Current Medicinal Chemistry - Volume 20, Issue 28, 2013

The contribution of adult stem cells to cardiac repair is mostly ascribed to an indirect paracrine effect, rather than to their actual engraftment and differentiation into new contractile and vascular cells. This effect consists in a direct reduction of host cell death, promotion of neovascularization, and in a “bystander effect” on local inflammation. A number of cytokines secreted by adult stem/progenitor cells has been proposed to be responsible for the consistent beneficial effect reported in the early attempts to deliver different stem cell subsets to the injured myocardium. Aiming to maximize their beneficial activity on the diseased myocardium, the genetic modification of adult stem cells to enhance and/or control the secretion of specific cytokines would turn them into active drug delivery vectors. On the other hand, engineering biocompatible scaffolds as to release paracrine factors could result in multiple advantages: (1) achieve a local controlled release of the drug of interest, thus minimizing off-target effects, (2) enhance stem cell retention in the injured area and (3) boost the beneficial paracrine effects exerted by adult stem cells on the host tissue. In the present review, a critical overview of the state-of-the-art in the modification of stem cells and the functionalization of biocompatible scaffolds to deliver beneficial soluble factors to the injured myocardium is offered. Besides the number of concerns to be addressed before a clinical application can be foreseen for such concepts, this path could translate into the generation of active scaffolds as smart cell and drug delivery systems for cardiac repair.

DNAzymes are DNA-based catalytic molecules that have potential use in a range of disorders where the targeted gene plays an important role in disease pathogenesis. DNAzymes are at a comparatively early developmental stage as alternatives to conventional therapies. The biological action of DNAzymes on target mRNA requires efficient delivery into target cells and this hurdle has hampered their broader use, particularly in systemic settings. DNAzymes have been delivered in naked form without a carrier or combined with agents such as polymers and liposomes. This article reviews these and other delivery approaches and offers perspectives on future methodologies for improved DNAzyme delivery and utility as novel drugs.

Nucleic acid (NA) based drugs offer the potential of highly selective treatments for malignant diseases. They act as an initially inactive pro-drug being activated at the intended site of action, either by translation into a protein in case of plasmid DNA or through expression shutdown by interfering specifically with messenger RNA (RNAi technology). In case of already metastasized cancer, systemic treatment via the blood stream is often inevitable to reach the lesion. This makes it necessary to protect NAs from enzymatic degradation, but also to target them to the tumor with appropriate ligands. Polycationic molecules can provide such functions by condensing NAs into virus sized particles by virtue of charge interaction with the negatively charged phosphate backbone of NAs. Here we review the application of NA carrier systems based on the polycation polyethylenimine (PEI), where peptide based ligands are attached to the polycation via heterobifunctional polyethylene glycol linker molecules. Conjugate synthesis, in vitro testing and in vivo application in subcutaneous and disseminated cancer models in rodents are discussed.

In recent years there has been an outburst of interest regarding the employment of nanoparticles for biomedical applications. Among the different types, such as metallic, organic, biological and hybrid systems, virus based nanoparticles have become a popular field of research. Viruses are able to form organized structures by molecular self assembly of repetitive building blocks, which implies non covalent interactions of protein monomers to form the quaternary structure of viral capsids. Plant virus based systems, in particular, are among the most advanced and exploited for their potential use as bioinspired structured nanomaterials and nanovectors. Plant viruses have a size particularly suitable for nanoscale applications and can offer several advantages. In fact, they are structurally uniform, robust, biodegradable and easy to produce. Moreover, many are the examples regarding functionalization of plant virus based nanoparticles by means of modification of their external surface and by loading cargo molecules into their internal cavity. This plasticity in terms of nanoparticles engineering is the ground on which multivalency, payload containment and targeted delivery can be fully exploited. This review aims primarily to summarize the most important plant virus based nanoparticles systems through their recent applications in biomedicine, such as epitope display for vaccine development and targeted delivery for diagnosis or therapy. In addition, their production in the most commonly used plant propagation and expression systems will be also reviewed.

Pluronic-based core/shell nanoparticles (NPs) were formed using various strategies such as self-assembly and temperature induced-phase transition. To improve their functionality as a nanomedicine for diagnosis and therapy, the vesicle fusion and layer by layer approach were employed. Because of the hydrophilic nature of the Pluronic shell and the relatively small size, Pluronic-based core/shell NPs were used in order to improve their pharmacokinetic behaviors in drugs and in imaging agents. This review will introduce various types of Pluronic-based core/shell NPs according to their preparation method and formation mechanism. The focus will be on the Pluronic-based core/shell NPs for tumor targeting, stimulated release of proteins, and cancer imaging capabilities.

Site directed drug delivery with high efficacy is the biggest challenge in the area of current pharmaceuticals. Biodegradable polymer-based controlled release nanoparticle platforms could be beneficial for targeted delivery of therapeutics and contrast agents for a myriad of important human diseases. Biodegradable nanoparticles, which can be engineered to load multiple drugs with varied physicochemical properties, contrast agents, and cellular or intracellular component targeting moieties, have emerged as potential alternatives for tracking and treating human diseases. In this review, we will highlight the current advances in the design and execution of such platforms for their potential application in the diagnosis and treatment of variety of diseases ranging from cancer to Alzheimer’s and we will provide a critical analysis of the associated challenges for their possible clinical translation.

The thickening of the vessel wall (intimal hyperplasia) is a pathological process which often follows revascularization approaches such as transluminal angioplasty and artery bypass graft, procedures used to re-vascularize stenotic artery. Despite the significant improvements in the treatment of intimal hyperplasia obtained in the last years, the problem has not completely solved. Nucleic acid based-drugs (NABDs) represent an emergent class of molecules with potential therapeutic value for the treatment of intimal hyperplasia. NABDs of interest in the field of intimal hyperplasia are: ribozymes, DNAzymes, antisense oligonucleotides, decoy oligonucleotides, small interfering RNAs and micro interfering RNAs. These molecules can recognize, in a sequencespecific fashion, a target which, depending on the different NABDs, can be represented by a nucleic acid or a protein. Upon binding, NABDs can down-modulate the functions of the target (mRNA/proteins) and thus they are used to impair the functions of disease-causing biological molecules.In spite of the great therapeutic potential demonstrated by NABDs in many experimental model of intima hyperplasia, their practical use is hindered by the necessity to identify optimal delivery systems to the vasculature. In the first part of this review a brief description of the clinical problem related to intima hyperplasia formation after revascularization procedures is reported. In the second part, the attention is focused on the experimental evidences of NABD therapeutic potential in the prevention of intimal hyperplasia. Finally, in the third part, we will describe the strategies developed to optimize NABD delivery to the diseased vessel.

The facile self-assembly and nanomanipulation of nucleic acids hold great promise in the design of innovative, programmable materials, with applications ranging from biosensing to cellular targeting and drug delivery. Little is known, however, of the effects of confinement on biochemical reactions within such systems, in which the level of packing and crowding is similar to that of intracellular environments. In this review article we outline novel, unexpected properties of nucleic acids that arise from nanoscale confinement, as mainly revealed by atomic force and electron microscopy, electrochemistry, fluorescence spectroscopy, and gel electrophoresis. We review selected scientific studies over the last decade that describe the novel behavior of nanoconfined nucleic acids with respect to hybridization, denaturation, conformation, stability, and enzyme accessibility. The nanoscale systems discussed include self-assembled, water-soluble, DNA or RNA nanostructures, ranging in width from a few to several tens of nm; gold nanoparticles coated with DNA monolayers; and self-assembled monolayers of DNA, from a few to several hundreds of bp in length. These studies reveal that the functionality of nucleic acid-based nanosystems is highly dependent upon the local density, molecular flexibility and network of weak interactions between adjacent molecules. These factors significantly affect steric hindrance, molecular crowding and hydration, which in turn control nucleic acid hybridization, denaturation, conformation, and enzyme accessibility. The findings discussed in this review article demonstrate that nucleic acids function in a qualitatively different manner within nanostructured systems, and suggest that these novel properties, if better understood, will enable the development of powerful molecular tools for nanomedicine.