Molecular transporters: synthesis of oligoguanidinium transporters and their application to drug delivery and real-time imaging.

TLDR: Research in this area offers the possibility of improving the bioavailability of existing drugs, enabling the delivery of new cargoes and drug candidates, and accessing difficult sites for cell penetration, all of which could dramatically enhance human therapy and the fundamental understanding of living systems.

Abstract: Biological barriers are of fundamental importance in understanding evolution, systems biology, and the prevention, ACHTUNGTRENNUNGdetection, and treatment of disease. Methods to enhance or ACHTUNGTRENNUNGcontrol selective passage of therapeutics or probes into or through such barriers are a key to the future of drug therapy and many fundamental advances in science. Research in this area offers the possibility of improving the bioavailability of existing drugs, enabling the delivery of new cargoes and drug candidates (e.g. , RNAi, shRNA, DNA, proteins, imaging agents, and sensors), accessing difficult sites (e.g. , the blood–brain barrier and eye), achieving tissueor cell-selective entry, modulating the activity of agents and controlling their release, and avoiding or minimizing toxicity and metabolism—all of which could dramatically enhance human therapy and our fundamental understanding of living systems. Biological barriers have evolved to perform many functions. They provide compartmentalization and are critical to the ACHTUNGTRENNUNGselective import, concentration, and export of compounds needed for sustenance, protection, movement, adherence, and replication. However, these very functions often present a formidable challenge for chemotherapy, limiting or precluding the uptake, and therefore the therapeutic benefit, of a variety of drugs. The perceived effectiveness of barriers is so great that most approaches to drug design select only drug candidates that fall into a rather narrow logP range so as to allow passage of the molecule through the polar extracellular milieu and diffusion across the relatively nonpolar membrane of a cell. A not uncommon view is that polar molecules cannot cross the nonpolar membrane of a cell. Reinforcing these selection criteria are the problems often encountered with molecules that fall outside of the preferred logP range. Poorly water-soluble taxol, for example, must be formulated in ethanol :Cremophor EL, and, at the other end of the polarity range, charged polar molecules, like oligonucleotides, often must be modified into less polar analogues to achieve cellular uptake. Thus, while much emphasis in recent years has been placed on “diversity” in drug discovery, many drug discovery strategies achieve only structural diversity while maintaining physical property (logP) homogeneity. In contrast, Nature utilizes molecules that cover a wide range of physical properties and structural diversity, offering important inspirations for new approaches to cell entry and hence to drug delivery. Several physical and molecular techniques have been developed over the years to enable drug or probe uptake into cells and tissue. The needle is one of the most commonly used devices for this purpose, although high pressure injections and other mechanical techniques have also been deployed more recently. Molecular approaches to enable or enhance drug uptake have traditionally centered on adjusting the physical properties of the drug candidate through the synthesis of numerous analogues from which those with optimal logP and absorption, distribution, metabolism and excretion (ADME) characteristics are selected for advancement. This is a synthesis and time intensive exercise, as often hundreds if not thousands of analogues are made before an optimal candidate is identified. The time and effort involved in this approach have contributed to the increasing interest in other strategies. Encapsulation of drugs, even those with suboptimal physical properties, by using, for example, liposomes, provides an increasingly important means of overriding the problematic solubility characteristics of a drug candidate while often also offering advantages with respect to distribution and metabolism. Nature provides inspiration for other strategies for cell penetration as it has evolved a wide variety of delivery techniques ranging from the remarkably exquisite mechanism of fertilization to various entry mechanisms, including macropinocytosis, clathrinand caveolin-mediated entry, and receptor-mediated uptake. Folate, for example, is actively imported into cells. By attaching folic acid to a drug that cannot enter cells, or does so only poorly, a conjugate can be prepared that readily enters