was found to be non- immunogenic following repeat administration in healthy animals. At very high doses (>10x therapeutic dose) it caused anorexia and weight loss in mice. Conclusions: The TR4 protein, a Notch inhibitor, can induce tumor regression and resolution of breast and colon cancer xenografts. It is non- immunogenic following repeat administration and has acceptable toxicity profile. No significant financial relationships to disclose.
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Xu, Jianping, Xiaoyan Liu, Sheng Yang, Xiangru Zhang et Yuankai Shi. « A retrospective analysis of apatinib in advanced non-small cell lung cancer patients refractory to chemotherapy. » Journal of Clinical Oncology 35, no 15_suppl (20 mai 2017) : e20562-e20562. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20562.
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e20562 Background: Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. A phase II clinical study proved that 750 mg qd apatinib showed clinical benefit in patients with advanced non-squamous NSCLC refractory to two or more lines of chemotherapy (Zhang et al. 2012 ASCO, 7548). In this retrospective study, we assessed the efficacy of apatinib at a more frequently used dose of 500 mg qd in advanced chemo-refractory NSCLC. The preliminary clinical outcome of apatinib in patients with brain metastases was also reported. Methods: Clinical data of 25 advanced NSCLC patients who received oral apatinib 500 mg once daily as second-line and beyond therapy between August 2015 and May 2016 were reviewed. Results: The median progression-free survival (PFS) was 5.17 months (95% CI: 0.76–9.57 months). The response rate (RR) and disease control rate (DCR) were 8.0% and 68.0%, respectively. In the second-line setting (n=13), the mPFS was 7.37 months (95% CI: 0.01–14.72 months), and the RR and DCR were 0.0% and 61.5%, respectively. In the third-line and beyond setting (n=12), the mPFS was 5.17 months (95% CI: 1.78–8.55 months), and the PR and DCR were 16.7% and 75.0%, respectively. The DCR was 57.1% for 7 patients with brain metastases following apatinib administration. All patients were well tolerant to apatinib without any Grade 3 or 4 adverse events. The most common Grade 1 or 2 adverse events included hypertension (72.0%), hand-foot syndrome (24.0%), fatigue (24.0%), abnormal liver function (20.0%), nausea (12.0%) and palpitation (8.0%). Conclusions: Apatinib is effective and well tolerated in patients with advanced NSCLC, even at a dose of 500 mg qd, and might offer a new option for the treatment of such patients with brain metastases.
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Paisana, Eunice, Rita Cascão, Carlos Custódia, Nan Qin, Daniel Picard, David Pauck, Tânia Carvalho et al. « LMD-12. Ubiquitin Conjugating Enzymes promote leptomeningeal dissemination and decrease survival in patients with brain metastatic disease ». Neuro-Oncology Advances 3, Supplement_3 (1 août 2021) : iii10. http://dx.doi.org/10.1093/noajnl/vdab071.037.
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Abstract The dissemination of cancer cells to the brain parenchyma (brain metastases - BMs) and to the leptomeninges (leptomeningeal dissemination – LD) are a late-stage complication of systemic cancers, with a poor survival. Despite advances in radiation and chemotherapy, including intrathecal administration of anticancer agents, these forms of advanced cancer are incurable. Therefore, there is an unmet clinical need for novel effective therapies that target both parenchymal and leptomeningeal disease. We analysed the transcriptomic profile of BMs from patients with diverse primary tumors, treated at CHULN, to identify genetic drivers of cancer cell dissemination to the brain and potential novel targets for therapy. The most differentially expressed gene codifies a ubiquitin conjugating enzyme (UCE). UCE levels were evaluated in tissue microarrays of BMs from an independent cohort of patients and correlated with clinical data. UCE functional role was assessed in vitro and in vivo using modulated lung and breast cancer cell lines. A high-throughput drug screening was performed to find UCE-targeting compounds. High protein levels of the UCE were associated with decreased survival in patients with BMs, independently of the primary tumor origin. High levels of UCE led to increased migration and invasion abilities in cancer cell lines in vitro, with no effect in proliferation. In vivo, high levels of UCE increased leptomeningeal dissemination and decreased survival in orthotopic models of breast cancer BMs. Leptomeningeal disease promoted by UCE was prevented by oral administration of inhibitor A, identified in our high-throughput drug screening. In conclusion, we have identified UCE as a prognostic marker in patients with BMs from different primary tumors. In orthotopic mouse models of the disease, UCE led to a worse survival and promoted leptomeningeal dissemination. Strikingly, this aggressive disease phenotype was prevented by oral therapy with inhibitor A.
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Wolf, Walter, Jashovam Shani, Rehir Dahalan, Rajesh Parti, Shaharuddin bin Mohd et Tom K. Kawada. « A New Approach to Organ Pharmacokinetics Using Noninvasive Radionuclide Measurement Methods ». Journal of Pharmacy Practice 2, no 3 (juin 1989) : 196–99. http://dx.doi.org/10.1177/089719008900200310.
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Proper chemotherapy requires that the right dose of the right drug be administered to a given patient at the correct rate. This can be achieved if there is proper monitoring of the drug's biodistribution and metabolism in an individual patient. We have documented that radionuclidic measurements, coupled to a systems-based multicompartmental model approach, are ideally suited in providing proper monitoring of the time course of a drug in a patient. The results achieved to date can best be illustrated through the studies we have conducted with cisplatin and with KS1 /4, a monoclonal antibody directed against a human lung tumor. Radiolabeled cisplatin has been used to monitor the relative rate of drug localization and retention in patients with brain astrocytomas, following either standard intravenous (IV) or intraarterial (IA) drug administration. The preliminary results obtained in such patient studies have shown that a much higher amount of radioactive platinum (Pt) was deposited in such tumors during IA infusion. The differential diffusion (washout) rates of radioactive platinum from these tumors are consistent with higher local uptake of the free (eg, active) drug following IA administration. It is of interest to note that no detectable differences could be observed in the blood levels of either the free drug, platinated proteins, or RBC bound Pt, following either IV or IA administration to the same patient. A six-compartment subsystem has been proposed to help analyze and rationalize these data. Similarly, a nine-compartmental model has been shown to represent the biodistribution of KS1 /4 labeled with iodine 131I. The studies reported here illustrate that the pharmacokinetics of drug biodistribution, targeting, and metabolism can be estimated using noninvasive measuring techniques coupled with compartmental model analysis. The availability of such new pharmacokinetic data should be of value in helping to monitor and optimize chemotherapeutic regimens in patients.
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Débare, Héloïse, Nathalie Moiré, Firmin Baron, Louis Lantier, Bruno Héraut, Nathalie Van Langendonck, Caroline Denevault-Sabourin, Isabelle Dimier-Poisson et Françoise Debierre-Grockiego. « A Novel Calcium-Dependent Protein Kinase 1 Inhibitor Potently Prevents Toxoplasma gondii Transmission to Foetuses in Mouse ». Molecules 26, no 14 (10 juillet 2021) : 4203. http://dx.doi.org/10.3390/molecules26144203.
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Treatments currently used to prevent congenital toxoplasmosis are non-specific of Toxoplasma gondii and have grievous side effects. To develop a more specific and less toxic drug, we have designed SP230, an imidazo[1,2-b]pyridazine salt targeting the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) and active against acute toxoplasmosis in mice. Efficiency of SP230 to inhibit foetal transmission of the parasite was evaluated in a mouse model of congenital toxoplasmosis. Swiss mice were infected at mid-pregnancy with tachyzoites or cysts of the ME49 strain of T. gondii by intraperitoneal and oral route, respectively, and treated with SP230 at 50 mg/kg for 5 days by the same routes. Parasite burden in organs of dams and in foetuses was measured by quantitative PCR. Intraperitoneal administration of SP230 drastically reduced the number of parasites (more than 97% of reduction) in the brain and lungs of dams, and led to a reduction of 66% of parasite burden in foetuses. Oral administration of SP230 was particularly efficient with 97% of reduction of parasite burdens in foetuses. SP230 did not impact number and weight of offspring in our conditions. This inhibitor of TgCDPK1 is a promising candidate for the development of alternative therapeutics to treat infected pregnant women.
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Song, Yoo-Kyung, Yun-Hwan Seol, Min Ju Kim, Jong-Woo Jeong, Hae-In Choi, Seung-Won Lee, Yoon-Jee Chae et al. « Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats ». Pharmaceutics 13, no 3 (11 mars 2021) : 373. http://dx.doi.org/10.3390/pharmaceutics13030373.
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Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5–5 mg/kg, the terminal half-life (i.e., 2.54–2.80 h), systemic clearance (i.e., 691–865 mL/h/kg), and steady state volume of distribution (i.e., 2040–3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9–57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.
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Bomba, Hunter, Kevin Sheets, Alain Valdivia, Simon Khagi, Laura Ruterbories, Christopher Mariani, Luke Borst, Debra Tokarz et Shawn Hingtgen. « EXTH-52. GLIOBLASTOMA-TARGETING AUTOLOGOUS INDUCED NEURAL STEM CELL THERAPY : EVALUATING SAFETY, TOXICITY, PERSISTENCE, AND TRANSPLANT METHODS IN A POST-SURGICAL CANINE MODEL ». Neuro-Oncology 22, Supplement_2 (novembre 2020) : ii98. http://dx.doi.org/10.1093/neuonc/noaa215.406.
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Abstract BACKGROUND Glioblastoma patient survival statistics have remained unchanged for more than three decades. Despite tumor resection and chemoradiotherapy, recurrence is inevitable. Moreover, the invasive behavior of glioblastoma confounds treatment. To improve patient survival statistics, a targeted therapy that can home to distant tumor foci is desperately needed. Induced neural stem cells (iNSCs) armed with cytotoxic payloads have proven efficacious against human xenograft models of glioblastoma. To further propel iNSCs to human clinical trials, we investigated the safety, toxicity, and persistence of iNSCs in a canine model. METHODS Autologous iNSCs generated from the skin of four non-tumor-bearing, purpose-bred, male beagles were engineered to express TRAIL and thymidine kinase (TK). iNSCs were loaded with ferumoxytol to facilitate MRI-tracking. Canines were divided into two cohorts to denote iNSC administration route: scaffold encapsulation or intracerebroventricular (ICV). Two dose levels were investigated: 1′106 iNSCs/kg or 3′106 iNSCs/kg. The scaffold cohort received a single dose of iNSCs while the ICV cohort received three doses of iNSCs via a Rickham reservoir. To activate TK, canines were administered valganciclovir. Canine health was assessed via neurological exams, MRI, and serial blood, urine, and CSF analyses. RESULTS No acute injection reactions were observed. Three of four canines exhibited surgery-induced blindness. Urine and CSF analyses were unremarkable. Unexpectedly, blood analyses showed transient neutropenia. Hypodense signal was observed on all MRI sequences through endpoint. Post-mortem histopathology of the spleen, liver, and lung were unremarkable. As expected, brain tissues exhibited gliosis, fibrous thickening, and inflammation. Spinal cords exhibited acute hemorrhaging, attributed to perimortem CSF draws. Surprisingly, significant testicular degeneration was observed; this was confirmed to be caused by valganciclovir. In conclusion, iNSCs exhibit limited toxicity and warrant further exploration. FUTURE DIRECTIONS Prospective studies will investigate the efficacy of autologous iNSCs in a spontaneous canine glioma model in preparation for human clinical trials.
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Hu, Yonghan, Xin Li, Bin Huang, Liang Kong, Meijie Le, Yan Li, Cungang Liu et al. « Abstract A071 : XNW14010:A highly selective KRASG12C inhibitor with potent efficacy in animal model of pancreatic cancer ». Cancer Research 82, no 22_Supplement (15 novembre 2022) : A071. http://dx.doi.org/10.1158/1538-7445.panca22-a071.
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Abstract KRAS mutations are frequently found in various types of cancers with an overall mutation frequency of 19.3%. G12C mutation of KRAS (KRASG12C) represents 11.4% of all KRAS mutations in cancer. Targeting KRAS mutations as a cancer treatment strategy has long been investigated for over 30 years already but still remains unconquered field. XNW14010 is a highly selective KRASG12C inhibitor that is rationally designed from AMG510, another proven covalent inhibitor of KRASG12C with potential antineoplastic activity. Compared to AMG510, XNW14010 demonstrated a better pharmaceutical potential and a better safety profile. XNW14010 does not have an axial chiral center shown in AMG510, thus the production cost of this agent could be vastly reduced. The in vitro efficacy of XNW14010 was tested in a variety of cancer cell lines with either wild type KRAS or different mutant KRAS, including lung cancer, colorectal cancer, and pancreatic cancer. The result shows that XNW14010 potently inhibits the activity of KRASG12C, but not wild type KRAS or KRAS bearing other mutations. Specifically, in a pancreatic cancer cell line MIA PaCa-2, which bears KRASG12C, the IC50 of XNW14010 is 26 nM. Furthermore, XNW14010 demonstrated a much less plasma protein binding (PPB) than AMG510 (50.4% versus 93.2%, respectively), suggesting much great potential to penetrating into tumor tissue for XNW14010 compared to AMG510. XNW14010 exhibited comparable or superior pharmacokinetic characteristics compared to AMG510 after oral administration in animal studies. More interestingly, XNW14010 has an improved brain penetration capability. The brain/plasma ratio of XNW14010 exposure is two folds as high as that of AMG510 and the Cmax of XNW14010 in brain tissue is also much higher. XNW14010 had a wider therapeutic window and good tolerance compared to AMG510, both in mouse and dog models, suggesting potentially better safety profile in humans. We also compared the antineoplastic activity of XNW14010 with that of AMG510 in vivo in Xenograft mouse models including lung cancer, colorectal cancer, and pancreatic cancer. The results demonstrated that XNW14010 has comparable antineoplastic activities to AMG510 when administered at the same doses. In pancreatic cancer, the total growth inhibition (TGI) is 90% when administered at the dose of 10 mg/kg QD. Given the better PPB, superior brain penetrating capacity, and similar antineoplastic activitie of XNW14010 compared to AMG510 in non-clinical studies, XNW14010 is expected to be a potent therapeutic candidate in treating cancers bearing KRASG12C, including pancreatic cancer. Citation Format: Yonghan Hu, Xin Li, Bin Huang, Liang Kong, Meijie Le, Yan Li, Cungang Liu, Xiaojun Liu, Bin Qian, Jing Qiang, Qifeng Shi, Wengui Wang, Yuchuan Wu, Zhenwei Wu, Linfeng Xu, Jinfeng Zhao. XNW14010:A highly selective KRASG12C inhibitor with potent efficacy in animal model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A071.
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Razzak, Rene, Joe Zhou, XiaoHong Yang, Nadim Pervez, Eric LR Bédard, Ronald B. Moore, Andrew Shaw, John Amanie et Wilson H. Roa. « The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model ». Clinical & ; Investigative Medicine 36, no 3 (1 juin 2013) : 133. http://dx.doi.org/10.25011/cim.v36i3.19724.
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Purpose: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). Methods: Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. Results: An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 µg/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra-tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. Conclusions: GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra-tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake.
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Khan, Saad A., David E. Gerber, Hong Zhu, Randall S. Hughes, Samantha Mannala, Sawsan Rashdan, Jonathan Dowell et al. « Phase II trial of clinical activity and safety of ceritinib combined with stereotactic ablative radiotherapy (SABR) in lung adenocarcinoma patients. » Journal of Clinical Oncology 38, no 15_suppl (20 mai 2020) : e21571-e21571. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21571.
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e21571 Background: ALK -targeting drugs and SABR are combined in patients with metastatic cancer, anecdotally yielding clinical benefit. However, the precise impact of the combination and the optimal time to introduce SABR remain unknown. Methods: This completed phase 2 study (NCT02513667) had a primary objective of doubling progression free survival (PFS) for ALK+ lung adenocarcinoma patients by consolidating all remaining disease with SABR, 8-10 weeks after ceritinib initiation. Patients who then progressed could receive repeat SABR as long as they then resumed ceritinib. Patients were divided into ALK-inhibitor naïve vs previously treated cohorts. Oligometastatic disease was NOT a requirement for study entry, CNS disease was permitted. Blood was serially analyzed for variation in 1. blood cfDNA detection of resistance mechanisms 2. flow cytometric analysis of white cell populations. Results: 14 patients were enrolled out of a planned 33; 7 female; 3 hispanic/latino; median age was 53 years (range 31-78); 5 patients had previously received crizotinib. 4 patients stopped ceritinib within 30 days due to toxicity, despite dose reductions or with-food administration. However, all patients still completed initial SABR consistent with protocol time-points. Patients predominantly had thoracic disease irradiated (11/14, 78%). Two patients had only brain metastases treated and 1 had bone only metastases treated. 4 had one fraction SBRT regimens (16-24 Gy per fraction) delivered to disease, 3 had three fraction SBRT regimens (9-11 Gy per fraction) delivered to disease, and 7 had five fraction SBRT or 15 fraction hypofractionated regimens (6 Gy per fraction or 3Gy per fraction, respectively) delivered to disease. Disease control in all irradiated areas was 100%. There was no significant grade 3 or higher toxicity associated with radiation. Broad variability in baseline and serial levels of circulating PMN-MDSC, VEGFR2, FoxP3+, CD56+CD16+ and various T-cell populations showed no clinical correlation. The trial terminated early due to increased use of alternative targeted therapies, thus the primary endpoint was not met. 8 patients had CR/PR/SD as best response. Including those who did not tolerate ceritinib, median PFS was 12 months, max of 31 months with 1 ongoing response. Conclusions: Consolidative SABR after ALK therapy is well tolerated, can be repeated and may prolong PFS compared to drug alone. Ceritinib toxicity meant higher rates of discontinuation but this did not prevent consolidative SABR in any patient. Clinical trial information: NCT02513667.
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McKean, Meredith, Gerald Steven Falchook, Johanna C. Bendell, Babar Bashir, Neil Palmisiano, Roshawn Watson, Mary-Anne McKenna et al. « Association of combined phase I/II study of a novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies with Nectin-4 expression. » Journal of Clinical Oncology 39, no 15_suppl (20 mai 2021) : TPS2668. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps2668.
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TPS2668 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via a valine-citrulline (val-cit) cleavable linker. Nectins (Nectin-1, -2, -3, and -4) and nectin-like molecules (Necl) are Ca2+ independent immunoglobulin-like cell adhesion molecules. Recent studies have shown the importance of Nectin-4 in several human cancers, including lung, ovarian, breast and bladder cancer; however, the precise roles and clinical relevance of Nectin-4 in tumors remain largely unknown. The Nectin-4 targeted enfortumab vedotin, linked to MMAE via a val-cit linker, is highly active in late-stage bladder cancer and demonstrates notable additional clinical activity as a single agent and in combination with pembrolizumab1. Skin toxicities, bone marrow suppression, peripheral neuropathy and diabetes have been associated with enfortumab, with some of these toxicities already noted with MMAE-bearing antibody therapies. We anticipate a similar toxicity profile for BT8009 in clinical studies. BT8009 exhibited a favorable preclinical profile and was effective in a range of cell-derived xenograph tumor models. Methods: Study BT8009-100 (NCT04561362) will evaluate safety and tolerability of weekly and every other week BT8009 administration, alone and in combination with q4w nivolumab. Determination of both a realistic phase 2 dose and a sequence will also be key to further exploration of safety and efficacy signals, along with an early examination of the role of baseline immunohistochemistry-ascertained levels of tumor Nectin-4. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression after exhausting SOC options (i.e., bladder, breast, pancreatic, head and neck, gastric, esophageal and ovarian). Patients must have available tumor tissue, acceptable hematologic and other critical organ function and be willing to participate. Appropriate ethical and regulatory approvals and advice will be in place and adhered to. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, concomitant CYP3A4 inhibitors and significant history of autoimmune disease for the nivolumab cohorts. PK serial collections will be taken on D1 through D15. Radiologic tumor assessments for response per RECIST will be taken every two months. 1. Enfortumab Vedotin. FDA_data. 761137Orig1s000MultiDiscliplineR.pdf (fda.gov). Clinical trial information: NCT04561362.
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March, R. J., B. Mirtsching, S. Modi et M. Wertheim. « A phase II study of XL999 in patients (pts) with NSCLC ». Journal of Clinical Oncology 25, no 18_suppl (20 juin 2007) : 18112. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.18112.
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18112 Background: XL999 is a potent spectrum-selective inhibitor of receptor tyrosine kinases including VEGFR2/KDR, FGFR1/3, PDGFR-β, FLT3, RET, KIT, & SRC. A Ph 1 clinical study in pts w/advanced malignancies evaluating weight-based (0.2 - 6.4 mg/kg) & fixed dose (200 mg & 160 mg) XL999 administered by 4hr IV infusion on a wkly or every other wk schedule has shown preliminary evidence of anti- tumor activity (3 PRs & 10 pts w/SD lasting 3–26+ months). The safety profile was characterized by hypertension & cardiovascular changes including EKG, LVEF decrease &/or cardiac enzyme elevation following 1st dose administration. DLTs were cardiac failure & transaminase elevation. A dose of 2.4 mg/kg/wk was selected for phase II evaluation. Methods: The 1 objectives of this phase II study are to determine the RR & to further evaluate the safety & tolerability of XL999. Adult pts w/NSCLC (stage IIIB with malignant effusion, stage IV, or recurrent) & previously treated with no more than 2 prior systemic cytotoxic chemotherapy regimens, including a platinum-or taxane-containing regimen, & no more than one prior target agent targeting VEGF or EGFR, are eligible. Additional inclusion criteria include ECOG PS 0–1 & absence of known brain metastases. Pts with LVEF<50% or below lower limits of normal or with significant cardiovascular abnormalities are excluded. Tumor response is assessed every 8 wks by RECIST criteria. XL999 is administered wkly at 2.4 mg/kg as a 4hr IV infusion. Results: Nine pts received XL999. Three pts remain on study drug. One pt has a confirmed PR with complete resolution of a 2cm lung nodule. Another has a total reduction of 23% in multiple hepatic lesions (by RECIST). A third pt continues with SD for 3.5 months. Six pts with PD are discontinued. AEs reported in at least 2 pts were grade 1 diarrhea, fatigue, anorexia, & dizziness. Grade 3 AEs included 1 report each of N/V. No Grade 4 or 5 AEs or serious cardiac AEs have been reported. Conclusions: Wkly IV dose at 2.4 mg/kg appears generally well-tolerated & shows preliminary evidence of anti-tumor activity in advanced NSCLC pts refractory to multiple prior anti-cancer therapies. No significant financial relationships to disclose.
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Graziano, Vincenzo, Andreas Dannhorn, Kate Williamson, Heather Hulme, Hannah Buckley, Sheng Y. Lee, Sabita Islam et al. « Abstract 6103 : Reshaping the myeloid-dependent pro-tumorigenic microenvironment in PDAC by targeting the extracellular adenosine pathway : A therapeutic opportunity ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 6103. http://dx.doi.org/10.1158/1538-7445.am2022-6103.
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Abstract The prognosis for patients with pancreatic adenocarcinoma (PDAC) remains extremely poor. PDAC is resistant to both conventional therapies and emerging immunotherapies (IOT), apart from tumors with mismatch repair deficiency. This may be explained in part by its low tumor mutational burden (TMB) but also by its immunosuppressive tumor microenvironment (TME). It has been suggested that CD73, a member of the adenosine pathway, expressed on cancer cells contributes to immune escape and resistance to cytotoxic/radiotherapy treatment. The adenosine pathway converts the immune activator ATP, released by dying cells during cell turnover or after treatment, to extracellular Adenosine (eAdo), which is immunosuppressive. Using syngeneic, in vivo models by s.c. implantation of KPC-derived cell lines (courtesy of Ben Stanger, UPenn) with differential immune infiltration and response to IOT [resistant (IOTResi) or responsive (IOTResp)], we showed by flow cytometry that the adenosine pathway is enriched in the tumor-infiltrating immune cells (in particular myeloid populations) which co-express CD39 and CD73, enabling the formation of eAdo. Mass Spec Imaging (MSI) revealed that adenosine distribution is heterogeneous in the tumors with high concentrations in the hypoxic margins that surround necrotic areas. Subpopulations of myeloid cells infiltrating the lesions are a target for eAdo, expressing high levels of adenosine receptor Adora2a. We discovered that pro-tumorigenic M2 macrophages have the highest expression of the receptor and significantly higher in the IOTResi model. Blocking the in vivo formation and function of eAdo in IOTResi tumors, using a combination of anti-CD73 antibody (2C5, murine IgG1-Fc) and an inhibitor of Adora2a (AZD4635) reduced the presence of eAdo, slowed tumor growth and reduced the lung metastatic burden. The combination remodeled the TME, reducing the infiltration by M2 macrophages, particularly those that are PD-L1 positive and diminished the frequency of infiltrating Tregs. Bulk RNAseq analysis demonstrated a profound dependency of the TME on the presence of eAdo. Genes related to cytokine/chemokine signaling, immunosuppression/inflammation, hypoxia, metastasis and collagen production are strongly downregulated following administration of anti-CD73Ab/Adora2ai. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxics (gemcitabine/ATR inhibitor) and immunotherapy (aCD40/anti-PDL1Ab). The formation of eAdo appears to be a factor in the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway using a CD73Ab and an Adora2ai may represent a strategy to modulate the PDAC stroma and improve therapy response in patients with PDAC. Citation Format: Vincenzo Graziano, Andreas Dannhorn, Kate Williamson, Heather Hulme, Hannah Buckley, Sheng Y. Lee, Sabita Islam, James E. Thaventhiran, Richard Goodwin, Rebecca Brais, Simon J. Dovedi, Alwin Schuller, Jim Eyles, Duncan I. Jodrell. Reshaping the myeloid-dependent pro-tumorigenic microenvironment in PDAC by targeting the extracellular adenosine pathway: A therapeutic opportunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6103.
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Nonaka, Naoko, Susan A. Farr, Tomoya Nakamachi, John E. Morley, Masanori Nakamura, Seiji Shioda et William A. Banks. « Intranasal administration of PACAP : Uptake by brain and regional brain targeting with cyclodextrins ». Peptides 36, no 2 (août 2012) : 168–75. http://dx.doi.org/10.1016/j.peptides.2012.05.021.
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Zhao, Mengfan, Ziwei Jing, Lin Zhou, Hongyu Zhao, Qiuzheng Du et Zhi Sun. « Pharmacokinetic Research Progress of Anti-tumor Drugs Targeting for Pulmonary Administration ». Current Drug Metabolism 21, no 14 (30 décembre 2020) : 1117–26. http://dx.doi.org/10.2174/1389200221999201111193910.
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Background:: Cancer is a major problem that threatens human survival and has a high mortality rate. The traditional chemotherapy methods are mainly intravenous injection and oral administration, but have obvious toxic and side effects. Anti-tumor drugs for pulmonary administration can enhance drug targeting, increase local drug concentration, and reduce the damage to systemic organs, especially for the treatment of lung cancer. Methods:: The articles on the pharmacokinetics of anti-tumor drugs targeting pulmonary administration were retrieved from the Pub Med database. This article mainly took lung cancer as an example and summarized the pharmacokinetic characteristics of anti-tumor drugs targeting for pulmonary administration contained in nanoparticles, dendrimers, liposomes and micelles. Results:: The review shows that the pharmacokinetics process of pulmonary administration is associated with a drug carrier by increasing the deposition and release of drugs in the lung, and retarding the lung clearance rate. Among them, the surface of dendrimers could be readily modified, and polymer micelles have favorable loading efficiency. In the case of inhalation administration, liposomes exhibit more excellent lung retention properties compared to other non-lipid carriers. Therefore, the appropriate drug carrier is instrumental to increase the curative effect of anti-tumor drugs and reduce the toxic effect on surrounding healthy tissues or organs. Conclusion:: In the process of pulmonary administration, the carrier-embedded antitumor drugs have the characteristics of targeted and sustained release compared with non-packaging drugs, which provides a theoretical basis for the clinical rational formulation of chemotherapy regimens. However, there is currently a lack of comparative research between drug packaging materials, and more importantly, the development of safe and effective anti-tumor drugs targeting for pulmonary administration requires more data.
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Brewster, M. E., W. R. Anderson, A. I. Webb, L. M. Pablo, D. Meinsma, D. Moreno, H. Derendorf, N. Bodor et E. Pop. « Evaluation of a brain-targeting zidovudine chemical delivery system in dogs. » Antimicrobial Agents and Chemotherapy 41, no 1 (janvier 1997) : 122–28. http://dx.doi.org/10.1128/aac.41.1.122.
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AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered. Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the central nervous system. Ratios of the area under the concentration-time curve of AZT for cerebrospinal fluid to that for blood were 0.32, and ratios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueous formulation of the AZT-CDS resulted in rapid tissue uptake and conversion of the CDS to the corresponding quaternary salt with the subsequent production of AZT. Delivered in this way, the levels of AZT in brain were 1.75- to 3.3-fold higher than those associated with conventional AZT administration. In addition, the levels of AZT in blood were 46% lower than those associated with AZT administration. The higher concentrations in brain and lower concentration in blood combined to significantly increase the ratio of the concentration of AZT in the brain to that in blood after AZT-CDS administration compared to that after AZT dosing.
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Botti, Giada, Alessandro Dalpiaz et Barbara Pavan. « Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration ». Pharmaceutics 13, no 8 (27 juillet 2021) : 1144. http://dx.doi.org/10.3390/pharmaceutics13081144.
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About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.
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Hangargekar, Sachin Raosaheb, Pradeepkumar Mohanty et Ashish Jain. « Solid Lipid Nanoparticles for Brain Targeting ». Journal of Drug Delivery and Therapeutics 9, no 6-s (15 décembre 2019) : 248–52. http://dx.doi.org/10.22270/jddt.v9i6-s.3783.
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Brain is considered to be highly impermeable barrier, possessing different obstacles like presence of enzymes, presence of tight junctions that limit the entry for most of the drugs. The presence of these obstacles, possess a challenge for administration of the drugs. The conventional means of drug delivery in form of emulsions, fail to overcome these obstacles, and hence there is a need for newer drug delivery approach, that will cross these barriers of the brain. So, these nanoparticles can be an alternative to other conventional systems. They offer several advantages such as improved bioavailability and solubility that are composed of macromolecular materials like lipids and polymers possess low cytotoxicity, high drug loading capability, and good scalability these are the most effective colloidal carriers that have the ability to incorporate drugs into nanocarriers and used as drug targeting to specific area. Thus, this article will emphasise on properties of Blood Brain Barrier, strategies to overcome the blood–brain barrier, literature regarding the use of SLNs in various neurological disease states, production methods of SLN and its evaluation. Hence, these solid lipid formulations can be a new form and one of the promising approach for drug delivery system in future, that have remarkable possibility to cross the BBB.
Keywords: Solid lipid nanoparticles, Nanocarriers, Blood–brain barrier
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Tosi, Giovanni, Barbara Ruozi et Maria Angela Vandelli. « Brain targeting with polymeric nanoparticles : which administration route should we take ? » Nanomedicine 8, no 9 (septembre 2013) : 1361–63. http://dx.doi.org/10.2217/nnm.13.135.
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Erdő, Franciska, Luca Anna Bors, Dániel Farkas, Ágnes Bajza et Sveinbjörn Gizurarson. « Evaluation of intranasal delivery route of drug administration for brain targeting ». Brain Research Bulletin 143 (octobre 2018) : 155–70. http://dx.doi.org/10.1016/j.brainresbull.2018.10.009.
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Wang, Dongxing, Yongliang Gao et Liuhong Yun. « Study on brain targeting of raltitrexed following intranasal administration in rats ». Cancer Chemotherapy and Pharmacology 57, no 1 (19 juillet 2005) : 97–104. http://dx.doi.org/10.1007/s00280-005-0018-3.
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Singh, Sheila, Blessing Bassey-Archibong, Nikoo Aghaei, Agata Kieliszek, Chitra Venugopal, Chirayu Chokshi et Neil Savage. « BSCI-20. THERAPEUTIC TARGETING OF HLA-G IN BRAIN METASTASES ». Neuro-Oncology Advances 1, Supplement_1 (août 2019) : i5. http://dx.doi.org/10.1093/noajnl/vdz014.018.
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Abstract Brain metastases (BM) are the most common brain tumor in adults, with an incidence ten times greater than that of primary brain tumors. The most common sources of BM in adult cancer patients include cancers of the lung, breast and melanoma, which together account for almost 80% of all BM. Current clinical modalities for BM include surgery, whole brain radiation therapy and stereotactic radiosurgery but these therapies still offer limited efficacy and reduced survival of only months in treated patients, emphasizing the need for novel BM research approaches and better therapeutic strategies. Our laboratory recently discovered that stem-like cells exist in patient-derived BM from lung, breast and melanoma cancers, which we termed “brain metastasis-initiating cells” or BMICs. Through clinically relevant human-mouse xenograft models established with these patient-derived BMICs, we captured lung, breast and melanoma BMICs at pre-metastasis – a key stage where circulating metastatic cells extravasate and initially seed the brain, prior to organization into micro-metastatic foci. Transcriptome analysis of pre-metastatic BMICs revealed a unique genetic profile and several genes commonly up-regulated among lung, breast and melanoma BM, including the non-classical human leukocyte class I antigen-G (HLA-G). Loss of HLA-G in lung, breast and melanoma BMICs using two HLA-G specific shRNAs attenuated sphere formation, migratory and tumor initiating abilities of lung, breast and melanoma BMICs compared to control BMICs. HLA-G knockdown also resulted in reduced phospho(p)-STAT3 expression in patient-derived BMICs suggesting a potential cooperative role between HLA-G and pSTAT3 in BM. Since HLA-G is highly expressed at the cell surface in control tumors, ongoing experiments are focused on developing HLA-G specific chimeric antigen receptor -T cells (CAR-Ts) and determining their efficacy in targeting lung-, breast- and melanoma-BM as blocking the brain metastatic process will markedly extend patient survival and ultimately transform a fatal systemic disease into a more treatable one.
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Hu, Jinqi, Guanbin Gao, Meng He, Qiang Yin, Xiaobing Gao, Haixing Xu et Taolei Sun. « Optimal route of gold nanoclusters administration in mice targeting Parkinson’s disease ». Nanomedicine 15, no 6 (mars 2020) : 563–80. http://dx.doi.org/10.2217/nnm-2019-0268.
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Aim: To explore the optimal route of gold nanoclusters (AuNCs) administration in mice targeting Parkinson’s disease. Materials & methods: Assessing the pharmacokinetic and bioavailability of AuNCs in mice administrated following intravenous, intraperitoneal, gavage and intranasal injection. Investigating the biodistribution of AuNCs in mice by atomic absorption spectrometry and transmission electron microscope. Toxicity assessments of AuNCs were carried out both in cells and in mice. Results: Administration of AuNCs via intraperitoneal injection showed the greatest bioavailability and the longest residence in brain. AuNCs could penetrate blood–brain barrier and be excreted mainly through kidney. No obvious toxicity of AuNCs found in cells and in mice. Conclusion: The optimal route of AuNCs administration in mice targeting Parkinson’s disease is intraperitoneal administration.
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Carregal-Romero, Susana, Lucía Fadón, Edurne Berra et Jesús Ruíz-Cabello. « MicroRNA Nanotherapeutics for Lung Targeting. Insights into Pulmonary Hypertension ». International Journal of Molecular Sciences 21, no 9 (4 mai 2020) : 3253. http://dx.doi.org/10.3390/ijms21093253.
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In this review, the potential future role of microRNA-based therapies and their specific application in lung diseases is reported with special attention to pulmonary hypertension. Current limitations of these therapies will be pointed out in order to address the challenges that they need to face to reach clinical applications. In this context, the encapsulation of microRNA-based therapies in nanovectors has shown improvements as compared to chemically modified microRNAs toward enhanced stability, efficacy, reduced side effects, and local administration. All these concepts will contextualize in this review the recent achievements and expectations reported for the treatment of pulmonary hypertension.
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Doshi, K. J., F. D. Boudinot, J. M. Gallo, R. F. Schinazi et C. K. Chu. « Brain Targeting of anti-HIV Nucleosides : in vitro and in vivo Evaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine ». Antiviral Chemistry and Chemotherapy 5, no 5 (octobre 1994) : 304–11. http://dx.doi.org/10.1177/095632029400500504.
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Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg−1 of the active nucleoside was 3%. Following oral administration of 250 mg kg−1 ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-CI-ddP were 19–25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.
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Cheng, H., M. Feng, N. Fan, E. S. Sokol, F. Wang, Y. Zou, B. Farran et al. « 1696O Genomic profiling and molecular targeting of lung cancer brain metastases ». Annals of Oncology 33 (septembre 2022) : S1316. http://dx.doi.org/10.1016/j.annonc.2022.07.1774.
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Karreman, Matthia A., et Frank Winkler. « Targeting an adhesion molecule to prevent brain colonization of lung cancer ». Neuro-Oncology 22, no 7 (16 avril 2020) : 899–900. http://dx.doi.org/10.1093/neuonc/noaa099.
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Zhang, Isabella, Nicholas G. Zaorsky, Joshua D. Palmer, Ranee Mehra et Bo Lu. « Targeting brain metastases in ALK-rearranged non-small-cell lung cancer ». Lancet Oncology 16, no 13 (octobre 2015) : e510-e521. http://dx.doi.org/10.1016/s1470-2045(15)00013-3.
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Bales, Kelly R., Sharon M. O’Neill, Nikolay Pozdnyakov, Feng Pan, David Caouette, YeQing Pi, Kathleen M. Wood et al. « Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity ». Brain 139, no 2 (22 octobre 2015) : 563–77. http://dx.doi.org/10.1093/brain/awv313.
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Abstract Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer’s disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function.
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Wen, Ziyi, Zhiqiang Yan, Rui He, Zhiqing Pang, Liangran Guo, Yong Qian, Xinguo Jiang et Liang Fang. « Brain targeting and toxicity study of odorranalectin-conjugated nanoparticles following intranasal administration ». Drug Delivery 18, no 8 (4 août 2011) : 555–61. http://dx.doi.org/10.3109/10717544.2011.596583.
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Li, Pengyue, Jie Bai, Yang Lu, Ran Wen et Shouying Du. « Bioavailability and Brain-Targeting of Puerarin by Different Administration Routes in Rats ». Journal of Drug Delivery Science and Technology 23, no 6 (2013) : 583–86. http://dx.doi.org/10.1016/s1773-2247(13)50088-8.
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Trotta, Valentina, Barbara Pavan, Luca Ferraro, Sarah Beggiato, Daniela Traini, Larissa Gomes Des Reis, Santo Scalia et Alessandro Dalpiaz. « Brain targeting of resveratrol by nasal administration of chitosan-coated lipid microparticles ». European Journal of Pharmaceutics and Biopharmaceutics 127 (juin 2018) : 250–59. http://dx.doi.org/10.1016/j.ejpb.2018.02.010.
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Bianchi, Andrea, Damien Moncelet, François Lux, Marie Plissonneau, Silvia Rizzitelli, Emeline Julie Ribot, Nawal Tassali et al. « Orotracheal administration of contrast agents : a new protocol for brain tumor targeting ». NMR in Biomedicine 28, no 6 (29 avril 2015) : 738–46. http://dx.doi.org/10.1002/nbm.3295.
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Petkova, Asya I., Ilona Kubajewska, Alexandra Vaideanu, Andreas G. Schätzlein et Ijeoma F. Uchegbu. « Gene Targeting to the Cerebral Cortex Following Intranasal Administration of Polyplexes ». Pharmaceutics 14, no 6 (26 mai 2022) : 1136. http://dx.doi.org/10.3390/pharmaceutics14061136.
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Gene delivery to the cerebral cortex is challenging due to the blood brain barrier and the labile and macromolecular nature of DNA. Here we report gene delivery to the cortex using a glycol chitosan—DNA polyplex (GCP). In vitro, GCPs carrying a reporter plasmid DNA showed approximately 60% of the transfection efficiency shown by Lipofectamine lipoplexes (LX) in the U87 glioma cell line. Aiming to maximise penetration through the brain extracellular space, GCPs were coated with hyaluronidase (HYD) to form hyaluronidase-coated polyplexes (GCPH). The GCPH formulation retained approximately 50% of the in vitro hyaluronic acid (HA) digestion potential but lost its transfection potential in two-dimensional U87 cell lines. However, intranasally administered GCPH (0.067 mg kg−1 DNA) showed high levels of gene expression (IVIS imaging of protein expression) in the brain regions. In a separate experiment, involving GCP, LX and naked DNA, the intranasal administration of the GCP formulation (0.2 mg kg−1 DNA) resulted in protein expression predominantly in the cerebral cortex, while a similar dose of intranasal naked DNA led to protein expression in the cerebellum. Intranasal LX formulations did not show any evidence of protein expression. GCPs may provide a means to target protein expression to the cerebral cortex via the intranasal route.
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Devi, Rajni, et Anjana Devi. « Nasal Drug Delivery System for Brain Targeting : A Potential Route ». Research Journal of Chemistry and Environment 26, no 8 (25 juillet 2022) : 180–89. http://dx.doi.org/10.25303/2608rjce1800189.
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Targeted drug delivery aims to concentrate medication in the target tissues while lowering the relative concentration in the remainder of the body. As a result, the drug's efficacy and adverse effects are improved. The Blood brain barrier prevents possible therapeutic molecules from reaching the brain. Approximately 1.5 billion people suffer from CNS illnesses which must be treated with effective drug delivery to the brain. Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, seizures, epilepsy, migraine and other CNS illnesses can now be efficiently treated using intranasal medication delivery to the brain. The intranasal route of administration allows for direct medication delivery to the brain without the need for systemic absorption, improving efficacy and reducing side effects in neurotherapeutics. The olfactory and trigeminal neural pathways allow direct drug delivery to the brain over the BBB and this has become a popular method for delivering a wide spectrum of therapeutic molecules to the brain. When compared to other mucous membranes, the nasal mucosa is highly accessible and serves as a convenient entry point for tiny and big molecules. Intranasal administration has a quick beginning of action, no first-pass effect, no gastrointestinal or pulmonary toxicity and is non-invasive. It also increases bioavailability. This review will give ways for improving drug delivery to the brain via the nasal mucosa as well as recent clinical trials in this area.
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Bonferoni, Maria, Silvia Rossi, Giuseppina Sandri, Franca Ferrari, Elisabetta Gavini, Giovanna Rassu et Paolo Giunchedi. « Nanoemulsions for “Nose-to-Brain” Drug Delivery ». Pharmaceutics 11, no 2 (17 février 2019) : 84. http://dx.doi.org/10.3390/pharmaceutics11020084.
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The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding the first-pass effect and bypassing the BBB. Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity. Nanoemulsions are formulations belonging to the field of nanomedicine. They consist of emulsions (commonly oil in water) stabilized by one or more surfactants—and eventually co-surfactants—delivered in droplets of small dimensions (sizes of 100–300 nm or less) with a high surface area. A mucoadhesive polymer such as chitosan can be added to the formulation to impair rapid nasal clearance. Nanoemulsions represent promising formulations to deliver drugs directly into the brain through the intranasal route. Therefore, they can be used as a possible alternative to oral administration, avoiding problems such as low solubility in water, poor bioavailability, enzymatic degradation and slow onset of action. This review focuses the present situation in literature regarding the use of nanoemulsions for nose-to-brain targeting, with particular attention to recent publications. Nasal nanoemulsions appear to be effective, non-invasive and safe drug delivery systems to achieve brain targeting for the treatment of neurological diseases.
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Psilopatis, Iason, Ioannis Karniadakis, Konstantinos Stylianos Danos, Kleio Vrettou, Kleita Michaelidou, Konstantinos Mavridis, Sofia Agelaki et Stamatios Theocharis. « May EPH/Ephrin Targeting Revolutionize Lung Cancer Treatment ? » International Journal of Molecular Sciences 24, no 1 (21 décembre 2022) : 93. http://dx.doi.org/10.3390/ijms24010093.
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Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHs/ephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPH/ephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPH/ephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHs/ephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPH/ephrin targeting in the clinical setting.
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Del Sorbo, Lorenzo, Andrea Costamagna, Giuseppe Muraca, Giuseppe Rotondo, Federica Civiletti, Barbara Vizio, Ornella Bosco et al. « Intratracheal Administration of Small Interfering RNA Targeting Fas Reduces Lung Ischemia-Reperfusion Injury* ». Critical Care Medicine 44, no 8 (août 2016) : e604-e613. http://dx.doi.org/10.1097/ccm.0000000000001601.
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Hafner, Anita. « Advances in Development, Characterisation and Application of Nasal Drug Delivery Systems ». Pharmaceutics 14, no 8 (27 juillet 2022) : 1562. http://dx.doi.org/10.3390/pharmaceutics14081562.
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Singh, Mohini, Chitra Venugopal, Tomas Tokar, Nicole McFarlane, Minomi K. Subapanditha, Maleeha Qazi, David Bakhshinyan et al. « Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis ». Cancer Research 78, no 17 (9 juillet 2018) : 5124–34. http://dx.doi.org/10.1158/0008-5472.can-18-1022.
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Kushwaha, Swatantra Kumar Singh, Neelottama Kushwaha, Bushra Fatma et Piyush Pandey. « Nanostructured Lipid Carriers (NLC) : A Targeting Approach to the Brain via Intranasal Administration ». International Journal of Pharmaceutical Investigation 10, no 3 (10 octobre 2020) : 253–56. http://dx.doi.org/10.5530/ijpi.2020.3.46.
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