Role of calcium in gene delivery

The treatment of genetic diseases using therapeutic gene transfer is considered to be a significant development. This development has brought with it certain limitations, and the process of overcoming these barriers has seen a drastic change in gene delivery. Many metal ions such as Mg²⁺, Mn²⁺, Ba²⁺ and, most importantly, Ca²⁺ have been demonstrated to have significant roles in gene delivery. Recently, calcium phosphate alone, or in combination with viral and nonviral vectors, was found to exert a positive effect on gene transfer when incorporated in the colloidal particulate system, which is an advancing approach to gene delivery. This review elaborates on various successful methods of using calcium in gene delivery.     

An update on calcium carbonate nanoparticles as cancer drug/gene delivery system

Introduction: In recent years, the applications of calcium carbonate (CaCO₃) nanoparticles (NPs) have gained extensive interest as targeted drug/gene delivery systems to cancerous tissues and cells due to their accessibility, low cost, safety, biocompatibility, pH-sensitivity, and slow biodegradability.

Areas covered: Drug-loaded CaCO₃ NPs (CCNPs) have been reviewed. An updated search on the current state of CCNPs as cancer drug/gene delivery systems with a focus on their special properties including pH-sensitivity, biodegradability, and sustained release performance has been also assessed.

Expert opinion: Based on the reviewed literature, CCNPs, because of their superior features, will have a great aiding role in safe and efficient cancer treatment in the near future.     

pDNA loaded calcium phosphate nanoparticles: highly efficient non-viral vector for gene delivery

Nanoparticles of calcium phosphate encapsulating plasmid DNA (pDNA) of size 100-120 nm in diameter were prepared. XRD studies of these nanoparticles showed them to be crystalline in nature having hydroxyapatite structure. The maximum loading of pDNA and its release from nanoparticles were studied using gel electrophoresis. The time dependent size measurement of these particles demonstrated that these particles show strong aggregational behaviour in aqueous dispersion. Calcium phosphate nanoparticles were found to be dissolved even in low acidic buffer (pH 5.0) releasing the pDNA, which suggested that DNA release from these particles in the endosomal compartment was possible. In vitro transfection efficiency of these calcium phosphate nanoparticles was found to be higher than that of the commercial transfecting reagent Polyfect.     

Dendrimers in gene delivery

Dendrimers have unique molecular architectures and properties that make them attractive materials for the development of nanomedicines. Key properties such as defined architecture and a high ratio of multivalent surface moieties to molecular volume also make these nanoscaled materials highly interesting for the development of synthetic (non-viral) vectors for therapeutic nucleic acids. Rational development of such vectors requires the link to be made between dendrimer structure and the morphology and physicochemistry of the respective nucleic acid complexes and, furthermore, to the biological performance of these systems at the cellular and systemic level. The review focuses on the current understanding of the role of dendrimers in those aspects of synthetic vector development. Dendrimer-based transfection agents have become routine tools for many molecular and cell biologists but therapeutic delivery of nucleic acids remains a challenge.     

Role of calcium in brain aging

• 1.1. Calcium is a universal messenger of extracellular signals in a great variety of cells; it regulates several neuronal functions, such as neurotransmitter synthesis and release, neuronal excitability, phosphorylation and so on. Calcium is also involved in long-term processes, like memory.
• 2.2. Recent studies demonstrated that brain aging is characterized by alterations in neuronal function due to the changes in calcium homeostasis. This occurs for various reasons, such as changes in calcium channels, decrease of ion binding to specific proteins and changes in the mechanisms involved in its sequestration and extrusion from neuronal cell.
• 3.3. Moreover, it has been shown that high levels of glucocorticoids are neurotoxic, because they alter calcium homeostasis on hypothalamic neurons by increasing calcium voltage-dependent flow, especially in aged neurons.
• 4.4. New information about the role of calcium in brain aging could derive from the expansion of new imaging techniques, such as positron emission tomography, single photon emission tomography and nuclear magnetic resonance, which allow in vivo quantitative measurements of functional parameters and their comparison with behavioural data.

     

Role of metabolism in ocular drug delivery

Metabolism is one of the primary routes of drug elimination from the body. This process comprises of mechanisms, such as oxidation and conjugation, which lead to inactivation and/or elimination from hepatic, biliary, pulmonary, renal and ocular tissues. Enzymes involved in metabolism are expressed in various tissues of the body, liver being the primary site. Studies involving ocular tissues have demonstrated the expression of several metabolic enzymes such as esterases, peptidases, ketone reductases, and CYP-450's in these tissues. These enzymes play an important role in ocular homeostasis by preventing entry and/or eliminating xenobiotics from the ocular tissues. Scientists have targeted these enzymes in drug design and delivery through prodrug derivatization. The prodrugs undergo biotransformation to the parent drug by ocular enzymatic degradation. This review examines the distribution pattern of various metabolic enzymes in the ocular tissues, their physiological role and utility in targeted prodrug delivery.     

Ultrasound-mediated gene delivery

Importance of the field: The use of ultrasound with microbubbles raises the possibility of an efficient and safe gene delivery.

Areas covered in this review: This review summarizes the current state of the art of gene delivery by sonoporation under the following topics. First, the basic ultrasound parameters and the characteristics of microbubble in biological systems are discussed. Second, the extensions of sonoporation to other fields of gene delivery such as viral and non-viral vector are briefly reviewed. Finally, recent applications in an animal model for various diseases are introduced.

What the reader will gain: Information and comments on gene delivery by sonoporation or enhanced cell membrane permeability by means of ultrasound.

Take home message: Ultrasound-mediated gene delivery combined with microbubble agents provides significant safety advantages over other methods of local gene delivery.     

Role of students in global health delivery

What role do students have in global health activities? On one hand, students have much to offer, including innovative ideas, fresh knowledge and perspective, and inspiring energy. At the same time, students lack technical credentials and may drain resources from host communities. Here, we examine the dynamic, contemporary roles of students in global health activities, including health delivery. We focus on 3 themes that guide engagement: (1) fostering an enabling policy environment (eg, toward greater health equity); (2) understanding and working within the local context and governments' needs; and (3) leading bidirectional partnerships. We next study the implications of short-term exposure and long-term engagement programs. We conclude with 4 recommendations on how to better equip students to engage in the next frontier of global health education and future action.     

Peptide-guided gene delivery

Although currently less efficient than their viral counterparts, nonviral vectors are under intense investigation as a safer alternative for gene therapy. For successful delivery, the nonviral vector must be able to overcome many barriers to protect DNA and specifically deliver it for efficient gene expression in target cells. The use of peptides as gene delivery vectors is advantageous over other nonviral agents in that they are able to achieve all of these goals. This review will focus on the application of peptides to mediate nonviral gene delivery. By examining the literature over the past 20 years, it becomes clear that no other class of biomolecules are simultaneously capable of DNA condensation, blocking metabolism, endosomal escape, nuclear localization, and receptor targeting. Based on virtually limitless diversity of peptide sequence and function information from nature, it is increasingly clear that peptide-guided gene delivery is still in its infancy.     

Viral gene delivery

Experimental studies of viral gene delivery generally support the principle that virus-mediated gene transfer is indeed possible. However, the field of gene therapy has not yet been realised as a practicable clinical intervention. The delay in translation of laboratory work to clinical utility largely reflects the inability of gene delivery vectors to convey adequate genetic material to a desired location, with adequate durability and low enough toxicity to be effective. Current studies of viral gene therapy vehicles have focused on re-engineering viruses being tested as vectors at present, treating the host to facilitate viral gene transfer and the development of new vectors. Initial enthusiasm for oncoretroviral and adenoviral vectors has cooled, while adeno-associated virus and lentiviral vectors are attracting more interest. Experimental studies with modified SV40-based vectors have also been very promising. The future of gene therapy will probably entail using an array of gene delivery vehicles, each with its own strengths and weaknesses. The vector systems will probably be as diverse as the applications to which they will be put.     

Viral gene delivery

Experimental studies of viral gene delivery generally support the principle that virus-mediated gene transfer is indeed possible. However, the field of gene therapy has not yet been realised as a practicable clinical intervention. The delay in translation of laboratory work to clinical utility largely reflects the inability of gene delivery vectors to convey adequate genetic material to a desired location, with adequate durability and low enough toxicity to be effective. Current studies of viral gene therapy vehicles have focused on re-engineering viruses being tested as vectors at present, treating the host to facilitate viral gene transfer and the development of new vectors. Initial enthusiasm for oncoretroviral and adenoviral vectors has cooled, while adeno-associated virus and lentiviral vectors are attracting more interest. Experimental studies with modified SV40-based vectors have also been very promising. The future of gene therapy will probably entail using an array of gene delivery vehicles, each with its own strengths and weaknesses. The vector systems will probably be as diverse as the applications to which they will be put.     

Role of calcium ion in hormone-stimulated lipolysis

Using the flask-incubated fat cell system, the effects of Ca2+ removal from the incubation medium on the lipolytic system were studied. The removal of Ca2+ resulted in a total abolition of the lipolytic response and the increased cyclic AMP accumulation produced by ACTH. The lipolytic response to isoproterenol and forskolin were reduced approximately 40% by Ca2+ removal, but cyclic AMP accumulation was not altered in the presence of either of these agents using a Ca2+-free medium. The lipolytic response to the dibutyryl analog of cyclic AMP was also reduced by omission of Ca2+ from the incubation medium. It is concluded the Ca2+ is required for the interaction of ACTH with its receptor and the resultant activation of adenylate cyclase. Ca2+ also is required at some step in the lipolytic process distal to cyclic AMP.     

Novel cyclodextrin nanosponges for delivery of calcium in hyperphosphatemia

Cyclodextrin nanosponges are solid, porous nanoparticulate three dimensional structures, have been used as delivery system of different drugs. In this work, new cyclodextrin-based nanosponges of calcium carbonate were prepared by polymer condensation method to release the calcium in controlled manner in the treatment of hyperphosphatemia as novel carriers.     

Role of tumor vascular architecture in drug delivery

Tumor targeted drug delivery has the potential to improve cancer care by reducing non-target toxicities and increasing the efficacy of a drug. Tumor targeted delivery of a drug from the systemic circulation, however, requires a thorough understanding of tumor pathophysiology. A growing or receding (under the impact of therapy) tumor represents a dynamic environment with changes in its angiogenic status, cell mass, and extracellular matrix composition. An appreciation of the salient characteristics of tumor vascular architecture and the unique biochemical markers that may be used for targeting drug therapy is important to overcome barriers to tumor drug therapy and to facilitate targeted drug delivery. This review discusses the unique aspects of tumor vascular architecture that need to be overcome or exploited for tumor targeted drug delivery.     

Role of cyclodextrins in improving oral drug delivery

The use of high-throughput screening and similar techniques in drug discovery has put a number of evolutionary pressures on drug candidates such that over time there is a tendency for them to increase in molecular weight, increase in log K_{(octanol/water)} and decrease in water solubility. These trends provide an ever-increasing series of challenges for the drug formulator to generate effective, orally bioavailable dosage forms. An important tool in this regard is the use of cyclodextrins, especially chemically modified cyclodextrins. These starch derivatives interact via dynamic complex formation and other mechanisms in a way that camouflages undesirable physicochemical properties, including low aqueous solubility, poor dissolution rate and limited drug stability. Through these effects, cyclodextrins and their derivatives have become popular modalities for increasing oral bioavailability and absorption rate. These actions have positioned cyclodextrins as important enabling and functional excipients. This review aims to assess the use of cyclodextrins in oral and other administration routes in the context of the Biopharmaceutical Classification Systems (BCS), a US FDA-based characterization approach that bins drugs based on solubility and permeability features. Specifically, a framework based on Fickian theory as well as the Noyes-Whiney relationship is constructed to assess where cyclodextrins are likely to be useful and where their use is probably not justified. This working model is examined in the context of a number of published examples in which cyclodextrins have been applied to class I, II, III, and IV drugs and drug candidates.     

Drug delivery systems: 3A. Role of polymers in drug delivery

At present, polymers represent a class of ubiquitous materials. They are being used for a multitude of purposes and the almost inexhaustible varieties of molecular architecture that macromolecular materials can possess provides the possibility for a myriad of applications. Because of the increased interest being shown in the macromolecules by the pharmaceutical industry for the fabrication of drug delivery systems, numerous polymers have been synthesized and successfully used in drug delivery devices. The necessary conditions for developing the concept of pharmaceutically applicable polymers depend upon delineating a detailed knowledge of the relationship between the structure and properties of polymer networks. A number of polymers have been studied systematically from this point of view and there is every indication that the systems described have the potential to become clinically valuable and therefore marketable drug delivery systems. The potential of these promising polymers is still far from being exhausted and there is a strong possibility that many important developments will be forthcoming in this field in the future. In the current review article, polymers for controlled release have been divided into four major categories: diffusion-controlled systems; chemically controlled systems; solvent-activated systems; and magnetically controlled systems. Polymers as drug carriers also have been divided into various subgroups: soluble, biodegradable, mucoadhesive and other polymeric systems. The latter group includes polymers containing pendant bioactive substituents, matrix systems, heparin-releasing polymers, ionic polymers, oligomers and miscellaneous. At an introductory and fundamental level, an overview of these polymers and the materials science for the design of drug delivery systems will be discussed.     

Endosomal disruptors in non-viral gene delivery

Importance of the field: Non-viral gene delivery for the treatment of genetic and non-genetic diseases has been under investigation for several decades, but there has been very little application in patients because of poor gene expression and toxicity.

Areas covered in this review: As gene delivery almost invariably involves endocytosis, many of its limitations are related to compartmentalisation of the transgene within the endosomes. Gene expression enhancers have become an essential part of manipulating endosomal release, as well as protecting transgene from intracellular degradation. However, disruption of the endosomes can also release proteases that have been shown to activate apoptotic pathways.

What the reader will gain: An understanding of the role that endosomal release plays in the toxicity of gene delivery vehicles will help identify new approaches to minimise adverse effects while enhancing non-viral gene expression.

Take home message: The future of non-viral gene therapy needs to identify new approaches that limit endosome-induced toxicity while enhancing expression so that a pharmacological response can be reliably observed in vivo.