Pulmonary delivery of interleukin-7 provides efficient and safe delivery to the aging immune system

Abstract Age-associated atrophy of the thymus with coincident reduction in thymopoeisis, decline in thymic output, and subsequent immune dysfunction has been reversed by the use of interleukin-7 (IL-7). In the earlier studies and in clinical trials, delivery of IL-7 has been by multiple injections over several days to maintain effective activity levels in the tissues. This is unlikely to meet with high compliance rates in future clinical use, and so we tested alternate routes of delivery using a technique involving tagging IL-7 with fluorescent dye that emits in the near-infrared region and whose fluorescence can be visualized within the tissues of live animals. We have shown that intratracheal instillation, enabling transfer through the lungs, provides an effective route for delivering IL-7 into the bloodstream and from there into the tissues in older animals. Delivery is rapid and widespread tissue distribution is seen. Comparison of administration either subcutaneously or by instillation reveals that IL-7 delivery by the pulmonary route provides significantly greater transmission to lymphoid tissues when compared with injection. In functional assessment studies, pulmonary administration led to significantly improved intrathymic T cell development in older animals when compared with IL-7 delivered by injection. Furthermore, in these older animals, delivery of IL-7 by intratracheal instillation was not accompanied by any apparent adverse events when compared with controls receiving saline vehicle by instillation or animals receiving IL-7 by subcutaneous injection.     

Catheter-based delivery of cells to the heart

Clinical trials have begun to assess the feasibility, safety, and efficacy of administering progenitor cells to the heart in order to repair or perhaps reverse the effects of myocardial ischemia and injury. In contrast to surgical-based injections, which are often coupled with coronary bypass surgery, catheter-based injections are less invasive and make it possible to evaluate cell products used as sole interventions. The two methods that have been tested in humans are injecting cells directly into the ventricular wall with catheter systems dedicated to that purpose and infusing cells into coronary arteries with standard balloon angioplasty catheters. The catheters described in this article have been shown in both animal and clinical studies to be effective in cell delivery and to be safe. They are well-designed and user-friendly devices, but require further investigation to identify means for optimizing cell retention and to address other limitations. Randomized, placebo-controlled trials utilizing catheters for cell implantation are under way, and others are soon to follow. The results of these studies will help to shape the direction of future investigations, both clinical and basic. The spectrum of cardiac diseases, the variety of catheters for cell delivery, and the wide array of progenitor cell types open up this young field to creative discoveries.     

A comparison of two controlled-release delivery systems for the delivery of amiloride to control angiogenesis.

The diuretic amiloride has been reported to inhibit both Na+-H+ antiport and the urokinase-type plasminogen activator. As a consequence of these inhibitions, neovascularization may also be inhibited. We hypothesized that if amiloride could be effectively delivered in a site-specific manner, a system might be developed that could inhibit localized angiogenesis. In order to evaluate this possibility we conducted a study that compared two different controlled-release systems into which amiloride had been incorporated. The effectiveness of amiloride release from each delivery system was determined by quantitating angiogenic patterns in a chick chorioallantoic membrane (CAM) system using a fractal analysis software program. The two delivery systems compared were sucrose acetate isobutyrate (SAIB) and calcium alginate. Initial HPLC laboratory tests confirmed that amiloride could be released from both SAIB and calcium alginate in vitro in a sustained manner for 72 h. The CAM studies confirmed that neither SAIB nor calcium alginate alone promoted or inhibited angiogenesis when compared to nontreated controls. The release of amiloride from each delivery vehicle resulted in a significant (P < 0.05) inhibition of angiogenesis following both 24 and 48 h of release compared to controls. There was no difference in inhibition of angiogenesis, however, when comparing SAIB + amiloride treated CAMs with calcium alginate + amiloride treated CAMs. These data suggest that both SAIB and calcium alginate may be useful delivery vehicles for the localized application of amiloride to control angiogenesis. Such a system could potentially control tumor angiogenesis without systemic effects.     

Preterm delivery

Preterm delivery and its short-term and long-term sequelae constitute a serious problem in terms of mortality, disability, and cost to society. The incidence of preterm delivery, which has increased in recent years, is associated with various epidemiological and clinical risk factors. Results of randomised controlled trials suggest that attempts to reduce these risk factors by use of drugs are limited by side-effects and poor efficacy. An improved understanding of the physiological pathways that regulate uterine contraction and relaxation in animals and people has, however, helped to define the complex processes that underlie parturition (term and preterm), and has led to new scientific approaches for myometrial modulation. The continuing elucidation of the mechanisms that regulate preterm labour, combined with rigorous clinical assessment, offer hope for future solutions.     

Drug delivery to the small intestine

Oral delivery of drugs to the small intestine is an important topic in the research and development of more effective oral dose forms. This review highlights several important developments in this area. An overriding theme in drug delivery to the small intestine is how to increase the efficiency (ie, how to increase bioavailability) of absorption. The role of P-glycoprotein and intestinal transporters is discussed in this regard. These systems are normally studied under defined in vitro conditions; recent data suggest that this approach, though useful, may not fully represent the in vivo situation. Recent advances and issues in the characterization and prediction of drug absorption from the small intestine are reviewed. These efforts, if successful, will shorten development timelines by eliminating compounds with poor absorption characteristics early in the process. Nanoparticulate delivery systems and those prepared by microfabrication technology are being used to improve bioavailability of poorly absorbed drugs. A relatively new technique (electroporation) has been proposed to enhance oral delivery of macromolecules, still an unrealized objective in drug delivery.     

瘢痕子宫再次妊娠分娩方式的选择及经阴道分娩结局的临床分析

目的分析瘢痕子宫产妇不同分娩方式的母婴结局和经阴道分娩的安全性。方法选取2014-03～2017-03该院瘢痕子宫产妇422例,按照分娩方式的不同分为剖宫产组与阴道分娩组,其中阴道分娩组210例,剖宫产组212例,对阴道试产成功率、两组产妇的产后出血量、住院天数、新生儿Apgar评分及新生儿体重进行统计学分析。结果阴道分娩组试产成功率为80. 77%。阴道分娩组产妇出血量少于剖宫产组,住院时间显著短于剖宫产组,差异有统计学意义(P 0. 05)。两组新生儿Apgar评分比较差异无统计学意义(P 0. 05)。结论瘢痕子宫产妇在严格控制阴道分娩指征下通过阴道分娩成功率高,且安全性良好。     

Specific drug delivery to the kidney

The mesangial cells of the glomerulus, the proximal tubular cells and the interstitial fibroblasts are the first choice targets for renal drug delivery since they play a pivotal role in many disease processes in the kidney. In the present review, only targeting to the proximal tubular cell is addressed because only this has been studied extensively. Two approaches of drug delivery to the proximal tubular cell have been studied up to now, the prodrug/softdrug and low-molecular-weight protein (LMPWP) approach. Most research on tubular specific drug delivery has focused on the development of amino-acid prodrugs that, after delivery, require activation by more or less kidney-selective enzymes. Large differences in renal selectivity are found. For some prodrugs, a rapid removal of the released drug from the kidney explained the low renal selectivity whereas for others, cleavage in non-target tissue and insufficient transport across the cell to the enzyme site seemed mainly responsible.The LMWP approach is based on drug attachment to a protein (<30 kD) that is freely filtered through the glomerulus and after accumulation is selectively catabolized in the lysosomes of the proximal tubular cell. Using LMWPs as drug carriers, a higher renal selectivity can be attained and a broader range of drugs can be attached while the rate of drug release can also be manipulated. The studies with captopril-lysozyme and naproxen-lysozyme clearly showed that targeting resulted in a higher renal selectivity and that drugs delivered into and regenerated in the proximal tubular cell exert renal selective pharmacological activity. Further testing will provide more definite data on the added value of this delivery technology.     

The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery

Summary. The optimal mode of delivery of a haemophilia carrier expecting a child is still a matter of uncertainty and debate. The aim of this commentary/review is to suggest that normal vaginal delivery should be the recommended mode of delivery for the majority of carriers, based on review of studies on obstetric aspects of haemophilia. About 2.0–4.0% of all haemophilia boys born in countries with a good standard of health care will suffer from ICH during the neonatal period. This is an average figure including all modes of delivery and regardless of whether the carrier status of the mother or the haemophilia status of the foetus was known or not at the time of delivery. On the basis of current literature, one may conclude that the risk of serious bleeding in the neonate affected with haemophilia is small in conjunction with normal vaginal delivery. It should be possible to further reduce the low frequency of complications if appropriate precautions are taken when planning the delivery in pregnant woman with known carrier status, if the sex of the foetus is known and, even more, when the haemophilia status of the foetus is known. Instrumental delivery such as use of vacuum extraction and foetal scalp monitors must be avoided at delivery of carriers.     

The optimal mode of delivery for the haemophilia carrier expecting an affected infant is caesarean delivery

Summary. While a majority of affected infants of haemophilia carriers who deliver vaginally do not suffer a head bleed, the outcome of labour cannot be predicted. A planned vaginal delivery puts a woman at risk of an abnormal labour and operative vaginal delivery, both of which predispose to intracranial haemorrhage. Furthermore, vaginal delivery does not eliminate the risk to the haemophilia carrier herself. Overall, maternal morbidity and mortality from planned vaginal delivery are not significantly different from those from planned caesarean delivery. Caesarean delivery is recommended or elected now in conditions other than haemophilia carriage, where the potential benefits are not nearly as great. Additionally, vaginal delivery of the haemophilia carrier poses medical/legal risks if the infant is born with cephalohaematoma or intracranial haemorrhage. Caesarean delivery allows for a planned, controlled delivery. Caesarean delivery reduces the risk of intracranial haemorrhage by an estimated 85% and the risk can be nearly eliminated by performing elective caesarean delivery before labour. Therefore, after a discussion of the maternal and foetal risks with planned vaginal delivery versus planned caesarean delivery, haemophilia carriers should be offered the option of an elective caesarean delivery.     

Convection-enhanced delivery of macromolecules in the brain.

For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.     

Targeted delivery of liquid microvolumes into the lung

The ability to deliver drugs to specific sites in the lung could radically improve therapeutic outcomes of a variety of lung diseases, including cystic fibrosis, severe bronchopneumonia, chronic obstructive pulmonary disease, and lung cancer. Using conventional methods for pulmonary drug administration, precise, localized delivery of exact doses of drugs to target regions remains challenging. Here we describe a more controlled delivery of soluble reagents (e.g., drugs, enzymes, and radionuclides) in microvolume liquid plugs to targeted branches of the pulmonary airway tree: upper airways, small airways (bronchioles), or the most distal alveoli. In this approach, a soluble liquid plug of very small volume (<1 mL) is instilled into the upper airways, and with programmed air ventilation of the lungs, the plug is pushed into a specific desired (more distal) airway to achieve deposition of liquid film onto the lung epithelium. The plug volume and ventilation conditions were determined by mathematical modeling of plug transport in a tubular geometry, and targeted liquid film deposition was demonstrated in rat lungs by three different in vivo imaging modalities. The experimental and modeling data suggest that instillation of microvolumes of liquid into a ventilated pulmonary airway could be an effective strategy to deliver exact doses of drugs to targeted pathologic regions of the lung, especially those inaccessible by bronchoscopy, to increase in situ efficacy of the drug and minimize systemic side effects.Effective treatment strategies for lung diseases such as cystic fibrosis, tuberculosis, bronchopneumonia, and lung cancer would involve a small, highly concentrated dose of drug delivered directly to the pathologic site (1, 2). Unfortunately, delivery of a precise drug dose to specific sites in the lung is challenging using conventional systemic drug administration methods, resulting in inefficient treatments for many lung diseases (3, 4). For example, orally administered drugs often require high doses to achieve therapeutic effects due to first-pass metabolism, which in turn leads to systemic side effects (5). Although drugs administered i.v. can avoid first-pass metabolism, they can still incur a range of side effects (6).On the other hand, inhalation of aerosolized drugs has the advantage of noninvasively bringing a drug locally into the lung, and so it has been a first-line treatment option for many lung diseases in the outpatient setting (7, 8). In particular, dry powder inhalers can allow for local delivery of drugs in specific lung regions (9). Because properties of powders such as particle size, density, and cohesiveness strongly affect particle transport behavior, dry powders should be prepared with appropriate properties conducive to delivery into specific locations in the structurally complex pulmonary airway tree (10).Alternatively, microvolumes of a liquid plug containing the drug could be instilled into the lung using an airway catheter or bronchoscope, distributed across the airway epithelium, and absorbed locally (11, 12). This liquid plug instillation approach has been an effective delivery method for surfactant replacement therapy, in which microliters of pharmaceutical pulmonary surfactant are instilled into the lungs to treat respiratory distress syndrome (13–16). Although the plug instillation approach is rather invasive and more suitable for treatment in the inpatient setting, improved therapeutic effect could be achieved with minimal systemic absorption and more precise determination of the effective drug dose (12). Because a very small liquid volume is required in this process, potential flow-induced damage to delicate airway structures could be significantly reduced (17). Although liquid plug instillation may have great therapeutic potential, its applications have not been explored, largely because of limited understanding of the transport of liquid plugs in a ventilated lung.We hypothesized that a simple modulation of the initial liquid plug volume and ventilation parameters would allow for the precise localized delivery of drugs to specific targeted regions of the lung, for optimal therapeutic effect. To this end, we conducted experimental and theoretical studies of plug transport and film deposition in a simple tubular geometry (e.g., glass capillary tube) to develop a theoretical foundation for liquid plug transport and to establish relationships between tube geometry, plug volume, and ventilation parameters. Based on these findings, we developed a mathematical framework for delivering therapeutic agents by film deposition onto targeted generations of the pulmonary airway tree. Because the ability to translate the findings for plug motion in capillary tubes to the behavior of instilled liquids in the actual lung airway is not obvious, we conducted extensive experimental studies in a rat model. By selecting the plug volumes and ventilation parameters according to our mathematical model, we demonstrated deposition of liquid film in targeted regions of the rat lung using three different imaging modalities. We report here the conditions and methods for delivering drug solutions into targeted regions of the lung.     

提高经鼻给药效率的研究进展

目前,经鼻给药研究已进入临床试验阶段.近年来,对于如何提高经鼻给药的效率进行了大量研究.文章就一些影响经鼻给药靶向性和中枢神经系统药物浓度的因素进行了简要综述.     

Targeted delivery of proteins across the blood-brain barrier

Treatment of many neuronal degenerative disorders will require delivery of a therapeutic protein to neurons or glial cells across the whole CNS. The presence of the blood-brain barrier hampers the delivery of these proteins from the blood, thus necessitating a new method for delivery. Receptors on the blood-brain barrier bind ligands to facilitate their transport to the CNS; therefore, we hypothesized that by targeting these receptors, we may be able to deliver proteins to the CNS for therapy. Here, we report the use of the lentivirus vector system to deliver the lysosomal enzyme glucocerebrosidase and a secreted form of GFP to the neurons and astrocytes in the CNS. We fused the low-density lipoprotein receptor-binding domain of the apolipoprotein B to the targeted protein. This approach proved to be feasible for delivery of the protein and could possibly be used as a general method for delivery of therapeutic proteins to the CNS.