Virosomes for antigen and DNA delivery

Specific targeting and delivery as well as the display of antigens on the surface of professional antigen-presenting cells (APCs) are key issues in the design and development of new-generation vaccines aimed at the induction of both humoral and cell-mediated immunity. Prophylactic vaccination against infectious diseases in general aims at the induction of humoral immune responses to prevent infection. This humoral immune response is mediated by antibody-producing B cells. On the other hand, therapeutic immunisation against virally infected cells and tumour cells requires the induction of cytotoxic T lymphocytes (CTLs) that can specifically recognise and lyse infected cells or transformed tumour cells. The induction of Major Histocompatibility Complex (MHC) class I restricted CTL activity is optimally achieved by synthesis of antigens within APCs, for example, after immunisation with live attenuated virus. However, immunisation with live vaccines bears the risk of causing disease. Therefore, alternative vaccine delivery systems, which enable introduction of nonreplicating antigen into the MHC class I presentation pathway, are sought. Furthermore, for the induction of effective humoral and cellular responses, MHC class II restricted activation of T helper cells (Th cells) is required. Among other delivery systems, as described in this theme issue of Advanced Drug Delivery Reviews, virosomes seem ideally suited for delivery of antigens into both MHC pathways. In this review, we will focus on the use of virosomes as carrier vehicles for the intracellular delivery of protein antigens and DNA, and the induction of a cellular immune response against encapsulated protein antigens and proteins expressed by virosome-associated plasmids.     

Self-assembling nanoclusters in living systems: application for integrated photothermal nanodiagnostics and nanotherapy

Nanotechnologies represent an unprecedented recent advance that may revolutionize many areas of medicine and biology, including cancer diagnostics and treatment. Nanoparticle-based technologies have demonstrated especially high potential for medical purposes, ranging from diagnosing diseases to providing novel therapies. However, to be clinically relevant, the existing nanoparticle-based technologies must overcome several challenges, including selective nanoparticle delivery, potential cytotoxicity, imaging of nanoparticles, and real-time assessment of their therapeutic efficacy. This review addresses these issues by summarizing the recent advances in medical diagnostics and therapy with a focus on the self-assembly of gold nanoparticles into nanoclusters in live cells, in combination with their detection using photothermal (PT) techniques.     

Polymeric nano- and microparticle technologies for oral gene delivery

Gene therapy refers to local or systemic administration of a nucleic acid construct that can prevent, treat and even cure diseases by changing the expression of genes that are responsible for the pathological condition. Oral gene therapy has significant promise for treatment of local diseases such as inflammatory bowel disease and for systemic absorption of the expressed protein therapeutics. In addition, efficient oral delivery of DNA vaccines can have significant impact in disease prevention. The use of polymeric gene delivery vectors promises the translation of this experimental medical concept into clinical reality. This review addresses the challenges and opportunities in the development of polymer-based nano- and microparticle technologies for oral gene therapy. Specifically, the discussion is focused on different synthetic and natural polymers used for formulating nano- and microparticle technologies and the use of these delivery systems for oral DNA administration for therapeutic and vaccination purposes.     

Polymeric nano- and microparticle technologies for oral gene delivery

Gene therapy refers to local or systemic administration of a nucleic acid construct that can prevent, treat and even cure diseases by changing the expression of genes that are responsible for the pathological condition. Oral gene therapy has significant promise for treatment of local diseases such as inflammatory bowel disease and for systemic absorption of the expressed protein therapeutics. In addition, efficient oral delivery of DNA vaccines can have significant impact in disease prevention. The use of polymeric gene delivery vectors promises the translation of this experimental medical concept into clinical reality. This review addresses the challenges and opportunities in the development of polymer-based nano- and microparticle technologies for oral gene therapy. Specifically, the discussion is focused on different synthetic and natural polymers used for formulating nano- and microparticle technologies and the use of these delivery systems for oral DNA administration for therapeutic and vaccination purposes.     

Cell delivery to the central nervous system

A dysfunctional central nervous system (CNS) resulting from neurological disorders and diseases impacts all of humanity. The outcome presents a staggering health care issue with a tremendous potential for developing interventive therapies. The delivery of therapeutic molecules to the CNS has been hampered by the presence of the blood-brain barrier (BBB). To circumvent this barrier, putative therapeutic molecules have been delivered to the CNS by such methods as pumps/osmotic pumps, osmotic opening of the BBB, sustained polymer release systems and cell delivery via site-specific transplantation of cells. This review presents an overview of some of the CNS delivery technologies with special emphasis on transplantation of cells with and without the use of polymer encapsulation technology.     

Recent advances in the use of encapsulated cells for effective delivery of therapeutics

Cell encapsulation can be defined as a living cell approach for the long-term delivery of therapeutic products. It consists of the immobilization of therapeutically active cells within a general polymer matrix that permits the ingress of nutrients and oxygen and the egress of therapeutic protein products but impedes the immune contact of the enclosed cells. In recent decades many attempts have evaluated the potential of this technology to release therapeutic agents for the treatment of different pathologies and disorders. At present, cell encapsulation may be used as a technological platform to improve knowledge and clinical use of stem cells. This review describes the main issues related to this cell-based approach and summarizes some of the most interesting therapeutic applications.     

Comparative analysis of the methods of drug and protein delivery for the treatment of cancer, genetic diseases and diagnostics

The methods of protein and drug delivery for the treatment of cancer, genetic diseases and diagnostics were summarized. The potential of protein transduction is discussed and the recent developments in the field are reviewed. An overview is provided of the non-viral delivery methods such as liposomes, polymer-based delivery, cell-penetrating peptides, bacterial secretion, cells, virosomes, physical methods including electroporation, microinjection, osmotic lysis, nanoparticles, sonoporation to locally inject therapeutic molecules. The characteristic properties of non-viral vectors and their use for the delivery of therapeutic molecules for the diagnosis and treatment of disorders and to target tumors are also discussed. The potential of the transduced peptides and proteins was used as new therapeutic compounds against infectious diseases, to complement deficiencies in specific genes, to specifically kill tumour cells, for gene therapy. The protein delivery vectors can enhance the transfection at low concentrations and help to develop future gene delivery systems with reduced toxicity. Vitamin B12, folic acid, biotin, and riboflavin are essential in the treatment of cancer. Ultrasound has a potential in the delivery of therapeutic agents. The new developing technologies of drug delivery and targeting offer the possibility to improve the therapeutic possibilities of the existing drugs and to develop novel therapeutics.     

Comparative analysis of the methods of drug and protein delivery for the treatment of cancer,genetic diseases and diagnostics

The methods of protein and drug delivery for the treatment of cancer, genetic diseases and diagnostics were summarized. The potential of protein transduction is discussed and the recent developments in the field are reviewed. An overview is provided of the non-viral delivery methods such as liposomes, polymer-based delivery, cell-penetrating peptides, bacterial secretion, cells, virosomes, physical methods including electroporation, microinjection, osmotic lysis, nanoparticles, sonoporation to locally inject therapeutic molecules. The characteristic properties of non-viral vectors and their use for the delivery of therapeutic molecules for the diagnosis and treatment of disorders and to target tumors are also discussed. The potential of the transduced peptides and proteins was used as new therapeutic compounds against infectious diseases, to complement deficiencies in specific genes, to specifically kill tumour cells, for gene therapy. The protein delivery vectors can enhance the transfection at low concentrations and help to develop future gene delivery systems with reduced toxicity. Vitamin B12, folic acid, biotin, and riboflavin are essential in the treatment of cancer. Ultrasound has a potential in the delivery of therapeutic agents. The new developing technologies of drug delivery and targeting offer the possibility to improve the therapeutic possibilities of the existing drugs and to develop novel therapeutics.     

A new frontier in pharmacology: the endoplasmic reticulum as a regulated export pathway in health and disease

The endoplasmic reticulum (ER), the first secretory compartment of eukaryotic cells, co-ordinates the biogenesis and export of all membrane-bound and soluble cargo molecules to the cell surface. ER function is now recognised to have unprecedented links with signalling pathways regulating cell growth and differentiation and host physiology. Misfolding and aggregation of newly synthesised proteins in the ER or alterations in ER processing of cargo mediated by pathogens is responsible for a broad range of diseases including cystic fibrosis, emphysema and neuropathies such as Alzheimer's disease. The central, integrative role of the ER in determining cell physiology in health and disease represents an untapped area for pharmacological intervention. This review focuses on the potential use of pharmacological agents to modulate cargo selection, folding and degradation in the ER with the goal of alleviating ER export disease. In addition, implementation of novel technologies that utilise normal ER function to store and release biologically active substances of therapeutic relevance are presented as a new frontier in drug delivery.     

A new frontier in pharmacology: the endoplasmic reticulum as a regulated export pathway in health and disease

The endoplasmic reticulum (ER), the first secretory compartment of eukaryotic cells, co-ordinates the biogenesis and export of all membrane-bound and soluble cargo molecules to the cell surface. ER function is now recognised to have unprecedented links with signalling pathways regulating cell growth and differentiation and host physiology. Misfolding and aggregation of newly synthesised proteins in the ER or alterations in ER processing of cargo mediated by pathogens is responsible for a broad range of diseases including cystic fibrosis, emphysema and neuropathies such as Alzheimer’s disease. The central, integrative role of the ER in determining cell physiology in health and disease represents an untapped area for pharmacological intervention. This review focuses on the potential use of pharmacological agents to modulate cargo selection, folding and degradation in the ER with the goal of alleviating ER export disease. In addition, implementation of novel technologies that utilise normal ER function to store and release biologically active substances of therapeutic relevance are presented as a new frontier in drug delivery.     

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.     

Advances in the delivery of treatments for Parkinson's disease

Innovative drug delivery in Parkinson's disease (PD) has the potential to reduce or avoid many side effects of current treatment, such as wearing-off type fluctuations, dyskinesia, on-off phenomena or bouts of motor freezing. The traditional orally administered formulations of l-dihydroxyphenylalanine combined with a peripheral aromatic acid decarboxylase inhibitor remain the mainstay of treatments for PD. However, such combination therapies have been further formulated to extend their duration of action by including a catechol-O-methyltransferase inhibitor. Preventing the breakdown of dopamine has also been achieved by monoamine oxidase-B inhibition; this approach now having been formulated for sublingual use (Zelapar, Valeant Pharmaceuticals). An alternative approach bypasses the oral route of administration and instead relies on continuous duodenal infusion (Duodopa, Solvay, NeoPharma AB) for better therapeutic effect. The clinical use of dopamine agonists as antiparkinsonian drugs now incorporates a variety of delivery techniques. For example, apomorphine, which relies on parenteral administration for maximum bioavailability, may be delivered via rectal, intranasal, sublingual and subcutaneous (e.g., Apokyn, Mylan Bertek) routes. Meanwhile, rotigotine and lisuride have both been formulated for delivery via skin patches. Finally, the authors examine more experimental delivery techniques, including the delivery of genes via viral vectors or liposomes, intracranial transplant of a variety of cells and of L-dihydroxyphenylalanine by prodrug-dispensing liposomes or pulmonary delivery (AIR, Alkermes). The advent and application of these varied technologies will help encourage patient-specific means of treatment for PD.     

The cutting-edge technologies of siRNA delivery and their application in clinical trials

siRNA therapeutics allows precise regulation of disease specific gene expression to treat various diseases. Although gene silencing approaches using siRNA therapeutics shows some promising results in the treatment of gene-related diseases, the practical applications has been limited by problems such as inefficient in vivo delivery to target cells and nonspecific immune responses after systemic or local administration. To overcome these issues, various in vivo delivery platforms have been introduced. Here we provide an overview for three different platform technologies for the in vivo delivery of therapeutic siRNAs (siRNA–GalNAc conjugate, SAMiRNA technology, and LNP-based delivery method) and their applications in the treatment of various diseases. In addition, a brief introduction to some rare diseases and mechanisms of siRNA therapeutics-mediated treatment is described.     

Vaccine delivery to animals

For many years vaccination of animals has been practiced to prevent infectious diseases using inactivated organisms or modified live organisms. The live vaccines were effective but lacked safety. The vaccines made with inactivated organisms required an adjuvant to induce an immune response that was not as effective as either the clinical disease or live vaccines. An 'ideal' vaccine would induce effective immunity specific for the type of infection, have long duration, require minimal or no boosters, have impeccable safety, would not induce adverse reactions, and be easy to administer. The desire to meet these criteria, and especially safety, has resulted in the development of vaccines that do not depend on the use of the viable disease agent. The emphasis on subunit or inactivated vaccines that meet the desired criteria of a perfect vaccine has resulted in a critical need for better adjuvants and delivery systems. This has resulted in a technological innovation revolution with development of a wide array of different technologies to generate effective vaccines. This review will describe the historical relevance of adjuvants used for parenterally administered inactivated/subunit vaccines as well as describe some of the exciting technological advances including adjuvants (ISCOMS), delivery systems (recombinant vectors, microparticles), and novel approaches (transgenic plants, naked DNA) that are currently being, or will be used in the future, in the search for better, more effective vaccines that meet the current and future needs of veterinary medicine.     

Cellular transplants as sources for therapeutic agents

Soluble factors normally produced by cells of the human body are of increasing importance as potential therapeutic agents. Although considerable progress has been made in understanding the etiology and pathogenesis of disease, in developing animal models and newer experimental therapeutics, few discoveries have been translated into clinically effective ways of delivering the multiple therapeutic agents obtained from living mammalian cells. This review examines the use of transplanted cells as alternatives to conventional delivery systems to deliver a variety of protein based therapeutic agents. The chapter begins with a set of questions to establish the complexity and challenges of this form of drug delivery. The following section focuses the discussion on our understanding of genetic engineering, tissue engineering, and some areas of developmental biology as they relate to the development of this nascent field. Much of the discussion has a neuro/endocrine emphasis. The chapter ends by listing the basic ingredients needed to push the use of transplanted cells toward medical practice and some general comments about future developments.     

神经生长因子治疗阿尔采末病的胆碱能神经机制

神经生长因子 (nervegrowthfactor,NGF)是中枢胆碱能神经元存活和功能维持最重要的神经营养因子之一 ,对阿尔采末病 (Alzheimersdisease,AD)的治疗潜力已引起人们极大兴趣。投射于大脑皮质和海马的基底前脑胆碱能神经元退变是AD早期病变 ,也是导致患者认知功能降低的主要原因。NGF可通过兴奋残存神经元上高亲和性TrkA受体 ,促进中枢胆碱能神经元的存活和正常功能的发挥 ,同时神经元激活也使其自身免受AD的有害作用 ,即所谓“useitorloseit”现象。然而 ,NGF不能透过血脑屏障 ,如何使外源性NGF到达脑内靶区是亟待解决的难题 ,一旦获得理论和技术上的突破 ,NGF防治AD的临床应用才更具价值     

Encapsulation of Nucleic Acids and Opportunities for Cancer Treatment

The development of nucleic acid drugs for the treatment of various cancers has shown great promise in recent years. However, efficient delivery of these drugs to target cells remains a significant challenge towards the successful development of such therapies. This review provides a comprehensive overview of encapsulation technologies being developed for the delivery of nucleic acid-based anti-cancer agents. Both micro and nanoparticles systems are discussed along with their use in delivering plasmid DNA as well as oligonucleotides. The majority of the systems discussed have used DNA immunotherapy as the potential mode of anticancer therapy, which requires targeting to antigen presenting cells. Other applications, including those with oligonucleotides, focus on targeting tumor cells directly. The results obtained so far show the excellent promise of encapsulation as an efficient means of delivering therapeutic nucleic acids.     

Nonviral delivery of genetic medicine for therapeutic angiogenesis

Genetic medicines that induce angiogenesis represent a promising strategy for the treatment of ischemic diseases. Many types of nonviral delivery systems have been tested as therapeutic angiogenesis agents. However, their delivery efficiency, and consequently therapeutic efficacy, remains to be further improved, as few of these technologies are being used in clinical applications. This article reviews the diverse nonviral gene delivery approaches that have been applied to the field of therapeutic angiogenesis, including plasmids, cationic polymers/lipids, scaffolds, and stem cells. This article also reviews clinical trials employing nonviral gene therapy and discusses the limitations of current technologies. Finally, this article proposes a future strategy to efficiently develop delivery vehicles that might be feasible for clinically relevant nonviral gene therapy, such as high-throughput screening of combinatorial libraries of biomaterials.     

Tissue engineering by modulated gene delivery

Tissue engineering is a newly emerging biomedical form to create a local environment which enables cells to promote the proliferation and differentiation for regeneration induction. The cell-induced regeneration of tissues and organs is achieved by making use of the tissue engineering technology or methodology. Several genetic approaches with virus and non-viral vectors or genetically engineered cells have been attempted to enhance tissue regeneration. The basic idea is to promote the cell proliferation and differentiation as well as the secretion of biological signal molecules for tissue regeneration from cells by gene transfection. For successful gene transfection and expression, it is important to develop drug delivery system (DDS) which allows a therapeutic gene to be delivered specifically to the target cell at an appropriate timing for a certain time period. This paper overviews the recent development of gene-modified tissue engineering, briefly explaining delivery technologies necessary to modulate the efficiency of gene transfection.     

Drug delivery technologies for autoimmune disease

Importance of the field: Targeting autoimmune disease poses two main challenges. The first is to identify unique targets to suppress directly or indirectly autoreactive cells exclusively. The second is to penetrate target tissues to deliver specifically drugs to desired cells that can achieve a therapeutic outcome.

Areas covered in this review: Herein, the range of drug delivery methods available and under development and how they can be useful to treat autoimmune diseases are discussed. Polymer delivery methods, as well as biological methods that include fusion proteins, targeted antibodies, recombinant viruses and cell products are compared.

What the reader will gain: Readers will gain insight into the progression of clinical trials for different technologies and drug delivery methods useful for targeting and modulating the function of autoreactive immune cells.

Take home message: Several tissue-specific polymer-based and biologic drug delivery systems are now in Phase II/III clinical trials. Although these trials are focused mainly on cancer treatment, lessons from these trials can guide the use of the same agents for autoimmunity therapeutics.