Light-Activatable Gold Nanoshells for Drug Delivery Applications

Gold nanoshells (AuNSs) are currently being investigated as nanocarriers for drug delivery systems and have both diagnostic and therapeutic applications, including photothermal ablation, hyperthermia, drug delivery, and diagnostic imaging, particularly in oncology. AuNSs are valuable for their localized surface plasmon resonance, biocompatibility, low immunogenicity, and facile functionalization. AuNSs used for drug delivery can be spatially and temporally triggered to release controlled quantities of drugs inside the target cells when illuminated with a near-infrared (NIR) laser. Recently, many research groups have demonstrated that these AuNS complexes are able to deliver antitumor drugs (e.g., doxorubicin, paclitaxel, small interfering RNA, and single-stranded DNA) into cancer cells, which enhances the efficacy of treatment. AuNSs can also be functionalized with active targeting ligands such as antibodies, aptamers, and peptides to increase the particles’ specific binding to the desired targets. This article reviews the current research on NIR light-activatable AuNSs used as nanocarriers for drug delivery systems and cancer theranostics.     

In vivo therapeutic applications of cell spheroids

Spheroids are increasingly being employed to answer a wide range of clinical and biomedical inquiries ranging from pharmacology to disease pathophysiology, with the ultimate goal of using spheroids for tissue engineering and regeneration. When compared to traditional two-dimensional cell culture, spheroids have the advantage of better replicating the 3D extracellular microenvironment and its associated growth factors and signaling cascades. As knowledge about the preparation and maintenance of spheroids has improved, there has been a plethora of translational experiments investigating in vivo implantation of spheroids into various animal models studying tissue regeneration.We review methods for spheroid delivery and how they have been utilized in tissue engineering experiments. We break down efforts in this field by organ systems, discussing applications of spheroids to various animal models of disease processes and their potential clinical implications. These breakthroughs have been made possible by advancements in spheroid formation, in vivo delivery and assessment. There is unexplored potential and room for further research and development in spheroid-based tissue engineering approaches. Regenerative medicine and other clinical applications ensure this exciting area of research remains relevant for patient care.     

纳米混悬药物传递系统研究进展

在新药研发过程中,约有40%的药物存在溶解性差的问题,限制了药物的开发与应用。纳米混悬剂是20世纪末发展起来的一种纳米药物传递系统,可增加难溶性药物的溶解度和溶出速率、改变药物的体内药物动力学特征、提高口服生物利用度、安全性和有效性。纳米混悬剂不但适用于水溶性差的药物,而且适用于水溶性、脂溶性均较差的药物,其制备方法主要包括"bottom up"和"top down"两种。本文从纳米混悬剂的特点、理论基础、专利技术及应用等方面对纳米混悬剂的研究进展进行了综述。纳米混悬剂对改善难溶性药物的溶出、吸收,提高难溶性药物的有效性、安全性等方面具有显著优势,且适合工业化生产,已有越来越多的产品问世。纳米混悬技术是未来药物传递系统的发展方向之一,将具有良好的应用前景。     

Biological function,regulatory mechanism,and clinical application of mannose in cancer

Studies examining the regulatory roles and clinical applications of monosaccharides other than glucose in cancer have been neglected. Mannose, a common type of monosaccharide found in human body fluids and tissues, primarily functions in protein glycosylation rather than carbohydrate metabolism. Recent research has demonstrated direct anticancer effects of mannose in vitro and in vivo. Simply supplementing cell culture medium or drinking water with mannose achieved these effects. Moreover, mannose enhances the effectiveness of current cancer treatments including chemotherapy, radiotherapy, targeted therapy, and immune therapy. Besides the advancements in basic research on the anticancer effects of mannose, recent studies have reported its application as a biomarker for cancer or in the delivery of anticancer drugs using mannose-modified drug delivery systems. This review discusses the progress made in understanding the regulatory roles of mannose in cancer progression, the mechanisms underlying its anticancer effects, and its current application in cancer diagnosis and treatment.     

Display of proteins on bacteria

Display of heterologous proteins on the surface of microorganisms, enabled by means of recombinant DNA technology, has become an increasingly used strategy in various applications in microbiology, biotechnology and vaccinology. Gram-negative, Gram-positive bacteria, viruses and phages are all being investigated in such applications. This review will focus on the bacterial display systems and applications. Live bacterial vaccine delivery vehicles are being developed through the surface display of foreign antigens on the bacterial surfaces. In this field, 'second generation' vaccine delivery vehicles are at present being generated by the addition of mucosal targeting signals, through co-display of adhesins, in order to achieve targeting of the live bacteria to immunoreactive sites to thereby increase immune responses. Engineered bacteria are further being evaluated as novel microbial biocatalysts with heterologous enzymes immobilized as surface exposed on the bacterial cell surface. A discussion has started whether bacteria can find use as new types of whole-cell diagnostic devices since single-chain antibodies and other type of tailor-made binding proteins can be displayed on bacteria. Bacteria with increased binding capacity for certain metal ions can be created and potential environmental or biosensor applications for such recombinant bacteria as biosorbents are being discussed. Certain bacteria have also been employed for display of various poly-peptide libraries for use as devices in in vitro selection applications. Through various selection principles, individual clones with desired properties can be selected from such libraries. This article explains the basic principles of the different bacterial display systems, and discusses current uses and possible future trends of these emerging technologies.     

Light-sensitive lipid-based nanoparticles for drug delivery: design principles and future considerations for biological applications

Abstract

Radiation-based therapies aided by nanoparticles have been developed for decades, and can be primarily categorized into two main platforms. First, delivery of payload of photo-reactive drugs (photosensitizers) using the conventional nanoparticles, and second, design and development of photo-triggerable nanoparticles (primarily liposomes) to attain light-assisted on-demand drug delivery. The main focus of this review is to provide an update of the history, current status and future applications of photo-triggerable lipid-based nanoparticles (light-sensitive liposomes). We will begin with a brief overview on the applications of liposomes for delivery of photosensitizers, including the choice of photosensitizers for photodynamic therapy, as well as the currently available light sources (lasers) used for these applications. The main segment of this review will encompass the details of strategies used to develop photo-triggerable liposomes for their drug delivery function. The principles underlying the assembly of photoreactive lipids into nanoparticles (liposomes) and photo-triggering mechanisms will be presented. We will also discuss factors that limit the applications of these liposomes for in vivo triggered drug delivery and emerging concepts that may lead to the biologically viable photo-activation strategies. We will conclude with our view point on the future perspectives of light-sensitive liposomes in the clinic.     

CRISPR-Cas9 base editors and their current role in human therapeutics

BackgroundConsistent progress has been made to create more efficient and useful CRISPR-Cas9-based molecular toolsfor genomic modification.MethodsThis review focuses on recent articles that have employed base editors (BEs) for both clinical and research purposes.ResultsCRISPR-Cas9 BEs are a useful system because of their highefficiency and broad applicability to gene correction and disruption. In addition, base editing has beensuggested as a safer approach than other CRISPR-Cas9-based systems, as it limits double-strand breaksduring multiplex gene knockout and does not require a toxic DNA donor molecule for genetic correction.ConclusionAs such, numerous industry and academic groups are currently developing base editing strategies withclinical applications in cancer immunotherapy and gene therapy, which this review will discuss, with a focuson current and future applications of in vivo BE delivery.     

Twin Screw Extruders as Continuous Mixers for Thermal Processing: a Technical and Historical Perspective

Developed approximately 100 years ago for natural rubber/plastics applications, processes via twin screw extrusion (TSE) now generate some of the most cutting-edge drug delivery systems available. After 25 or so years of usage in pharmaceutical environments, it has become evident why TSE processing offers significant advantages as compared to other manufacturing techniques. The well-characterized nature of the TSE process lends itself to ease of scale-up and process optimization while also affording the benefits of continuous manufacturing. Interestingly, the evolution of twin screw extrusion for pharmaceutical products has followed a similar path as previously trodden by plastics processing pioneers. Almost every plastic has been processed at some stage in the manufacturing train on a twin screw extruder, which is utilized to mix materials together to impart desired properties into a final part. The evolution of processing via TSEs since the early/mid 1900s is recounted for plastics and also for pharmaceuticals from the late 1980s until today. The similarities are apparent. The basic theory and development of continuous mixing via corotating and counterrotating TSEs for plastics and drug is also described. The similarities between plastics and pharmaceutical applications are striking. The superior mixing characteristics inherent with a TSE have allowed this device to dominate other continuous mixers and spurred intensive development efforts and experimentation that spawned highly engineered formulations for the commodity and high-tech plastic products we use every day. Today, twin screw extrusion is a battle hardened, well-proven, manufacturing process that has been validated in 24-h/day industrial settings. The same thing is happening today with new extrusion technologies being applied to advanced drug delivery systems to facilitate commodity, targeted, and alternative delivery systems. It seems that the “extrusion evolution” will continue for wide-ranging pharmaceutical products.     

The production of biopharmaceuticals in plant systems

Biopharmaceuticals present the fastest growing segment in the pharmaceutical industry, with an ever widening scope of applications. Whole plants as well as contained plant cell culture systems are being explored for their potential as cheap, safe, and scalable production hosts. The first plant-derived biopharmaceuticals have now reached the clinic. Many biopharmaceuticals are glycoproteins; as the Golgi N-glycosylation machinery of plants differs from the mammalian machinery, the N-glycoforms introduced on plant-produced proteins need to be taken into consideration. Potent systems have been developed to change the plant N-glycoforms to a desired or even superior form compared to the native mammalian N-glycoforms. This review describes the current status of biopharmaceutical production in plants for industrial applications. The recent advances and tools which have been utilized to generate glycoengineered plants are also summarized and compared with the relevant mammalian systems whenever applicable.     

Contribution of the Actinobacteria to the growing diversity of lantibiotics

Currently, 76 lantibiotics have been described; the vast majority being produced by members of the Firmicute phylum of bacteria. There is a growing number being identified from the Actinobacteria phylum and some of these exhibit novel modifications leading to an increased functional diversity among lantibiotics. In this review, we discuss the currently characterized lantibiotics highlighting the expanding diversity provided by those from the Actinobacteria. This increased diversity has the potential to expand lantibiotic applications as antimicrobials in foods and pharmaceuticals. In addition, a phylogenetic classification system based on the full prepropeptide sequences showed remarkable consistency with current classification systems and may provide a more rapid and convenient means for classifying lantibiotics.     

Light-sensitive lipid-based nanoparticles for drug delivery: design principles and future considerations for biological applications

Radiation-based therapies aided by nanoparticles have been developed for decades, and can be primarily categorized into two main platforms. First, delivery of payload of photo-reactive drugs (photosensitizers) using the conventional nanoparticles, and second, design and development of photo-triggerable nanoparticles (primarily liposomes) to attain light-assisted on-demand drug delivery. The main focus of this review is to provide an update of the history, current status and future applications of photo-triggerable lipid-based nanoparticles (light-sensitive liposomes). We will begin with a brief overview on the applications of liposomes for delivery of photosensitizers, including the choice of photosensitizers for photodynamic therapy, as well as the currently available light sources (lasers) used for these applications. The main segment of this review will encompass the details of strategies used to develop photo-triggerable liposomes for their drug delivery function. The principles underlying the assembly of photoreactive lipids into nanoparticles (liposomes) and photo-triggering mechanisms will be presented. We will also discuss factors that limit the applications of these liposomes for in vivo triggered drug delivery and emerging concepts that may lead to the biologically viable photo-activation strategies. We will conclude with our view point on the future perspectives of light-sensitive liposomes in the clinic.     

Production of Electrospun Fast-Dissolving Drug Delivery Systems with Therapeutic Eutectic Systems Encapsulated in Gelatin

Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.     

Carbon nanotubes in cancer diagnosis and therapy

During the past years, great progress has been made in the field of nanomaterials given their great potential in biomedical applications. Carbon nanotubes (CNTs), due to their unique physicochemical properties, have become a popular tool in cancer diagnosis and therapy. They are considered one of the most promising nanomaterials with the capability of both detecting the cancerous cells and delivering drugs or small therapeutic molecules to these cells. Over the last several years, CNTs have been explored in almost every single cancer treatment modality, including drug delivery, lymphatic targeted chemotherapy, thermal therapy, photodynamic therapy, and gene therapy. In this review, we will show how they have been introduced into the diagnosis and treatment of cancer. Novel SWNT-based tumor-targeted drug delivery systems (DDS) will be highlighted. Furthermore, the in vitro and in vivo toxicity of CNTs reported in recent years will be summarized.     

Skin Electroporation: Effects on Transgene Expression,DNA Persistence and Local Tissue Environment

Background

Electrical pulses have been used to enhance uptake of molecules into living cells for decades. This technique, often referred to as electroporation, has become an increasingly popular method to enhance in vivo DNA delivery for both gene therapy applications as well as for delivery of vaccines against both infectious diseases and cancer. In vivo electrovaccination (gene delivery followed by electroporation) is currently being investigated in several clinical trials, including DNA delivery to healthy volunteers. However, the mode of action at molecular level is not yet fully understood.

Methodology/Principal Findings

This study investigates intradermal DNA electrovaccination in detail and describes the effects on expression of the vaccine antigen, plasmid persistence and the local tissue environment. Gene profiling of the vaccination site showed that the combination of DNA and electroporation induced a significant up-regulation of pro-inflammatory genes. In vivo imaging of luciferase activity after electrovaccination demonstrated a rapid onset (minutes) and a long duration (months) of transgene expression. However, when the more immunogenic prostate specific antigen (PSA) was co-administered, PSA-specific T cells were induced and concurrently the luciferase expression became undetectable. Electroporation did not affect the long-term persistence of the PSA-expressing plasmid.

Conclusions/Significance

This study provides important insights to how DNA delivery by intradermal electrovaccination affects the local immunological responses of the skin, transgene expression and clearance of the plasmid. As the described vaccination approach is currently being evaluated in clinical trials, the data provided will be of high significance.     

Recent applications of starch derivatives in nanodrug delivery

Starch has found use in industries as diverse as food, textiles, cosmetics, plastics, adhesives, paper, and pharmaceuticals. From a pharmaceutical standpoint, starch finds its value in solid-oral dosage forms, where it has been used as a binder, diluent, and disintegrant. However, only recently has the use of starch in nanotechnology started to make significant advances in biomedical applications, including newer drug delivery techniques. There has been a considerable effort to develop biodegradable nanoparticles as effective drug delivery systems. Being cheap, non-toxic, renewable, biodegradable and compatible with many other materials for industrial applications, starch is attracting the interest of drug delivery scientists. We have put together in a short and concise format, recent applications of starch derivatives in the emerging field of nanodrug delivery with the conclusion that a lot still needs to be done.     

前列腺癌适配体的研究进展及其应用

寻找一种高特异性高灵敏度的方法对于前列腺癌的早期发现和及早干预,进而提高患者的生存率及生活质量十分重要。适配体(Aptamer)是由一段寡聚核苷酸链折叠形成的特定三维结构,能高亲和性、高特异性地靶向不同的分子。自上世纪90年代,许多研究者致力于适配体的研究,目前,适配体在药物递送、肿瘤诊疗等方面的研究已取得较大进展。本文将对前列腺癌适配体新近的研究进展及其应用进行综述,以期为将来进一步的研究和临床应用提供参考。     

Delivering on the promise of bone morphogenetic proteins.

The advent of bone growth factors has been widely anticipated since their successful production using recombinant DNA technology. Bone morphogenetic proteins (BMPs) are an important class of bone growth factors and will be the focus of this article. In the near future these therapeutics might revolutionize how clinicians treat such diverse orthopedic applications as the healing of broken bones, increasing bone density lost through aging, and strengthening the spine. These potent proteins require application directly at the site of repair via a delivery system. The choice of delivery system has a profound effect on the clinical outcome. In the past decade, researchers have focused on developing efficient delivery systems and advancing these factors from the bench to the clinic.     

Gene therapy vectors: the prospects and potentials of the cut-and-paste transposons

Gene therapy applications require efficient tools for the stable delivery of genetic information into eukaryotic genomes. Most current gene delivery strategies are based on viral vectors. However, a number of drawbacks, such as the limited cargo capacity, host immune response and mutational risks, highlight the need for alternative gene delivery tools. A comprehensive gene therapy tool kit should contain a range of vectors and techniques that can be adapted to different targets and purposes. Transposons provide a potentially powerful approach. However, transposons encompass a large number of different molecular mechanisms, some of which are better suited to gene delivery applications than others. Here, we consider the range and potentials of the various mechanisms, focusing on the cut-and-paste transposons as one of the more promising avenues towards gene therapy applications. Several cut-and-paste transposition systems are currently under development. We will first consider the mechanisms of piggyBac and the hAT family elements Tol1 and Tol2, before focusing on the mariner family elements including Mos1, Himar1 and Hsmar1.     

A Review of the Advancements in Probiotic Delivery: Conventional vs. Non-conventional Formulations for Intestinal Flora Supplementation

Probiotic delivery systems are widely used nutraceutical products for the supplementation of natural intestinal flora. These delivery systems vary greatly in effectiveness to exert health benefits for a patient. Probiotic delivery systems can be categorized into conventional, pharmaceutical formulations, and non-conventional, mainly commercial food-based, products. The degree of health benefits provided by these probiotic formulations varies in their ability to deliver viable, functional bacteria in large enough numbers (effectiveness), to provide protection against the harsh effects of the gastric environment and intestinal bile (in vivo protection), and to survive formulation processes (viability). This review discusses the effectiveness of these probiotic delivery systems to deliver viable functional bacteria focusing on the ability to protect the encapsulated probiotics during formulation process as well as against harsh physiological conditions through formulation enhancements using coatings and polymer enhancements. A brief overview on the health benefits of probiotics, current formulation, patient and legal issues facing probiotic delivery, and possible recommendations for the enhanced delivery of probiotic bacteria are also provided. Newer advanced in vitro analyses that can accurately determine the effectiveness of a probiotic formulation are also discussed with an ideal probiotic delivery system hypothesized through a combination of the two probiotic delivery systems described.     

Stimuli-responsive nanocarriers for intracellular delivery

The emergence of different nanoparticles (NPs) has made a significant revolution in the field of medicine. Different NPs in the form of metallic NPs, dendrimers, polymeric NPs, carbon quantum dots and liposomes have been functionalized and used as platforms for intracellular delivery of biomolecules, drugs, imaging agents and nucleic acids. These NPs are designed to improve the pharmacokinetic properties of the drug, improve their bioavailability and successfully surpass physiological or pathological obstacles in the biological system so that therapeutic efficacy is achieved. In this review I present some of the current approaches used in intracellular delivery systems, with a focus on various stimuli-responsive nanocarriers, including cell-penetrating peptides, to highlight their various biomedical applications.