Novel Delivery Systems for Interferons

ABSTRACT

Interferons, IFNs, are among the most widely studied and clinically used biopharmaceuticals. Despite their invaluable therapeutic roles, the widespread use of IFNs suffers from some inherent limitations, mainly their relatively short circulation lifespan and their unwanted effects on some non-target tissues. Therefore, both these constraints have become the central focus points for the research efforts on the development of a variety of novel delivery systems for these therapeutic agents with the ultimate goal of improving their therapeutic end-points. Generally, the delivery systems currently under investigation for IFNs can be classified as particulate delivery systems, including micro- and nano-particles, liposomes, minipellets, cellular carriers, and non-particulate delivery systems, including PEGylated IFNs, other chemically conjugated IFNs, immunoconjugated IFNs, and genetically conjugated IFNs. All these strategies and techniques have their own possibilities and limitations, which should be taken into account when considering their clinical application. In this article, currently studied delivery systems/techniques for IFN delivery have been reviewed extensively, with the main focus on the pharmacokinetic consequences of each procedure.     

Formulations for delivery of therapeutic proteins

Advances in biotechnology have now created a capacity to produce therapeutically active proteins on a commercial scale, opening the potential for their application in an array of disease conditions. The process of translation of the variety of different therapeutic proteins into the medicines used in clinics is now occurring. To assist in this translation, new formulations to deliver proteins could play an important role. These new formulations need to more adequately address the pharmacological and therapeutic requirement for each particular protein/peptide and, in that way, either improve present therapies or extend with new entries the current list of protein based medicines used in clinic.

Designing of 'intelligent' liposomes for efficient delivery of drugs

The liposome- vesicles made by a double phospholipidic layers which may encapsulate aqueous solutions- have been introduced as drug delivery vehicles due to their structural flexibility in size, composition and bilayer fluidity as well as their ability to incorporate a large variety of both hydrophilic and hydrophobic compounds. With time the liposome formulations have been perfected so as to serve certain purposes and this lead to the design of "intelligent" liposomes which can stand specifically induced modifications of the bilayers or can be surfaced with different ligands that guide them to the specific target sites. We present here a brief overview of the current strategies in the design of liposomes as drug delivery carriers and the medical applications of liposomes in humans.     

An optimized live bacterial delivery vehicle safely and efficaciously delivers bacterially transcribed therapeutic nucleic acids

There is an unmet need for delivery platforms that realize the full potential of next-generation nucleic acid therapeutics. The in vivo usefulness of current delivery systems is limited by numerous weaknesses, including poor targeting specificity, inefficient access to target cell cytoplasm, immune activation, off-target effects, small therapeutic windows, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we characterize the safety and efficacy of a delivery platform comprising engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli SVC1) for intracellular cargo delivery. SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to allow escape of their cargo from the phagosome, and to have minimal immunogenicity. We describe SVC1's ability to deliver short hairpin RNA (shRNA), localized SVC1 administration to various tissues, and its minimal immunogenicity. To validate the therapeutic potential of SVC1, we used it to deliver influenza-targeting antiviral shRNAs to respiratory tissues in vivo. These data are the first to establish the safety and efficacy of this bacteria-based delivery platform for use in multiple tissue types and as an antiviral in the mammalian respiratory tract. We expect that this optimized delivery platform will enable a variety of advanced therapeutic approaches.     

Controlled Topical Delivery of Hydrocortisone and Mannitol Via Select Pathways

Abstract

In an earlier report (1) we described the controlled follicular delivery of hydrophobic macromolecules from nonionic lipid-based formulations composed of glyceryl dilaurate (GDL), cholesterol (CH), and polyoxyethylene-10-stearyl ether (POE-10). However, the influence of lipid composition on topical delivery of marginally hydrophobic and hydrophilic drugs from these nonionic lipid-based systems has not been investigated. In this report we describe the effect of variation of GDL to POE-10 ratio in the nonionic lipid-based formulations on the extent and route of delivery of hydrocortisone and mannitol, a marginally hydrophobic and hydrophilic model drug, respectively, into and through hairless mouse skin mounted on Franz diffusion cells. The results indicate that the extent of hydrocortisone uptake increased with increasing GDL to POE-10 weight ratio whereas mannitol uptake was quite the opposite and decreased with increasing GDL to POE-10 weight ratio. The diametrically opposite trends for the two drug markers suggests strongly that hydrocortisone and mannitol are transported into and across skin from the nonionic lipid-based formulations via two distinctly different routes. Further, the finding from microautoradiographic studies that the delivery of hydrocortisone from nonionic lipid-based lipid melt formulations was predominantly across the transfollicular route compared to its transport across both the trans-epidermal and transfollicular pathways from nonionic lipid-based liposomes, suggests that it is possible to tailor formulations for specific and targeted delivery across a certain route.     

Microparticles and nanoparticles for drug delivery

Particulate drug delivery systems have become important in experimental pharmaceutics and clinical medicine. The distinction is often made between micro- and nanoparticles, being particles with dimensions best described in micrometers and nanometers respectively. That size difference entails real differences at many levels, from formulation to in vivo usage. Here I will discuss those differences and provide examples of applications, for local and systemic drug delivery. I will outline a number of challenges of interest in particulate drug delivery.     

分娩方式不同的护理理念

分娩了两种分娩方式的不同,阐述了阴道分娩的益处和剖宫产的不足。提出医护人员应改变自己的观念,并采取行之有效的护理措施,提倡经阴道分娩,并降低剖宫产率。     

持续镇痛分娩对产妇分娩结局和新生儿评分的影响

目的:研究持续镇痛分娩对产妇分娩结局和新生儿评分的影响。方法:选择2018年7月～2019年7月中国医科大学航空总医院(本院)采取硬膜外分娩镇痛的101例产妇,将其随机分为两组。当产生确切的镇痛效果,进入第二产程后,观察组的51例产妇采用0.4μg/m L舒芬太尼以及0.08%罗哌卡因进行持续镇痛分娩;对照组的50例产妇则在宫口开全后,使用生理盐水替代泵内的局麻药物,直到分娩结束。比较两组产妇催产素的使用率,宫口扩张度和第一、第二产程按压硬膜外自控镇痛泵的次数,分娩方式,新生儿的体质量,脐动脉血pH值,出生后1 min和5 min Apgar评分,产妇修复会阴部时的视觉模拟评分(visual analogue scale, VAS)评分及产妇对于第二产程镇痛的满意度评分。结果:两组产妇催产素的使用率、宫口扩张度和第一、第二产程按压硬膜外自控镇痛泵的次数、分娩方式(剖宫产率、器械助产率、自然分娩率)、第一产程镇痛时间、第一以及第二产程时间相比均无显著差异(P0.05);两组新生儿的体质量,脐动脉血pH值,出生后1 min和5 min Apgar评分小于8分的新生儿所占的比例相比没有明显的差异(P0.05);观察组产妇修复会阴部时的VAS评分明显低于对照组(P0.05),产妇对于第二产程镇痛的满意度评分明显高于对照组(P0.05)。结论:持续镇痛分娩对产妇分娩结局和新生儿评分无明显的影响,但可显著提高产妇对第二产程镇痛和修复会阴部时镇痛的满意度。     

Recombinant polymer-protein fusion: a promising approach towards efficient and targeted gene delivery

BACKGROUND: Synthetic vectors such as polymers have the potential to reduce the safety problems associated with viral vectors; however, their low transfection efficiency limits their clinical utility. To study the critical steps involved in an efficient transgene expression, there is a need for creative approaches that allow a systematic correlation between gene carrier structure and properties necessary for successful gene transfer. Using recombinant techniques a prototype vector comprised of tandem repeating units fused to a targeting moiety was biosynthesized to mediate gene transfer in mammalian cell lines. The carrier was designed to have the structure of (KHKHKHKHKK)6-FGF2 where lysine (K) residues would allow complexation with plasmid DNA, basic fibroblast growth factor (FGF2) to target cells over-expressing FGF2 receptors (FGFR), and histidine (H) residues to facilitate escape from the endosomal compartments. METHODS: The gene carrier was biosynthesized in E. coli, purified using a Ni-NTA column, characterized, complexed with pDNA, and the complexes were used to transfect NIH 3T3, T-47D and COS-1 mammalian cell types known to express FGFR. RESULTS: Results demonstrate the successful cloning and expression of the gene carrier with over 95% purity. The molecular weight of the gene carrier was determined by MALDI-TOF to be 27 402. Amino acid content analysis and Western blot confirmed the expression of the gene carrier in E. coli. The vector was able to condense pDNA, induce cell proliferation in NIH 3T3 fibroblasts, and mediate transgene expression in NIH 3T3, T-47D and COS-1 mammalian cell types. CONCLUSION: Genetic engineering techniques show promise for systematic investigation of structure-activity relationships of non-viral gene delivery vectors.     

Cationic liposome-mediated gene delivery in vivo

Several improvements have been made in liposomal delivery, thus making this technology potentially useful for treatment of certain diseases in the clinic. Success in non-viral delivery is complicated and requires optimization of several components. These components include nucleic acid purification, plasmid design, formulation of the delivery vehicle, administration route and schedule, dosing, detection of gene expression, and others. With further improvements, broad use of non-viral delivery systems to treat human disorders should be possible.     

Delivery of a lactose derivative of endomorphin 1 to the brain via the olfactory epithelial pathway

The rapid and direct delivery of a neuroactive endomorphin 1 derivative to the brain via nasal delivery is reported. A synthetic derivative of the native opioid peptide, endomorphin 1 bearing a lactose unit on the N-terminus of the peptide has been previously reported to exhibit antinoceceptive activity similar to morphine after both intravenous and oral administration. This compound has been administered nasally to rats and appeared in the olfactory bulb within 10 min of administration with negligible levels appearing in the circulating blood or in the rest of the brain. These results indicate that the peptide is absorbed into the brain via the olfactory epithelial pathway suggesting nasal delivery may be a viable alternative route of delivery in clinical applications.     

Tailored carbon nanotubes for tissue engineering applications

A decade of aggressive researches on carbon nanotubes (CNTs) has paved way for extending these unique nanomaterials into a wide range of applications. In the relatively new arena of nanobiotechnology, a vast majority of applications are based on CNTs, ranging from miniaturized biosensors to organ regeneration. Nevertheless, the complexity of biological systems poses a significant challenge in developing CNT‐based tissue engineering applications. This review focuses on the recent developments of CNT‐based tissue engineering, where the interaction between living cells/tissues and the nanotubes have been transformed into a variety of novel techniques. This integration has already resulted in a revaluation of tissue engineering and organ regeneration techniques. Some of the new treatments that were not possible previously become reachable now. Because of the advent of surface chemistry, the CNT's biocompatibility has been significantly improved, making it possible to serve as tissue scaffolding materials to enhance the organ regeneration. The superior mechanic strength and chemical inert also makes it ideal for blood compatible applications, especially for cardiopulmonary bypass surgery. The applications of CNTs in these cardiovascular surgeries led to a remarkable improvement in mechanical strength of implanted catheters and reduced thrombogenecity after surgery. Moreover, the functionalized CNTs have been extensively explored for in vivo targeted drug or gene delivery, which could potentially improve the efficiency of many cancer treatments. However, just like other nanomaterials, the cytotoxicity of CNTs has not been well established. Hence, more extensive cytotoxic studies are warranted while converting the hydrophobic CNTs into biocompatible nanomaterials. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009     

Room temperature vulcanizing silicone sheaths on a reusable support for progesterone delivery in estrous synchronization treatments in cattle

High temperature vulcanizing silicone elastomers have been widely used in controlled delivery systems of steroid hormones with the aim of controlling estrous cycle in livestock. This paper reports experiments conducted to evaluate the possibility of using room temperature vulcanizing (RTV) silicone elastomers for the intravaginal administration of progesterone to cattle. In vitro studies showed that RTV silicones and high-temperature vulcanizing silicone release progesterone at a similar rate.Y-shaped inserts made of different polymers were designed as supports of RTV silicone sheaths to test the in vivo release of progesterone. Field evaluation showed that RTV silicone sheaths containing 0.75 g of progesterone were at least as effective at estrous synchronization as commercially available intravaginal inserts.     

Low-temperature micronization of a peptide drug in fluid propellant: Case study cetrorelix

Aim of this study was to elaborate an efficient method for the micronization of the decapeptide cetrorelix (a GnRH-antagonist), in order to obtain a microsuspension as basis for other pharmaceutical preparations, such as e.g. inhalation aerosols. A modified pearl-mill coupled with a cryostat was used for the micronization of cetrorelix in fluid propellant and operated under different conditions. The obtained cetrorelix suspensions were analyzed for particle size distribution, purity of cetrorelix, and for metal contamination through abrasion from parts of the mill. The method allowed an effective micronization of cetrorelix. The mean particle size of the initial cetrorelix lyophilizate bulk ware was reduced from 52.5 μ (Volume Mean Diameter, VMD) down to 14.9, 6.1 and 3.1 μm, respectively, respectively. The HPLC analysis of all cetrorelix suspensions after micronization did not show signs of decomposition as compared to the initial product. The elementary analysis of the suspensions performed by inductively coupled plasma mass spectrometry revealed a negligible amount of contaminants in the suspension (Zr=max. 0.6 ppm; Fe, Cr, Ni, Ba, below limit of quantification, i.e.<0.14 ppm). The only appreciable contaminant. Aluminum (Al=1.1 ppm), was derived from the mechanical capping of aluminum canisters prior to analysis. The Zr determination in the suspension of 0.6 ppm, is still considered to be negligible as compared to the legally tolerated limit of air contamination. By low-temperature micronization in fluid propellant, fine drug suspensions of cetrorelix for pMDIs can be directly manufactured in one-step procedure without destruction of the peptide structure and without appreciable product contamination. Published: July 12, 2001.     

Transdermal applications of ethosomes – a detailed review

Skin, the largest organ of the body serves as a potential route of drug delivery for local and systemic effects. However, the outermost layer of skin, the stratum corneum (SC) acts as a tough barrier that prevents penetration of hydrophilic and high molecular weight drugs. Ethosomes are a novel phospholipid vesicular carrier containing high ethanol concentrations and offer improved skin permeability and efficient bioavailability due to their structure and composition. This article gives a review of ethosomes including their compositions, types, mechanism of drug delivery, stability, and safety behaviour. This article also provides a detailed overview of drug delivery applications of ethosomes in various diseases.