Littérature scientifique sur le sujet « Brain targeting lung administration »

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The blood-brain barrier (BBB) plays an important role in maintaining the homeostasis of the central nervous system and in protecting the brain from potentially harmful endogenous and exogenous compounds. Nevertheless, it represents also the major obstacle for the diagnosis and therapy of brain diseases. One of the most promising strategies to overcome the limited BBB penetration of drugs and contrast agents is based on nanoparticles (NP). Lipid based NP, mainly liposomes (LIP) and solid lipid nanoparticles (SLN), have several advantages in terms of biocompatibility, non-immunogenicity, non-toxicity; they can be used as carrier systems and they have a prolonged circulation time in blood. Moreover, their surface can be easily modified with ligands which mediate a site-specific targeting. The aim of the present investigation is related to the evaluation of the ability of NP functionalized with Apolipoprotein-E (ApoE) or a peptide derived from ApoE (mApoE) to cross the BBB and reaching the brain parenchyma. The thesis is structured in three main chapters. In the first one, the intratracheal instillation (IT) has been investigated as an alternative, non-invasive delivery route to reach the brain. It has already been proven that LIP functionalized with phosphatidic acid (PA) and mApoE (mApoE-PA-LIP) and administered by intraperitoneal (IP) or intravenous (IV) injection, are able to cross the BBB in vivo. The results here obtained showed that mApoE-PA-LIP were able to cross the pulmonary epithelium ([14C]-PA permeability=6.5±2.0×10-6 cm/min) in vitro and to reach the brain (0.6 ug PA/g brain) in vivo. In the second chapter, the interaction of SLN covalently coupled with mApoE (SLN-mApoE) and brain capillary endothelial cells (hCMEC/D3) has been evaluated. SLN without surface-located peptide displayed less membrane accumulation and cellular uptake compared to SLN-mApoE. Moreover the presence of mApoE significantly enhanced SLN permeability across the BBB in vitro model ([14C]-DPPA permeability=5.7±0.3×10-5 cm/min, [3H]-CE permeability=6.9±0.4×10-5 cm/min). The in vivo biodistribution of SLN has been evaluated by means of fluorescent microscopy tomography system, and the here obtained results demonstrated that IT administration of SLN-mApoE significantly increased SLN-related fluorescence in the brain compared to IV and IP administrations. Finally, the third chapter focuses on an alternative strategy to functionalize the surface of SLN with ApoE by mimicking an artificial apolipoprotein-E mediated protein corona. Two isoforms of apolipoprotein-E were utilized to produce non-covalent functionalized SLN and their in vivo biodistribution after IV injection was assessed. Thirty minutes after injection, SLN+ApoE4 reached the brain thus distributing in the brain microvessels as well as in the brain parenchyma. These results suggest that the functionalization of both LIP and SLN with ApoE-derived peptide increases NP brain targeting and that IT instillation could be exploited as an alternative route for the administration of NP specifically designed for brain targeting. Moreover, the ApoE-mediated artificial protein corona effect could be an elegant alternative to increase SLN-BBB crossing.

The experimental work presented in this Thesis involves new strategies focused during my Ph.D. activity to improve drug oral bioavailability, avoid side effects or promote the targeting of therapeutic agents to their action site. The co-crystallization strategy was applied to increase the dissolution rate and the permeability across the intestinal barrier of nitrofurantoin (NITRO), an antibiotic characterized by low aqueous solubility and low oral bioavailability. In particular, NITRO dissolution rate and permeability were compared with those of its cocrystals containing isoniazid (ISO), bipyridyl (BIP), or phenanthroline (PHE) as coformers, and their parent mixtures. NITRO dissolution profiles were evaluated via High-Performance Liquid Chromatography (HPLC), whereas permeation studies were performed by using an in vitro model of the small intestine based on rat intestine epithelial cells (IEC-6). The research activity was then focused on D-limonene, eugenol and cinnamaldehyde, natural compounds derived from essential oils promising in the prevention and protection of neurodegenerative diseases. In particular, I contributed to perform a systematic in vivo study to elucidate their pharmacokinetic profile, oral bioavailability, and aptitude to permeate the central nervous system from the bloodstream. Based on obtained data, eugenol was recruited for in vitro studies of viability and time/dose-dependent dopamine release in neuronal differentiated PC12 cells, a recognized cellular model mimicking dopaminergic neurons. The prodrug approach was considered to study self-assemble nanomicelles consisting in amphiphilic inulin-D-α-tocopherol succinate bioconjugates (INVITE) and loaded with an antioxidant compound, curcumin (INVITE C), to enhance curcumin biopharmaceutical properties and induce its targeting to the retina from the bloodstream. Transport experiments on polarized monolayers of human retinal pigment epithelium (HRPE) cells were performed, evaluating the transepithelial electrical resistance of the HRPE monolayer in physiologic and diabetic conditions. The prodrug approach for nasal formulations and brain targeting was then focused on ferulic acid (Fer), known for its antioxidant and anti-inflammatory activities, potentially useful against neurodegenerative diseases. A prodrug of Fer (methyl ferulate, Fer-Me) was synthesised and loaded in tristearin or stearic acid solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. In vitro pharmacokinetic studies were performed via HPLC to evaluate the prodrug behaviour of Fer-Me. The ability of SLMs to control the prodrug release and the dissolution rate were observed via dissolution and release from SLMs studies and quantification via HPLC. The prodrug approach on Fer was further developed and a conjugate of Fer itself methylated on the carboxylic moiety, without the use of linkers, was synthesised (Fer-Fer-Me). Fer-Fer-Me and its potential hydrolysis products, namely the non-methylated homologous (Fer-Fer-OH), Fer-Me and Fer, after appropriate purification of blood samples, were quantified via HPLC. The prodrug behaviour of Fer-Fer-Me was evidenced by in vitro pharmacokinetic studies, then it was loaded in tristearin and stearic acid SLMs. The results obtained by their characterization allowed to select the stearic acid SLMs loaded with Fer-Fer-Me for a nasal administration in rats, quantifying the prodrug in the cerebrospinal fluid of rats (CSF). A further approach related to nasal administration and brain targeting was studied considering the use of cyclodextrins focusing on geraniol (GER), a natural compound derived from essential oils that may exert anti-inflammatory effects in neurodegenerative diseases. Inclusion complexes with β-cyclodextrin (βCD) and its hydrophilic derivative hydroxypropyl-β-cyclodextrin (HPβCD) were formulated and the biocompatibility with nasal mucosae and drug bioavailability into CSF were studied in rats.
Nuove strategie per migliorare la biodisponibilità orale dei farmaci, limitare effetti collaterali o promuovere il direzionamento di agenti terapeutici al loro sito di azione sono state presentate in questa Tesi. I cocristalli sono stati sfruttati per aumentare la velocità di dissoluzione e la permeabilità attraverso la barriera intestinale della nitrofurantoina (NITRO), antibiotico caratterizzato da bassa solubilità acquosa e biodisponibilità orale. NITRO è stata confrontata, in termini di velocità di dissoluzione e permeazione, con i cocristalli contenenti isoniazide, bipiridile o fenantrolina come coformeri e con le miscele fisiche. I profili di dissoluzione della NITRO sono stati valutati via cromatografia liquida ad alta prestazione (HPLC), gli studi di permeazione sono stati eseguiti su un modello in vitro basato su cellule epiteliali di intestino di ratto. Ho contribuito ad effettuare uno studio in vivo per valutare il profilo farmacocinetico, biodisponibilità orale e tendenza a permeare nel sistema nervoso centrale dal sangue di D-limonene, eugenolo e cinnamaldeide, composti naturali derivati da oli essenziali promettenti nella prevenzione e protezione di patologie neurodegenerative. In base ai risultati, l’eugenolo è stato selezionato per studi in vitro su vitalità e rilascio tempo/dose-dipendente della dopamina in cellule PC12 differenziate a fenotipo neuronale, un modello di neuroni dopaminergici. Sono state studiate nanomicelle self-assemblanti costituite da bioconiugati anfifilici di inulina-D-α-tocoferolo succinato caricate con un composto antiossidante (INVITE C), la curcumina, per migliorarne le proprietà biofarmaceutiche e indurne il direzionamento alla retina. Sono stati effettuati esperimenti di trasporto su monostrati polarizzati di cellule di epitelio pigmentato umano, valutandone la resistenza elettrica transepiteliale e il beneficio di INVITE C in condizioni diabetiche simulate. Sono stati progettati e sintetizzati profarmaci dell’acido ferulico (Fer), noto per le attività antiossidanti e antinfiammatorie, potenzialmente utili contro patologie neurodegenerative. È stato sintetizzato un profarmaco di Fer (metil ferulato, Fer-Me). Fer-Me è stato caricato in microparticelle solide lipidiche (SLM) di tristearina o acido stearico come sistema di trasporto e di direzionamento per Fer. Studi farmacocinetici in vitro sono stati condotti via HPLC per valutare se Fer-Me fosse un profarmaco. La capacità delle SLM di controllare il rilascio del profarmaco e la velocità di dissoluzione sono stati osservati attraverso studi di dissoluzione e rilascio dalle SLM, quantificando via HPLC. Inoltre, è stato sintetizzato un coniugato di Fer con se stesso senza l’uso di linkers, metilato sul carbossile (Fer-Fer-Me). Fer-Fer-Me e i suoi potenziali prodotti di idrolisi, ovvero l’omologo non metilato (Fer-Fer-OH), Fer-Me e Fer, sono stati quantificati via HPLC in seguito ad appropriate procedure di estrazione da fluidi fisiologici. Studi farmacocinetici in vitro hanno dimostrato che Fer-Fer-Me è un profarmaco di Fer, ed è stato caricato in SLM di tristearina e acido stearico. I risultati ottenuti dalla caratterizzazione hanno permesso di selezionare le SLM di acido stearico per una somministrazione nasale a ratti, quantificando il profarmaco nel liquido cerebrospinale (CSF) per dimostrare la capacità della formulazione di indurre il direzionamento nel sistema nervoso centrale. È stato studiato un ulteriore approccio relativo alla somministrazione nasale e al direzionamento centrale utilizzando ciclodestrine e geraniolo (GER), un composto naturale derivato dagli oli essenziali che potrebbe esercitare effetti antinfiammatori in patologie neurodegenerative. Sono stati formulati complessi di inclusione con β-ciclodestrina (β-CD) e il suo derivato idrofilico idrossipropil-β-ciclodestrina (HP-β-CD), studiando la biocompatibilità con la mucosa nasale e la biodisponibilità di GER nel CSF nei ratti.

Au cours de ce travail de thèse nous avons proposé une stratégie de ciblage des macrophages alvéolaires afin d’y vectoriser des glucocorticoïdes. Une prodrogue de budésonide, le palmitate de budésonide (BP) a été synthétisée dans le but de prolonger sa demi-vie dans les poumons après inhalation. Des nanoparticules PEGylées de BP ont été développées et étudiées pour obtenir une formulation stable avec des caractéristiques physico-chimiques appropriées et un taux de charge élevé pour pénétrer dans les macrophages alvéolaires, cellules centrales dans l'inflammation pulmonaire. Des tests in vitro sur les macrophages RAW 264.7 ont confirmé l'activité anti-inflammatoire et l'absence de cytotoxicité des nanoparticules. Celles-ci ont ensuite été séchée au sein de microparticules Troyennes obtenues par atomisation-séchage afin de faciliter leur administration pulmonaire sous forme de poudres et libérer les nanoparticules à proximité des alvéoles pulmonaires. Les microparticulessphériques creuses contenant de 0 % à 20 % de nanoparticules de BP présentent des diamètres aérodynamiques et une fraction de particules fines appropriés pour la délivrance pulmonaire. Les études pharmacocinétiques in vivo montrent des concentrations élevées et prolongées de budésonide dans les poumons, avec de faibles concentrations plasmatiques. Dans la deuxième partie de cette thèse, une autre stratégie de ciblage des macrophages a été évaluée par la décoration de la surface des nanoparticules avec du mannose. Après la synthèse d'un lipide mannosylé, des nanoparticules ont été formulées et caractérisées, démontrant un taux de charge élevé et une bonne stabilité jusqu'à 30 jours. Des tests in vitro sur les macrophages RAW 264.7 ont montré que la présence du mannose à la surface augmente l'internalisation des nanoparticules d’un facteur 2 après 48 h d'incubation, par rapport aux nanoparticules PEGylées
This work focuses on strategies to target glucocorticoids to alveolar macrophages. We have synthesized a budesonide prodrug, budesonide palmitate (BP), increasing its lipophilicity to extend drug half-life in the lungs. BP PEGylated nanoparticles were developed and studied to obtain a stable formulation with suitable physicochemical characteristics and high drug loading to enter alveolar macrophages, key players in lung inflammation. In vitro tests on RAW 264.7 macrophages confirmed the anti-inflammatory activity and absence of cytotoxicity of nanoparticles. These were then encapsulated into Trojan microparticles obtained by spray-drying to facilitate their delivery to the lung as dry powders and release nanoparticles directly to the pulmonary alveoli. Spherical hollow microparticles containing from 0 % to 20 % of BP nanoparticles presented suitable aerodynamic diameters and fine particle fraction for lung delivery. In vivo pharmacokinetic studies demonstrated high and extended budesonide concentrations in the lungs, with low plasma concentrations. In the second part of this thesis, another macrophage targeting strategy was assessed by decoration of nanoparticle surface with mannose. After synthesis of a mannosylated lipid, nanoparticles were formulated and characterized, demonstrating high drug loading and stability up to 30 days. In vitro tests on RAW 264.7 macrophages showed that the presence of mannose on the surface increases nanoparticles internalization 2 fold after 48 h incubation, as compared with PEGylated nanoparticles

Traumatic brain injury (TBI) is a common, clinically complex, heterogeneous global public health problem. Neuroprotection strategies focus on preventing secondary injury by creating a physiologic environment devoid of extremes while targeting normal physiologic parameters. Careful attention must be paid to aggressively avoid and treat hypoxia, hypotension, hypoglycemia, intracranial hypertension, and cerebral hypoperfusion (low cerebral perfusion pressure). Aggressive management of intracranial pressure and cerebral perfusion pressure through optimal patient positioning, appropriate use of sedation and analgesia, and administration of hyperosmolar therapy remain the hallmark for the care of the TBI patient. Surgical decompressive craniectomy and hypothermia hold promise but remain controversial and should be used in carefully selected clinical situations. Early identification of injury progression is aided through careful monitoring by clinical examination and cerebral physiological monitoring. Multimodal monitoring provides an early warning system to guide appropriate clinical responses to identified deranged physiology.

The application of nuclear medicine techniques in the diagnosis and management of rheumatological conditions relies on its ability to detect physiological and pathological changes in vivo, usually at an earlier stage compared to structural changes visualized on conventional imaging. These techniques are based on the in-vivo administration of a gamma-emitting radionuclide whose distribution can be monitored externally using a gamma camera. To guide a radionuclide to the area of interest, it is usually bound to a chemical label to form a 'radiopharmaceutical'. There are hundreds of radiopharmaceuticals in clinical use with different 'homing' mechanisms, such as 99 mTc HDP for bone scan and 99 mTc MAA for lung scan. Comparing pre- and posttherapy scans can aid in monitoring response to treatment. More recently, positron emission tomography combined with simultaneous computed tomography (PET/CT) has been introduced into clinical practice. This technique provides superb spatial resolution and anatomical localization compared to gamma-camera imaging. The most widely used PET radiopharmaceutical, flurodeoxyglucose (18F-FDG), is a fluorinated glucose analogue, which can detect hypermetabolism and has therefore been used in imaging and monitoring response to treatment of a variety of cancers as well as inflammatory conditions such as vasculitis, myopathy, and arthritides. Other PET radiopharmaceuticals targeting inflammation and activated macrophages are becoming available and could open new frontiers in PET imaging in rheumatology. Nuclear medicine procedures can also be used therapeutically. Beta-emitting radiopharmaceuticals, such as yttrium-90, invoke localized tissue damage at the site of injection and can be used in the treatment of synovitis.

The treatment of brain disorders like Alzheimer's, Parkinson's, etc. has been challenging due to a variety of obstacles of effective delivery of the drugs to the brain. Intranasal drug delivery (INDD) is a non-invasive and convenient route of drug intake and hence has been useful for drugs targeting neurological (brain) disorders. This method bypasses the blood-brain barrier (BBB), delivering the medication directly to the brain. The intranasal route is the direct transportation of drugs via the olfactory and trigeminal nerve pathways to the brain overcoming the BBB. An enormous range of macromolecular to micromolecular medications can be delivered to the CNS via this pathway. INDDS offers a non-invasive, safe, and convenient route of direct drug administration to the brain and increasing the bioavailability of the drug. Bypassing the BBB is an important factor due to the low permeability of some drugs, and INDDS helps overcome this barrier.

Once cancer metastasizes to distant organs like the bone, liver, lung, and brain, it is in an advanced stage. Metastasis is a major contributor to cancer-associated deaths. Countless molecules and complex pathways are involved in the dissemination and colonization of cancer cells from a primary tumor at metastatic sites. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. Emerging evidence suggested a variety of epigenetic regulations were identified to regulate cancer metastasis. Here we summarize the procedures and routes of cancer metastasis as well as the roles of epigenetics including ncRNA, DNA methylation, and histone modifications in common metastases. Then we further discuss the potentials and limitations of epigenetics-related target molecules in diagnosis, therapy, and prognosis.

Abstract Once a thorough assessment of the donor has been achieved through a standard approach described in the previous chapter, the team will proceed with acceptance of the organ and proceed with donor organ procurement. Conventional donation after brain death lung procurement is comprised of several steps, including mobilization of the great vessels, administration of cardioplegia, creation of the left atrial cuff, and division of the existing mediastinal structures, which are covered in this chapter. Donation after circulatory death lung procurement is also described. The use of controlled donation after circulatory death has increased in recent years due to comparable outcomes but remains less common worldwide than donation after brain death.

Several efforts have been focused on targeted drug delivery systems for delivering a drug to a particular region of the body for better control of systemic as well as local action. Liposomes have proven their efficiency as a choice of carrier for targeting the drugs to the site of action. The main reason for continuous research on liposomes drug delivery is they largely attributed to the fact that they can mimic biological cells. This also means that liposomes are highly biocompatible, making them an ideal candidate for a drug delivery system. The uses found for liposomes have been wide-spread and even include drug delivery systems for cosmetics. Several reports have shown the applicability of liposomal drug delivery systems for their safe and effective administration of different classes of drugs like anti tubercular, anti cancer, antifungal, antiviral, antimicrobial, antisense, lung therapeutics, skin care, vaccines and gene therapy. Liposomes are proven to be effective in active or passive targeting. Modification of the bilayer further found to increase the circulation time, improve elasticity, Trigger sensitive release such as pH, ultrasound, heat or light with appropriate lipid compositions. The present chapter focuses on the fundamental aspects of liposomes, their structural components, preparation, characterization and applications.

This chapter discusses the most important mechanisms of action of oxidants in the pathogenesis of chronic pulmonary oxidative diseases and the possible use of redox modulators in the prevention and treatment of oxidant/antioxidant intracellular imbalance. Recent acquisitions on cellular physiology reported the key role, in micromolecular doses, of reactive oxygen species (ROS) as signaling molecules although excessive ROS contribute to the development and progression of a large spectrum of diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Therefore, a correct understanding of the roles of redox regulation in the respiratory system during the impairment of oxidative balance and the subsequent development of chronic lung diseases appears to be important. Moreover, an interdependence between oxidant and inflammatory mediators has been shown in several experimental studies on chronic lung diseases, making more intriguing the comprehension of the pathophysiological phenomena and the therapeutic approach. This chapter discusses the role of various exogenous substances targeting oxidant/antioxidant balance in the treatment of COPD and IPF and their very limited beneficial effects due to the reduced bioavailability in the human body. Finally, the importance of novel routes of administration or a combination of redox modulators will be discussed as a promising avenue for the prevention and treatment of this common and highly disabling disease.

Flavonoids belong to a class of natural, polyphenolic dietary compounds which modify the neuropathological state of the brain. Some flavonoids like quercetin and other, reduce the inflammation, carcinogenicity, and oxidation promotes neuroprotection and comprises the major component of cosmetics, medicinal and dietary supplements. Daily intake of flavonoids helps to mitigate the risk of several neurological disorders like Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, etc. Flavonoids exhibit their pharmacological effect through various mechanisms like cholinesterase inhibition, scavenging free radicals, memory enhancement via attenuation of amyloid plaques, tau targeting detoxification and neural antiinflammation. Administration of flavonoids to biological system has to pass through several biological checkpoints like first pass metabolism, intestinal absorption, and entry into blood brain barrier. Flavonoids exhibit difference in pharmacokinetic and pharmacodyanmic profile due to difference in their structures. Recent literature reports have proved promising therapeutic potential in neurological disorders. This chapter highlights the recent development of flavonoids prevailing in the field of neurodegenerative, its limitations and drug delivery approaches to encounter the challenges.

Anticancer agents are known for their cytotoxic action against tumors, but the spread of their activity to noncancerous tissue is highly undesirable and may be toxic. The conventional methods of drug delivery pose numerous restrictions, involving side effects, lack of patient compliance, etc. Nanocarrier-based drug delivery alternatives offer the potential for the management of cancer, as they not only confer better delivery but also efficient targeting to the tissues with limited toxicity. Nanoparticles offer localization in tumors in the vicinity of capillaries, that accounts for improved penetration and prolonged detainment of drug in tumors. Under the tremendous potential of nanoparticles. The exploitation of multi-functional nanocarrier approaches is a burgeoning research subject, driven by increasing medical needs in the area of cancer therapy. Several nano-formulation have been approved for the treatment of cancer. This chapter is an attempt to provide an overview of the recent developments in nanoparticle formulations for cancer treatment and presents a comprehensive outlook of the clinical studies and utilization in different prevalent cancers affecting the brain, lung, breast, colon, cervix, and prostate, etc.

The application of nuclear medicine techniques in the diagnosis and management of rheumatological conditions relies on its ability to detect physiological and pathological changes in vivo, usually at an earlier stage compared to structural changes visualized on conventional imaging. These techniques are based on the in-vivo administration of a gamma-emitting radionuclide whose distribution can be monitored externally using a gamma camera. To guide a radionuclide to the area of interest, it is usually bound to a chemical label to form a ’radiopharmaceutical’. There are hundreds of radiopharmaceuticals in clinical use with different ’homing’ mechanisms, such as ^{99 m}Tc HDP for bone scan and ^{99 m}Tc MAA for lung scan. Comparing pre- and posttherapy scans can aid in monitoring response to treatment. More recently, positron emission tomography combined with simultaneous computed tomography (PET/CT) has been introduced into clinical practice. This technique provides superb spatial resolution and anatomical localization compared to gamma-camera imaging. The most widely used PET radiopharmaceutical, flurodeoxyglucose (¹⁸F-FDG), is a fluorinated glucose analogue, which can detect hypermetabolism and has therefore been used in imaging and monitoring response to treatment of a variety of cancers as well as inflammatory conditions such as vasculitis, myopathy, and arthritides. Other PET radiopharmaceuticals targeting inflammation and activated macrophages are becoming available and could open new frontiers in PET imaging in rheumatology. Nuclear medicine procedures can also be used therapeutically. Beta-emitting radiopharmaceuticals, such as yttrium-90, invoke localized tissue damage at the site of injection and can be used in the treatment of synovitis.