Current Medicinal Chemistry (v.19, #19)
Editorial [Hot Topic: Chemical Engineering of Nanocarrier Surfaces for an Efficient Drug Delivery to Severe Diseases (Guest Editor: Jose L. Arias)] by Jose L. Arias (3069-3069).
Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers by J. M. Rabanel (3070-3102).
Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilization, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers is their ability to either cross biological barriers themselves, or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, nanocarriers may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumor vasculature and blood brain barrier targeting), oral administration (gastrointestinal lining), and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting - size, shape, surface chemistry, surface patterning of nanovectors - will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers, although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature.
Antibody-Conjugated Nanoparticles for Therapeutic Applications by M. M. Cardoso (3103-3127).
A great challenge to clinical development is the delivery of chemotherapeutic agents, known to cause severe toxic effects, directly to diseased sites which increase the therapeutic index whilst minimizing off-target side effects. Antibody-conjugated nanoparticles offer great opportunities to overcome these limitations in therapeutics. They combine the advantages given by the nanoparticles with the ability to bind to their target with high affinity and improve cell penetration given by the antibodies. This specialized vehicle, that can encapsulate several chemotherapeutic agents, can be engineered to possess the desirable properties, allowing overcoming the successive physiological conditions and to cross biological barriers and reach a specific tissue or cell. Moreover, antibody-conjugated nanoparticles have shown the ability to be internalized through receptor-mediated endocytosis and accumulate in cells without being recognized by the P-glycoprotein, one of the main mediators of multi-drug resistance, resulting in an increase in the intracellular concentration of drugs. Also, progress in antibody engineering has allowed the manipulation of the basic antibody structure for raising and tailoring specificity and functionality. This review explores recent developments on active drug targeting by nanoparticles functionalized with monoclonal antibodies (polymeric micelles, liposomes and polymeric nanoparticles) and summarizes the opportunities of these targeting strategies in the therapy of serious diseases (cancer, inflammatory diseases, infectious diseases, and thrombosis).
Integrin-Mediated Drug Delivery in Cancer and Cardiovascular Diseases with Peptide-Functionalized Nanoparticles by D. Arosio (3128-3151).
In recent years progress has been speeding in studies of cell-cell interaction governed by adhesion molecules, and in particular by integrins and their ligands in cells and in the extracellular matrix. Integrins are distributed in a variety of tissues and blood cells. An increased expression of integrins and of their adhesion counterparts is often observed in sites relevant to disease states. Important roles are played by integrin αvβ3 in cancer angiogenesis and metastatic diffusion, in angiogenesis in ischemic tissues, in atherosclerotic damage and restenosis, and in osteoporosis; by integrin α5β1 in angiogenesis processes; by integrin αIIbβ3, mediating adhesion of platelets to fibrinogen, in thrombotic conditions; by integrins α4β1 and αLβ2 in inflammatory conditions, particularly autoimmune diseases and asthma. Therefore, medicinal chemists became attracted and engaged in research on integrins as therapeutic and diagnostic targets. Many efforts have been directed towards the development of molecular constructs including integrin ligands that can provide advanced tools for drug delivery, for imaging, or for their combination (theranostics), particularly by exploiting the new possibilities offered by nanoparticles. Here we will review the current status and the future perspective of integrin targeting of several kind of nanoparticles, going from most studied micelles, liposomes, polymeric nanoparticles to finish with inorganic nanoparticles of more recent employment. Perfluoroalkane filled microbubbles, although over the nanometric size (1-10 μm) will be shortly considered.
Active Drug Targeting of Disease by Nanoparticles Functionalized with Ligand to Folate Receptor by Q. Tu (3152-3162).
Drug-loaded nanoparticles have shown great potential in the study of carriers for disease-targeting drug delivery. Drug-loaded nanoparticles are excellent in keeping the drug in the systemic circulation for a prolonged period of time, introducing targeting molecules to improve targeting efficiency and to reduce side effects. A general review on active drug targeting of cancerous diseases by nanoparticles functionalized with ligands to folate receptors is presented including the (1) materials and methods for nanoparticle preparation, (2) methods for drug encapsulation, (3) surface functionalization of the nanoparticle with ligand to folate receptors, and (4) in vitro and in vivo experiments.
Exploiting the Properties of Biomolecules for Brain Targeting of Nanoparticulate Systems by S. Cramer (3163-3187).
The main obstacle in the treatment of central nervous system diseases is represented by a limited passage of diagnostic and therapeutic agents across the blood-brain barrier, which separates the blood stream from the cerebral parenchyma and maintains the homeostasis of the brain. The growing knowledge about the brain capillary endothelium and the discovery of specific mechanisms for the uptake of substances enables the development of various strategies to enhance the drug delivery rate into the brain. Among the different strategies, nanoparticles are promising candidates for drug delivery to the brain due to their potential in encapsulating drugs and thereby disguising their permeation limiting characteristics. Furthermore a surface functionalization of many nanoparticles can easily be achieved allowing the active targeting of nanoparticles to the brain. For this non-invasive approach, the surface functionalization of nanoparticles with biomolecules has shown promising potential for effective drug delivery to the brain. This review indexes the main classes of biomolecules used for the surface functionalization of nanoparticles and discusses their potential as drug delivery systems for an enhanced passage of diagnostic and therapeutic agents into the brain parenchyma.
Drug Targeting to Cancer by Nanoparticles Surface Functionalized with Special Biomolecules by M. A. Holgado (3188-3195).
Nanoparticulate-based drug carriers have been developed to overcome the problems of conventional anticancer pharmacotherapy, i.e., the little specificity and low accumulation of the drug into the tumor interstitium, and the extensive biodistribution leading to severe toxicity. Unfortunately, conventional nanoparticles have been demonstrated to merely accumulate the loaded drug into organs associated to the reticuloendothelial system, e.g., the liver. Recently, drug delivery strategies involving the use of nanoplatforms surface decorated with unique biomolecules have demonstrated their potential in concentrating the chemotherapy agent specifically into the malignant cells. This review will be focused on the analysis of the current state of the art and future perspectives of such passive and active targeting strategies based on the enhanced permeability and retention effect and on a ligand-mediated transport, respectively. Special attention will be given to the use of these surface functionalized nanocarriers to overcome multi-drug resistances in cancer cells.
Drug Targeting to Infectious Diseases by Nanoparticles Surface Functionalized with Special Biomolecules by Shyam Sundar (3196-3202).
The potential to deliver nanoparticles directly into the targeted cells is important in the therapeutic applications for infectious diseases. The possibility of therapeutic agent being attached to the nanoparticles by chemical modification has provided a novel drug delivery option. Interestingly, the discovery of carbon nanotubes and graphene has given an excellent imaging and therapeutic agent for the biomedical applications. In spite of continuous advancement in pharmaceutical drug delivery viz. micelles, vesicles, liquid crystals, etc., during the past decades, their prohibitive production has limited their use. Nanomaterials with their properties of biodegradation, equal biodistribution, mass production, and long time storage make them attractive alternatives for future biomedical applications. Nanoparticles surface functionalized with specific biomolecules based drug delivery has driven new direction for modulating the pharmacokinetics, pharmacodynamics, biorecognition, and increasing the efficacy of targeted drugs. These new strategies are likely to minimize drug degradation and loss, increase drug availability, and opens up new vistas for drug delivery.
Drug Delivery to Inflammation Based on Nanoparticles Surface Decorated with Biomolecules by B. Clares (3203-3211).
Anti-inflammatory molecules often display little affinity for inflamed tissues, leading to low accumulation into this site of action (and inefficiency), and high incidence of severe side effects. To face the problem, numerous strategies have been proposed, i.e., chemical modifications to the drug molecule, and engineering of drug nanocarriers. The later approach to the problem can result in optimized drug biodistribution and concentration into the target region, thus enhancing the anti-inflammatory effect while reducing the associated drug toxicity. Such nanoparticulate systems offer remarkable possibilities when they are made of biodegradable polymers, lipid-based structures, and/or inorganic particles. Recent advances in the field have been devoted to the optimization of the in vivo fate and effectiveness of these drug nanocarriers, e.g., passive targeting strategies based on the functionalization of nanoparticle surface with special biomolecules. In this contribution, we analyze the possibilities and future perspectives of nanoparticle therapy in inflammatory processes.
Polysaccharide-Based Nanoparticles: A Versatile Platform for Drug Delivery and Biomedical Imaging by G. Saravanakumar (3212-3229).
Polysaccharide-based nanoparticles have attracted interest as carriers for imaging and therapeutic agents because of their unique physicochemical properties, including biocompatibility and biodegradability. In addition, the functional groups of the polysaccharide backbone allow facile chemical modification to develop nanoparticles with diverse structures. Some polysaccharides have the intrinsic ability to recognize specific cell types, facilitating the design of targeted-drug delivery systems through receptor-mediated endocytosis. The main objective of this review is to provide an overview of various polysaccharide-based nanoparticles and to highlight the recent efforts that have been made to improve the characteristics of polysaccharide-based nanoparticles for drug delivery and biomedical imaging.
Image-Guided Nanosystems for Targeted Delivery in Cancer Therapy by A. K. Iyer (3230-3240).
Current challenges in early detection, limitations of conventional treatment options, and the constant evolution of cancer cells with metastatic and multi-drug resistant phenotypes require novel strategies to effectively combat this deadly disease. Nanomedical technologies are evolving at a rapid pace and are poised to play a vital role in diagnostic and therapeutic interventions - the so-called “theranostics” – with potential to advance personalized medicine. In this regard, nanoparticulate delivery systems can be designed with tumor seeking characteristics by utilizing the inherent abnormalities and leaky vasculature of solid tumors or custom engineered with targeting ligands for more specific tumor drug targeting. In this review we discuss some of the recent advances made in the development of multifunctional polymeric nanosystems with an emphasis on image-guided drug and gene delivery. Multifunctional nanosystems incorporate variety of payloads (anticancer drugs and genes), imaging agents (optical probes, radio-ligands, and contrast agents), and targeting ligands (antibodies and peptides) for multi-pronged cancer intervention with potential to report therapeutic outcomes. Through advances in combinatorial polymer synthesis and high-throughput testing methods, rapid progress in novel optical/radiolabeling strategies, and the technological breakthroughs in instrumentation, such as hybrid molecular and functional imaging systems, there is tremendous future potential in clinical utility of theranostic nanosystems.
Novel Gb3 Isoforms Detected in Urine of Fabry Disease Patients: A Metabolomic Study by C. Auray-Blais (3241-3252).
Fabry disease is characterized by the accumulation of globotriaosylsphingosine (lyso-Gb3) and globotriaosylceramide (Gb3) in biological fluids and tissues. Metabolomic studies recently undertaken by our group, showed the presence of novel plasma and urine lyso-Gb3-related analogs in male and female Fabry patients. These analogs are distinguished by differences in structure of the sphingosine moiety. The principal aim of this study was to evaluate the possibility of detecting other Fabry disease biomarkers structurally related to Gb3. A time-of-flight mass spectrometry metabolomic approach, focusing on mass-to-charge (m/z) ratios from 1000 to 1200 Da, was devised. This m/z window corresponds to the isoforms and potential analogs of Gb3. Five different categories of Gb3- related isoforms/analogs were detected: Gb3-related isoforms with saturated fatty acids, methylated Gb3-related isoforms, Gb3-related isoforms/analogs with one double bond, Gb3 analogs with hydrated sphingosine, and Gb3-related isoforms/analogs with two double bonds. A secondary objective was to elucidate the relationship between Gb3 and lyso-Gb3. The methylation observed on Gb3-related analogs was not detected on lyso-Gb3. We speculate that the methylated Gb3 may be an intermediate compound in the deacylation of Gb3 to generate the lyso-Gb3 molecule. We are in the process of devising a quantification methodology for these methylated Gb3-related analogs in Fabry patients to try to understand the underlying biochemical mechanisms involved in this complex disease.