Current Medicinal Chemistry (v.20, #28)

Adult Stem Cells and Biocompatible Scaffolds as Smart Drug Delivery Tools for Cardiac Tissue Repair by Stefania Pagliari, Sara Romanazzo, Diogo Mosqueira, Perpetua Pinto-do-O, Takao Aoyagi, Giancarlo Forte (3429-3447).
The contribution of adult stem cells to cardiac repair is mostly ascribed to an indirect paracrine effect, ratherthan to their actual engraftment and differentiation into new contractile and vascular cells. This effect consists in a directreduction of host cell death, promotion of neovascularization, and in a “bystander effect” on local inflammation. A numberof cytokines secreted by adult stem/progenitor cells has been proposed to be responsible for the consistent beneficialeffect 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 toenhance 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 retentionin 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 functionalizationof 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 pathcould translate into the generation of active scaffolds as smart cell and drug delivery systems for cardiac repair.

DNAzyme Delivery Approaches in Biological Settings by Cecilia W.S. Chan, Levon M. Khachigian (3448-3455).
DNAzymes are DNA-based catalytic molecules that have potential use in a range of disorders where the targetedgene plays an important role in disease pathogenesis. DNAzymes are at a comparatively early developmental stageas alternatives to conventional therapies. The biological action of DNAzymes on target mRNA requires efficient deliveryinto target cells and this hurdle has hampered their broader use, particularly in systemic settings. DNAzymes have beendelivered in naked form without a carrier or combined with agents such as polymers and liposomes. This article reviewsthese and other delivery approaches and offers perspectives on future methodologies for improved DNAzyme deliveryand utility as novel drugs.

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

Nanoparticles in Biomedicine: New Insights from Plant Viruses by C. Lico, A. Schoubben, S. Baschieri, P. Blasi, L. Santi (3471-3487).
In recent years there has been an outburst of interest regarding the employment of nanoparticles for biomedicalapplications. Among the different types, such as metallic, organic, biological and hybrid systems, virus based nanoparticleshave become a popular field of research. Viruses are able to form organized structures by molecular self assembly ofrepetitive building blocks, which implies non covalent interactions of protein monomers to form the quaternary structureof viral capsids. Plant virus based systems, in particular, are among the most advanced and exploited for their potential useas bioinspired structured nanomaterials and nanovectors. Plant viruses have a size particularly suitable for nanoscale applicationsand 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 modificationof their external surface and by loading cargo molecules into their internal cavity. This plasticity in terms ofnanoparticles engineering is the ground on which multivalency, payload containment and targeted delivery can be fullyexploited. This review aims primarily to summarize the most important plant virus based nanoparticles systems throughtheir recent applications in biomedicine, such as epitope display for vaccine development and targeted delivery for diagnosisor therapy. In addition, their production in the most commonly used plant propagation and expression systems willbe also reviewed.

Pluronic-Based Core/Shell Nanoparticles for Drug Delivery and Diagnosis by Yon Woo Jung, Hwanbum Lee, Jae Yeon Kim, Eun Jin Koo, Keun Sang Oh, Soon Hong Yuk (3488-3499).
Pluronic-based core/shell nanoparticles (NPs) were formed using various strategies such as self-assembly andtemperature induced-phase transition. To improve their functionality as a nanomedicine for diagnosis and therapy, thevesicle fusion and layer by layer approach were employed. Because of the hydrophilic nature of the Pluronic shell and therelatively small size, Pluronic-based core/shell NPs were used in order to improve their pharmacokinetic behaviors indrugs and in imaging agents. This review will introduce various types of Pluronic-based core/shell NPs according to theirpreparation 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.

Nanocarriers for Tracking and Treating Diseases by Sean Marrache, Rakesh Kumar Pathak, Kasey L. Darley, Joshua H. Choi, Dhillon Zaver, Nagesh Kolishetti, Shanta Dhar (3500-3514).
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 therapeuticsand contrast agents for a myriad of important human diseases. Biodegradable nanoparticles, which can be engineeredto load multiple drugs with varied physicochemical properties, contrast agents, and cellular or intracellular componenttargeting moieties, have emerged as potential alternatives for tracking and treating human diseases. In this review, wewill highlight the current advances in the design and execution of such platforms for their potential application in the diagnosisand treatment of variety of diseases ranging from cancer to Alzheimer’s and we will provide a critical analysis ofthe associated challenges for their possible clinical translation.

Therapeutic Potential of Nucleic Acid-Based Drugs in Coronary Hyper- Proliferative Vascular Diseases by G. Grassi, B. Scaggiante, B. Dapas, R. Farra, F. Tonon, G. Lamberti, A. Barba, S. Fiorentino, N. Fiotti, F. Zanconati, M. Abrami, M. Grassi (3515-3538).
The thickening of the vessel wall (intimal hyperplasia) is a pathological process which often follows revascularizationapproaches such as transluminal angioplasty and artery bypass graft, procedures used to re-vascularizestenotic artery. Despite the significant improvements in the treatment of intimal hyperplasia obtained in the last years, theproblem has not completely solved. Nucleic acid based-drugs (NABDs) represent an emergent class of molecules with potentialtherapeutic 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 sequencespecificfashion, 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 impairthe functions of disease-causing biological molecules.In spite of the great therapeutic potential demonstrated by NABDsin many experimental model of intima hyperplasia, their practical use is hindered by the necessity to identify optimal deliverysystems to the vasculature.In the first part of this review a brief description of the clinical problem related to intima hyperplasia formation after revascularizationprocedures is reported. In the second part, the attention is focused on the experimental evidences ofNABD therapeutic potential in the prevention of intimal hyperplasia. Finally, in the third part, we will describe the strategiesdeveloped to optimize NABD delivery to the diseased vessel.

Effects of Nanoscale Confinement on the Functionality of Nucleic Acids: Implications for Nanomedicine by M. Castronovo, A. Stopar, L. Coral, S. K. Redhu, M. Vidonis, V. Kumar, F. Del Ben, M. Grassi, A. W. Nicholson (3539-3557).
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 isknown, however, of the effects of confinement on biochemical reactions within such systems, in which the level of packingand crowding is similar to that of intracellular environments. In this review article we outline novel, unexpected propertiesof 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 lastdecade 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 DNAmonolayers; and self-assembled monolayers of DNA, from a few to several hundreds of bp in length. These studies revealthat the functionality of nucleic acid-based nanosystems is highly dependent upon the local density, molecular flexibilityand network of weak interactions between adjacent molecules. These factors significantly affect steric hindrance, molecularcrowding 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 differentmanner within nanostructured systems, and suggest that these novel properties, if better understood, will enable the developmentof powerful molecular tools for nanomedicine.