Metabolism-based anticancer drug design

Many conventional anticancer drugs display relatively poor selectivity for neoplastic cells, in particular for solid tumors. Furthermore, expression or development of drug resistance, increased glutathione transferases as well as enhanced DNA repair decrease the efficacy of these drugs. Research efforts continue to overcome these problems by understanding these mechanisms and by developing more effective anticancer drugs. Cyclophosphamide is one of the most widely used alkylating anticancer agents. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard, the active species of cyclophosphamide, have been investigated in an attempt to improve the therapeutic index. Solid tumors are particularly resistant to radiation and chemotherapy. There has been considerable interest in designing drugs selective for hypoxic environments prevalent in solid tumors. Much of the work had been centered on nitroheterocyclics that utilize nitroreductase enzyme systems for their activation. In this article, recent developments of anticancer prodrug design are described with a particular emphasis on exploitation of selective metabolic processes for their activation.     

Computational drug design targeting protein-protein interactions

Novel discoveries in molecular disease pathways within the cell, combined with increasing information regarding protein binding partners has lead to a new approach in drug discovery. There is interest in designing drugs to modulate protein-protein interactions as opposed to solely targeting the catalytic active site within a single enzyme or protein. There are many challenges in this new approach to drug discovery, particularly since the protein-protein interface has a larger surface area, can comprise a discontinuous epitope, and is more amorphous and less well defined than the typical drug design target, a small contained enzyme-binding pocket. Computational methods to predict modes of protein-protein interaction, as well as protein interface hot spots, have garnered significant interest, in order to facilitate the development of drugs to successfully disrupt and inhibit protein-protein interactions. This review summarizes some current methods available for computational protein-protein docking, as well as tabulating some examples of the successful design of antagonists and small molecule inhibitors for protein-protein interactions. Several of these drugs are now beginning to appear in the clinic.     

Recent advances in retrometabolic drug design and targeting approaches

A number of representative, recent advances achieved within the field of retrometabolic drug design are briefly summarized. For the soft drug approach, some of the results of recent in vivo studies of loteprednol etabonate, a soft corticosteroid approved by the FDA in 1998, are reviewed. For the chemical delivery system (CDS) approach, the latest advances achieved in the brain targeting of peptides such as kyotorphin and TRH analogues are described.     

Liposomes for intravenous drug targeting: design and applications

Drug targeting with liposomes has been studied for over 25 years and has demonstrated its value in clinical practice. This mini review offers an overview of the design and application of liposomes for i.v. drug targeting. Two approaches are outlined: passive and active targeting. The former approach is based on liposomes with prolonged circulation and selective target localization properties, while in the latter approach specific targeting ligands are coupled to the liposome surface in order to achieve enhanced interaction with target cell membranes.     

Antiangiogenesis drug design: multiple pathways targeting tumor vasculature

The initiation, growth, and development of new blood vessels through angiogenesis are essential for tumor growth. Tumor masses require access to blood vessels for a sufficient supply of oxygen and nutrients to maintain growth and metastasis. Inhibiting tumor blood vessel formation as proposed by Judah Folkman in the early 1970s, therefore, offers promising therapeutic approaches for treating tumor afflicted patients. The blood vessel growth in normal tissues is regulated though a delicate and complex balance between the collective action of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) and the collective action of angiogenic inhibitors (e.g., thrombospondin-1). In pathological angiogenesis, the angiogenic switch is shifted toward the proangiogenic factors, and if the imbalance continues, irregular tumor vessel growth is the result. Despite intense research, the mechanism of the angiogenic switch is not fully understood. Many factors, however, have been shown to be involved in regulating the equilibrium between angiogenic stimulants and inhibitors. VEGFR tyrosine kinase, methionine aminopeptidase-2 (MetAP-2), p53, tubulin, cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) all directly and/or indirectly influence the angiogenic switch. This review will describe some of the advances in inhibitor design and the mechanisms of action for the aforementioned factors (targets) involved in angiogenesis regulation. Our discussion reveals that a diaryl group separated by various connecting modules is one of the most common features for antiangiogenesis drug design. This idea has been a working pharmacophore hypothesis for our own antiangiogenic drug design endeavors over the years. The recent advances of combination therapy (angiogenesis inhibitors with other chemotherapy/radiation) are also discussed.     

New strategies for antibacterial drug design: targeting non-multiplying latent bacteria

During the past two decades, the number of antibacterials that has reached the marketplace each year has declined, whilst resistance to existing antibacterials has increased. New antibacterials are needed to replace those that have become less effective as a result of the emergence of a high level of resistance amongst target bacteria. Antibacterials are developed by targeting live multiplying whole bacterial cells, or essential bacterial molecules such as enzymes. Using these targets, libraries of natural, recombinant or chemically synthesised compounds are screened. Most existing antibacterials have been developed by creating novel analogues of established antibacterials, which are themselves derivatives of natural compounds. Recently, live non-multiplying bacteria have been used as targets. Bacteria in such a phase are much more tolerant to antibacterials than logarithmic phase organisms. Targeting of non-multiplying bacteria has the potential to yield new antibacterials that would shorten the duration of therapy. This would be more convenient for the patient, could reduce the incidence of adverse effects of treatment, and might reduce the emergence of antibacterial resistance. However, there is much to learn about non-multiplying bacteria, particularly the mechanisms that lie behind their profound antibacterial tolerance. New terminology has been proposed for susceptibility tests for antibacterial agents against non-multiplying bacteria, namely: the minimum stationary-cidal concentration and the minimum dormicidal concentration, which are defined as the minimum concentrations of drug that will kill stationary and dormant bacteria, respectively. The relationship between the antibiotic susceptibility of stationary and logarithmic phase bacteria is the stationary/logarithmic ratio. This terminology is suitable for both planktonic and biofilm cultures. In the future, it is likely that most antibacterial drug design will be based on existing antibacterial structures, but an increasing number of new molecular antibacterial structures may emerge from screening against multiplying and perhaps non-multiplying bacteria. The genomic approach has been disappointing so far, but it is still hoped that this will produce novel antibacterial agents.     

Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents

The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications.     

Hyperthermia-induced drug targeting

Introduction: Specific delivery of a drug to a target site is a major goal of drug delivery research. Using temperature-sensitive liposomes (TSLs) is one way to achieve this; the liposome acts as a protective carrier, allowing increased drug to flow through the bloodstream by minimizing clearance and non-specific uptake. On reaching microvessels within a heated tumor, the drug is released and quickly penetrates. A major advance in the field is ThermoDox® (Celsion), demonstrating significant improvements to the drug release rates and drug uptake in heated tumors (～ 41°C). Most recently, magnetic resonance-guided focused ultrasound (MRgFUS) has been combined with TSL drug delivery to provide localized chemotherapy with simultaneous quantification of drug release within the tumor.

Areas covered: In this article the field of hyperthermia-induced drug delivery is discussed, with an emphasis on the development of TSLs and their combination with hyperthermia (both mild and ablative) in cancer therapy. State-of-the-art image-guided heating technologies used with this combination strategy will also be presented, with examples of real-time monitoring of drug delivery and prediction of efficacy.

Expert opinion: The specific delivery of drugs by combining hyperthermia with TSLs is showing great promise in the clinic and its potential will be even greater as the use of image-guided focused ultrasound becomes more widespread – a technique capable of penetrating deep within the body to heat a specific area with improved control. In conjunction with this, it is anticipated that multifunctional TSLs will be a major topic of study in this field.     

LDL-mediated drug targeting

The possibilities and limitations in using the low-density lipoprotein (LDL) as a carrier for drugs are discussed. LDL, which may be regarded as the natural counterpart of liposomes, possesses a lipid core that may be utilized as a drug reservoir. Unlike most types of liposomes, the endogenous LDL particle is not avidly taken up by the reticuloendothelial system and may persist in the circulation for prolonged times after injection. A well-characterized membrane receptor recognizes LDL, and binding appears to be coupled to uptake and intracellular processing. Since many tumor tissues express a high amount of LDL receptors, there is a rationale for the design of a toxic LDL-cytostatic drug complex. The behavior of LDL in vivo will be discussed and the principles of LDL-mediated targeting to tumor cells will be evaluated. In addition, methods for drug incorporation into LDL will be critically assessed, while evaluation methods will be presented that may set the standards for future research.     

Amphotericin B formulations and drug targeting

Amphotericin B is a low-soluble polyene antibiotic which is able to self-aggregate. The aggregation state can modify its activity and pharmacokinetical characteristics. In spite of its high toxicity it is still widely employed for the treatment of systemic fungal infections and parasitic disease and different formulations are marketed. Some of these formulations, such as liposomal formulations, can be considered as classical examples of drug targeting. The pharmacokinetics, toxicity and activity are clearly dependent on the type of amphotericin B formulation. New drug delivery systems such as liposomes, nanospheres and microspheres can result in higher concentrations of AMB in the liver and spleen, but lower concentrations in kidney and lungs, so decreasing its toxicity. Moreover, the administration of these drug delivery systems can enhance the drug accessibility to organs and tissues (e.g., bone marrow) otherwise inaccessible to the free drug. During the last few years, new AMB formulations (AmBisome, Abelcet, and Amphotec) with an improved efficacy/toxicity ratio have been marketed. This review compares the different formulations of amphotericin B in terms of pharmacokinetics, toxicity and activity and discusses the possible drug targeting effect of some of these new formulations.     

Metabolism-based brain-targeting system for a thyrotropin-releasing hormone analogue

Gln-Leu-Pro-Gly, a progenitor sequence for the thyrotropin-releasing hormone (TRH) analogue [Leu(2)]TRH (pGlu-Leu-Pro-NH(2)), was covalently and bioreversibly modified on its N- and C-termini (by a 1,4-dihydrotrigonellyl and a cholesteryl group, respectively) to create lipoidal brain-targeting systems for the TRH analogue. The mechanism of targeting and the recovery of the parent peptide at the target site involve several enzymatic steps, including the oxidation of the 1,4-dihydropyridine moiety. Due to the lipid insolublity of the peptide pyridinium conjugate obtained after this reaction, one of the rudimentary steps of brain targeting (i.e., trapping in the central nervous system) can be accomplished. Our design also included spacer amino acid(s) inserted between the N-terminal residue of the progenitor sequence and the dihydrotrigonellyl group to facilitate the posttargeting removal of the attached modification. The release of the TRH analogue in the brain is orchestrated by a sequential metabolism utilizing esterase/lipase, peptidyl glycine alpha-amidating monooxygenase (PAM), peptidase cleavage, and glutaminyl cyclase. In addition to in vitro experiments to prove the designed mechanism of action, the efficacy of brain targeting for [Leu(2)]TRH administered in the form of chemical-targeting systems containing the embedded progenitor sequence was monitored by the antagonistic effect of the peptide on the barbiturate-induced anesthesia (measure of the activational effect on cholinergic neurons) in mice, and considerable improvement was achieved over the efficacy of the parent peptide upon using this paradigm.     

Strategy in structure-based drug design for influenza A virus targeting M2 channel proteins

The 2009 influenza A virus pandemic, with high level of drug resistance reported, has highlighted the urgent need of more effective anti-influenza drugs. M2 channel proteins on the influenza A virus membrane have emerged as an efficient structure-based drug design target since variety of M2 channel protein structures were constructed by different experiment methods to generate the high resolution of crystal, solution NMR and solid-state NMR structure. In an effort to facilitate the future design of M2 channel inhibitors, the binding modes of 200 Adamantane-based drugs in four different types of M2 channel protein structures were evaluated by the critical interactions in terms of ligand binding affinity. The molecular docking results and statistic testing of binding affinity showed that the effect of each representative type from M2 channel protein structures was significantly different. Moreover, pharmacophore analysis revealed that there are two mechanisms of binding interactions to critical residues, Ser31 in holo structures and Ala30 in apo structures, respectively. Molecular docking studies, drug-like filters, and structure-based pharmacophore approaches successfully led us identifying the final hits reduced the false positives and false negatives in strategy of designing new potential group of future M2 channel inhibitors.     

Reversible redox system-based drug design,synthesis, and evaluation for targeting nitrogen mustard across brain

Target drug delivery of nitrogen mustard anticancer agents for a brain tumor is still a challenge due to their high hydrophilicity, poor physicochemical properties, and toxicity to normal tissues. The present study is, therefore, an attempt to investigate the possibility of improving the targeting potential and sustained release of nitrogen mustard alkylating agent to brain by employing reversible redox chemical delivery system approach. Various redox derivatives CDS-L-M (4a–c) based on dihydropyridine ? quaternary pyridinium ion redox system were synthesized and characterized by IR, (¹H and ¹³C)-NMR, and CHN elemental studies. The potential of these CDS derivatives (4a–c) to penetrate the blood–brain barrier was computed through an online software program and the values analyzed lay between the ranges those are required for good brain penetration. The results of storage stability study, in vitro chemical oxidation (silver nitrate) and pharmacokinetic studies in human blood, rat blood and brain homogenate for all CDS-L-M (4a–c) demonstrated that all derivatives could be oxidized into corresponding quaternary salts at an adequate rate, which suggested that brain targeting could be possible with more stable CDS-L-M (4c). The in vivo study on rats showed that administration of the CDS-L-M (4c) resulted in the sustained level of the corresponding salt (3c) in the brain, while blood levels of the oxidized metabolite rapidly fell. The in vitro NBP alkylating activity of quaternary salt (3c) of CDS-L-M (4c) was comparable to the known drug chlorambucil among all the synthesized derivatives.     

肾靶向给药研究进展

常见肾脏病包括原发性和继发性肾小球、肾小管、肾介质及肾血管等疾病，其中最常见的有急性肾炎、慢性肾炎、原发性肾病综合征及尿路感染等。随着上述疾病的不断发展，病人可能出现慢性肾功能衰竭，不得不通过昂贵的血液透析或肾移植来延长生命。对临床上常用于治疗肾脏病的药物，如激素(强的松等)、抗生素(青霉素等)、降压药(巯基丙脯酸等)、血小板凝聚抑制剂(潘生丁等)和细胞毒类(环磷酰胺等)药物，采用靶向给药系统(targeted drug delivery systerm，TDDS)能降低其毒副作用，减小给药剂量和提高药效。     

Brain drug targeting and gene technologies.

Brain drug targeting technology is based on the application of four gene technologies that enable the delivery of drugs or genes across the blood-brain barrier (BBB) in vivo. I) Genetic engineering is used to produce humanized monoclonal antibodies that target endogenous BBB transporters and act as vectors for delivery of drugs or genes to the human brain. The conjugate of a neurotherapeutic and a BBB transport vector is called a chimeric peptide. Epidermal growth factor chimeric peptides have been used for neuroimaging of brain cancer. Brain-derived neutrophic factor chimeric peptides have marked neuroprotective effects in brain stroke models. II) Imaging gene expression in the brain in vivo is possible with sequence-specific antisense radiopharmaceuticals, which are conjugated to BBB drug targeting vectors. III) Brain gene targeting technology enables widespread expression of an exogenous gene throughout the central nervous system following an intravenous injection of a non-viral therapeutic gene. IV) A BBB genomics program enables the future discovery of novel transport systems expressed at the BBB. These transporters may be carrier-mediated transport systems, active efflux transporters, or receptor-mediated transcytosis systems. The future discovery of novel BBB transport systems and the application of brain drug targeting technology will enable the delivery to the brain of virtually any neurotherapeutic, including small molecules, large molecules and gene medicines.