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1.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS Journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
doi:10.1208/s12248-009-9085-4
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
2.  Glial–Neuronal Interactions—Implications for Plasticity and Drug Addiction 
The AAPS journal  2009;11(1):123-132.
Among neuroscientists, astrocytes have for long played Cinderella to their neuron stepsisters. While the importance of glia in regulating brain activity was predicted by Ramon y Cajal more than a century ago (Garcia-Marin et al., Trends. Neurosci. 30:479–787, 2007), these cells, until recently, have been thought to play mainly a passive part in synaptic signaling. Results obtained over the last decade have begun to suggest otherwise. Experiments carried out in a number of labs have shown that glial cells, especially astrocytes, directly participate in synaptic signaling and potentially regulate synaptic plasticity and network excitability. The presence of signaling pathways on astrocytes that are analogous to those at presynaptic terminals suggests a role for these cells in network plasticity. Findings that the same signaling pathways can be activated by receptors for drugs of abuse present on astrocytes suggest a role for these cells in the addictive process. In this review, we summarize current understanding of astrocytic role in synaptic signaling and suggest that a complete understanding of the process of addiction requires a better understanding of the functional role of these cells.
doi:10.1208/s12248-009-9085-4
PMCID: PMC2664886  PMID: 19238557
astrocyte; calcium; gliotransmission; nicotinic; synapse; tripartite synapse
3.  Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products 
The AAPS Journal  2012;14(3):646-655.
Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.
doi:10.1208/s12248-012-9378-x
PMCID: PMC3385830  PMID: 22684403
bioequivalence; fixed-dose combination; formulation; pharmacokinetics
4.  Compartmental Tissue Distribution of Antibody Therapeutics: Experimental Approaches and Interpretations 
The AAPS Journal  2012;14(3):612-618.
Monoclonal antibodies have provided many validated and potential new therapeutic candidates for various diseases encompassing the realms of neurology, ophthalmology, immunology, and especially oncology. The mechanism of action for these biological molecules typically involves specific binding to a soluble ligand or cell surface protein in order to block or alter a molecular pathway, induce a desired cellular response, or deplete a target cell. Many antigens reside within the interstitial space, the fluid-filled compartment that lies between the outer endothelial vessel wall and the plasma membranes of cells. This mini-review examines the concepts relevant to the kinetics and behavior of antibodies within the interstitium with a special emphasis on radiometric measurement of quantitative pharmacology. Molecular probes are discussed to outline chemical techniques, selection criteria, data interpretation, and relevance to the study of antibody pharmacokinetics. The importance of studying the tissue uptake of antibodies at a compartmental level is highlighted, including a brief overview of receptor occupancy and its interpretation in radiotracer studies. Experimental methods for measuring the spatial composition of tissues are examined in terms of relative vascular, interstitial, and cellular volumes using solid tumors as a representative example. Experimental methods and physiologically based pharmacokinetic modeling are introduced as distinct approaches to distinguish between free and bound fractions of interstitial antibody. Overall, the review outlines the available methods for pharmacokinetic measurements of antibodies and physiological measurements of the compartments that they occupy, while emphasizing that such approaches may not fully capture the complexities of dynamic, heterogeneous tumors and other tissues.
doi:10.1208/s12248-012-9374-1
PMCID: PMC3385837  PMID: 22648903
antibody; biodistribution; compartmental analysis; pharmacokinetics; physiology
5.  The Use of Modeling Tools to Drive Efficient Oral Product Design 
The AAPS Journal  2012;14(3):591-600.
Modeling and simulation of drug dissolution and oral absorption has been increasingly used over the last decade to understand drug behavior in vivo based on the physicochemical properties of Active Pharmaceutical Ingredients (API) and dosage forms. As in silico and in vitro tools become more sophisticated and our knowledge of physiological processes has grown, model simulations can provide a valuable confluence, tying-in in vitro data with in vivo data while offering mechanistic insights into clinical performance. To a formulation scientist, this unveils not just the parameters that are predicted to significantly impact dissolution/absorption, but helps probe explanations around drug product performance and address specific in vivo mechanisms. In formulation, development, in silico dissolution–absorption modeling can be effectively used to guide: API selection (form comparison and particle size properties), influence clinical study design, assess dosage form performance, guide strategy for dosage form design, and breakdown clinically relevant conditions on dosage form performance (pH effect for patients on pH-elevating treatments, and food effect). This minireview describes examples of these applications in guiding product development including those with strategies to mitigate observed clinical exposure liability or mechanistically probe product in vivo performance attributes.
doi:10.1208/s12248-012-9372-3
PMCID: PMC3385810  PMID: 22644702
dissolution and absorption; drug formulation; drug development; GastroPlus; modeling and simulation
6.  Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics 
The AAPS Journal  2012;14(3):554-558.
Monoclonal antibodies are increasingly being developed to treat multiple disease areas, including those related to oncology, immunology, neurology, and ophthalmology. There are multiple factors, such as charge, size, neonatal Fc receptor (FcRn) binding affinity, target affinity and biology, immunoglobulin G (IgG) subclass, degree and type of glycosylation, injection route, and injection site, that could affect the pharmacokinetics (PK) of these large macromolecular therapeutics, which in turn could have ramifications on their efficacy and safety. This minireview examines how characteristics of the antibodies could be altered to change their PK profiles. For example, it was observed that a net charge modification of at least a 1-unit shift in isoelectric point altered antibody clearance. Antibodies with enhanced affinity for FcRn at pH 6.0 display longer serum half-lives and slower clearances than wild type. Antibody fragments have different clearance rates and tissue distribution profiles than full length antibodies. Fc glycosylation is perceived to have a minimal effect on PK while that of terminal high mannose remains unclear. More investigation is warranted to determine if injection route and/or site impacts PK. Nonetheless, a better understanding of the effects of all these variations may allow for the better design of antibody therapeutics.
doi:10.1208/s12248-012-9369-y
PMCID: PMC3385840  PMID: 22610647
antibody; FcRn; glycosylation; isoelectric point; pharmacokinetics
7.  Paradigm Shift in Toxicity Testing and Modeling 
The AAPS Journal  2012;14(3):473-480.
The limitations of traditional toxicity testing characterized by high-cost animal models with low-throughput readouts, inconsistent responses, ethical issues, and extrapolability to humans call for alternative strategies for chemical risk assessment. A new strategy using in vitro human cell-based assays has been designed to identify key toxicity pathways and molecular mechanisms leading to the prediction of an in vivo response. The emergence of quantitative high-throughput screening (qHTS) technology has proved to be an efficient way to decompose complex toxicological end points to specific pathways of targeted organs. In addition, qHTS has made a significant impact on computational toxicology in two aspects. First, the ease of mechanism of action identification brought about by in vitro assays has enhanced the simplicity and effectiveness of machine learning, and second, the high-throughput nature and high reproducibility of qHTS have greatly improved the data quality and increased the quantity of training datasets available for predictive model construction. In this review, the benefits of qHTS routinely used in the US Tox21 program will be highlighted. Quantitative structure–activity relationships models built on traditional in vivo data and new qHTS data will be compared and analyzed. In conjunction with the transition from the pilot phase to the production phase of the Tox21 program, more qHTS data will be made available that will enrich the data pool for predictive toxicology. It is perceivable that new in silico toxicity models based on high-quality qHTS data will achieve unprecedented reliability and robustness, thus becoming a valuable tool for risk assessment and drug discovery.
doi:10.1208/s12248-012-9358-1
PMCID: PMC3385826  PMID: 22528508
computational toxicology; qHTS; risk assessment; Tox21
8.  Pain Assessment in Human Fetus and Infants 
The AAPS Journal  2012;14(3):456-461.
In humans, painful stimuli can arrive to the brain at 20–22 weeks of gestation. Therefore several researchers have devoted their efforts to study fetal analgesia during prenatal surgery, and during painful procedures in premature babies. Aim of this paper is to gather from scientific literature the available data on the signals that the human fetus and newborns produce, and that can be interpreted as signals of pain. Several signs can be interpreted as signals of pain. We will describe them in the text. In infants, these signs can be combined to create specific and sensible pain assessment tools, called pain scales, used to rate the level of pain.
doi:10.1208/s12248-012-9354-5
PMCID: PMC3385812  PMID: 22528505
analgesic drug; fetus; newborn; pain; pain scale
9.  ADME of Biologics—What Have We Learned from Small Molecules? 
The AAPS Journal  2012;14(3):410-419.
Thorough characterization and in-depth understanding of absorption, distribution, metabolism, and elimination (ADME) properties of a drug candidate have been well recognized as an important element in small molecule (SM) drug discovery and development. This has been the area of focus for drug metabolism and pharmacokinetics (DMPK) scientists, whose role has been evolving over the past few decades from primarily being involved in the development space after a preclinical candidate was selected to extending their involvement into the discovery stage prior to candidate selection. This paradigm shift has ensured the entry into development of the best candidates with optimal ADME properties, and thus has greatly impacted SM drug development through significant reduction of the failure rate for pharmacokinetics related reasons. In contrast, the sciences of ADME and DMPK have not been fully integrated into the discovery and development processes for large molecule (LM) drugs. In this mini-review, we reflect on the journey of DMPK support of SM drug discovery and development and highlight the key enablers that have allowed DMPK scientists to make such impacts, with the aim to provide a perspective on relevant lessons learned from SM drugs that are applicable to DMPK support strategies for LMs.
doi:10.1208/s12248-012-9353-6
PMCID: PMC3385832  PMID: 22484625
ADME; biologics; drug discovery and development; large molecules; small molecules
10.  Challenges in Development of Targeted Liposomal Therapeutics 
The AAPS Journal  2012;14(2):303-315.
Liposomes, phospholipid vesicles with a bilayered membrane structure, have been widely used as pharmaceutical carriers for drugs and genes, in particular for treatment of cancer. To enhance the efficacy of the liposomal drugs, drug-loaded liposomes are targeted to the tumors by means of passive (enhanced permeability and retention mediated) targeting, based on the longevity of liposomes in blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the liposomal surface to bind certain antigens on the target cells. Antibody-targeted liposomes loaded with anticancer drugs demonstrate high potential for clinical applications. This review highlights evolution of liposomes for both passive and active targeting and challenges in development of targeted liposomal therapeutics specifically antibody-targeted liposomes.
doi:10.1208/s12248-012-9330-0
PMCID: PMC3326155  PMID: 22415612
active targeting; immunoliposomes; passive targeting; stimuli sensitive; targeted liposomes
11.  Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation 
The AAPS Journal  2012;14(2):262-281.
Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK- or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.
doi:10.1208/s12248-012-9332-y
PMCID: PMC3326168  PMID: 22407287
allometric scaling; FIH dose; in vitro–in vivo correlations; pharmacokinetics; prediction
12.  Covariate Pharmacokinetic Model Building in Oncology and its Potential Clinical Relevance 
The AAPS Journal  2012;14(1):119-132.
When modeling pharmacokinetic (PK) data, identifying covariates is important in explaining interindividual variability, and thus increasing the predictive value of the model. Nonlinear mixed-effects modeling with stepwise covariate modeling is frequently used to build structural covariate models, and the most commonly used software—NONMEM—provides estimations for the fixed-effect parameters (e.g., drug clearance), interindividual and residual unidentified random effects. The aim of covariate modeling is not only to find covariates that significantly influence the population PK parameters, but also to provide dosing recommendations for a certain drug under different conditions, e.g., organ dysfunction, combination chemotherapy. A true covariate is usually seen as one that carries unique information on a structural model parameter. Covariate models have improved our understanding of the pharmacology of many anticancer drugs, including busulfan or melphalan that are part of high-dose pretransplant treatments, the antifolate methotrexate whose elimination is strongly dependent on GFR and comedication, the taxanes and tyrosine kinase inhibitors, the latter being subject of cytochrome p450 3A4 (CYP3A4) associated metabolism. The purpose of this review article is to provide a tool to help understand population covariate analysis and their potential implications for the clinic. Accordingly, several population covariate models are listed, and their clinical relevance is discussed. The target audience of this article are clinical oncologists with a special interest in clinical and mathematical pharmacology.
doi:10.1208/s12248-012-9320-2
PMCID: PMC3291194  PMID: 22274748
anticancer drugs; clinical covariate; covariate; nonlinear mixed effects model; pharmacokinetics; population analysis
13.  Vaccinomics: Current Findings, Challenges and Novel Approaches for Vaccine Development 
The AAPS Journal  2011;13(3):438-444.
Recent years have witnessed a growing interest in a field of vaccinology that we have named vaccinomics. The overall idea behind vaccinomics is to identify genetic and other mechanisms and pathways that determine immune responses, and thereby provide new candidate vaccine approaches. Considerable data show that host genetic polymorphisms act as important determinants of innate and adaptive immunity to vaccines. This review highlights examples of the role of immunogenetics and immunogenomics in understanding immune responses to vaccination, which are highly variable across the population. The influence of HLA genes, non-HLA, and innate genes in inter-individual variations in immune responses to viral vaccines are examined using population-based gene/SNP association studies. The ability to understand relationships between immune response gene variants and vaccine-specific immunity may assist in designing new vaccines. At the same time, application of state-of-the-art next-generation sequencing technology (and bioinformatics) is desired to provide new genetic information and its relationship to the immune response.
doi:10.1208/s12248-011-9281-x
PMCID: PMC3160164  PMID: 21671143
genetic association; HLA; immunogenetics; polymorphisms; SNPs; vaccines; vaccinomics
14.  Challenges in Development of Nanoparticle-Based Therapeutics 
The AAPS Journal  2012;14(2):282-295.
In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.
doi:10.1208/s12248-012-9339-4
PMCID: PMC3326161  PMID: 22407288
biodistribution; immune toxicity; nab-paclitaxel; nanoparticle; pharmacokinetics
15.  Challenges in Development of Nanoparticle-Based Therapeutics 
The AAPS Journal  2012;14(2):282-295.
In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.
doi:10.1208/s12248-012-9339-4
PMCID: PMC3326161  PMID: 22407288
biodistribution; immune toxicity; nab-paclitaxel; nanoparticle; pharmacokinetics
16.  Analyzing the Cryptome: Uncovering Secret Sequences 
The AAPS Journal  2011;13(2):152-158.
The mammalian cryptome consists of bioactive peptides generated by the proteolysis of precursor proteins. It is speculated that the cryptide repertoire increases the complexity of the proteome by an order of magnitude. Cryptides have been found to function in a wide range of processes including neuronal signaling, antigen presentation, and the inflammatory response. Due to their potential as therapeutic agents, there has been an increasing interest in studying cryptides. In this review, we discuss different approaches for discovering these hidden peptides and how proteomic tools can be utilized to aid in their identification and characterization.
doi:10.1208/s12248-011-9252-2
PMCID: PMC3085711  PMID: 21327597
bioactive peptides; cryptides; cryptome; cryptomics; mass spectrometry-based proteomics
17.  Structure-Based Virtual Screening for Drug Discovery: a Problem-Centric Review 
The AAPS Journal  2012;14(1):133-141.
Structure-based virtual screening (SBVS) has been widely applied in early-stage drug discovery. From a problem-centric perspective, we reviewed the recent advances and applications in SBVS with a special focus on docking-based virtual screening. We emphasized the researchers’ practical efforts in real projects by understanding the ligand-target binding interactions as a premise. We also highlighted the recent progress in developing target-biased scoring functions by optimizing current generic scoring functions toward certain target classes, as well as in developing novel ones by means of machine learning techniques.
doi:10.1208/s12248-012-9322-0
PMCID: PMC3282008  PMID: 22281989
docking; machine learning; structure-based virtual scoring; target-biased scoring function
18.  Structure-Based Virtual Screening for Drug Discovery: a Problem-Centric Review 
The AAPS Journal  2012;14(1):133-141.
Structure-based virtual screening (SBVS) has been widely applied in early-stage drug discovery. From a problem-centric perspective, we reviewed the recent advances and applications in SBVS with a special focus on docking-based virtual screening. We emphasized the researchers’ practical efforts in real projects by understanding the ligand-target binding interactions as a premise. We also highlighted the recent progress in developing target-biased scoring functions by optimizing current generic scoring functions toward certain target classes, as well as in developing novel ones by means of machine learning techniques.
doi:10.1208/s12248-012-9322-0
PMCID: PMC3282008  PMID: 22281989
docking; machine learning; structure-based virtual scoring; target-biased scoring function; Biomedicine; Biotechnology; Pharmacy; Pharmacology/Toxicology; Biochemistry, general
19.  The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic 
The AAPS Journal  2011;13(1):111-120.
Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two-pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/PD models will become a standard approach for drug discovery and development.
doi:10.1208/s12248-011-9253-1
PMCID: PMC3032092  PMID: 21246315
anticancer drugs; drug discovery and development; pharmacokinetic/pharmacodynamic model; physiologically based pharmacokinetic model
20.  The Coulter Principle for Analysis of Subvisible Particles in Protein Formulations 
The AAPS Journal  2010;13(1):54-58.
The Coulter principle can be used for analysis of subvisible particles in protein formulations. The approach has several advantages including: an orthogonal operating principle, high sensitivity, ability to detect very small particles, excellent reproducibility, and high-resolution size information. This minireview discusses some of the important considerations that must be taken into account when utilizing the Coulter principle for subvisible particle analysis in protein formulations.
doi:10.1208/s12248-010-9245-6
PMCID: PMC3032098  PMID: 21161461
Coulter principle; protein aggregates; subvisible; USP 788
21.  Pancreatic Cancer: Pathobiology, Treatment Options, and Drug Delivery 
The AAPS Journal  2010;12(2):223-232.
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. The high mortality rate is partly due to lack of effective treatments. This review summarizes the pathobiology and current treatment options for pancreatic cancer. Moreover, the review discusses the opportunities of developing novel therapies for pancreatic cancer provided by the progress in understanding the genetic mutations, tumor microenvironment, cancer stem cells, and drug delivery.
doi:10.1208/s12248-010-9181-5
PMCID: PMC2844509  PMID: 20198462
Cancer stem cells; Drug delivery; Genetic profile; Microenvironment; Pancreatic cancer
22.  Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention 
The AAPS Journal  2009;12(1):87-97.
Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drug-metabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2–Keap 1, anti-inflammatory NFκB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.
doi:10.1208/s12248-009-9162-8
PMCID: PMC2811646  PMID: 20013083
dietary cancer chemoprevention; NF-kB; Nrf2; phenethyl isothiocyanate; sulforaphane
23.  Multidimensional Atomic Force Microscopy: A Versatile Novel Technology for Nanopharmacology Research 
The AAPS Journal  2010;12(4):716-728.
Nanotechnology is giving us a glimpse into a nascent field of nanopharmacology that deals with pharmacological phenomena at molecular scale. This review presents our perspective on the use of scanning probe microscopy techniques with special emphasis to multidimensional atomic force microscopy (m-AFM) to explore this new field with a particular emphasis to define targets, design therapeutics, and track outcomes of molecular-scale pharmacological interactions. The approach will be to first discuss operating principles of m-AFM and provide representative examples of studies to understand human health and disease at the molecular level and then to address different strategies in defining target macromolecules, screening potential drug candidates, developing and characterizing of drug delivery systems, and monitoring target–drug interactions. Finally, we will discuss some future directions including AFM tip-based parallel sensors integrated with other high-throughput technologies which could be a powerful platform for drug discovery.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9232-y) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-010-9232-y
PMCID: PMC2976997  PMID: 20957528
atomic force microscopy; drug discovery; multimodal AFM; nanopharmacology; nanotherapeutics
24.  Multidimensional Atomic Force Microscopy: A Versatile Novel Technology for Nanopharmacology Research 
The AAPS Journal  2010;12(4):716-728.
Nanotechnology is giving us a glimpse into a nascent field of nanopharmacology that deals with pharmacological phenomena at molecular scale. This review presents our perspective on the use of scanning probe microscopy techniques with special emphasis to multidimensional atomic force microscopy (m-AFM) to explore this new field with a particular emphasis to define targets, design therapeutics, and track outcomes of molecular-scale pharmacological interactions. The approach will be to first discuss operating principles of m-AFM and provide representative examples of studies to understand human health and disease at the molecular level and then to address different strategies in defining target macromolecules, screening potential drug candidates, developing and characterizing of drug delivery systems, and monitoring target–drug interactions. Finally, we will discuss some future directions including AFM tip-based parallel sensors integrated with other high-throughput technologies which could be a powerful platform for drug discovery.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9232-y) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-010-9232-y
PMCID: PMC2976997  PMID: 20957528
atomic force microscopy; drug discovery; multimodal AFM; nanopharmacology; nanotherapeutics
25.  Lipidic Systems for In Vivo siRNA Delivery 
The AAPS Journal  2009;11(4):639-652.
The ability of small-interfering RNA (siRNA) to silence specific target genes not only offers a tool to study gene function but also represents a novel approach for the treatment of various human diseases. Its clinical use, however, has been severely hampered by the lack of delivery of these molecules to target cell populations in vivo due to their instability, inefficient cell entry, and poor pharmacokinetic profile. Various delivery vectors including liposomes, polymers, and nanoparticles have thus been developed in order to circumvent these problems. This review presents a comprehensive overview of the barriers and recent progress for both local and systemic delivery of therapeutic siRNA using lipidic vectors. Different strategies for formulating these siRNA-loaded lipid particles as well as the general concern about their safe use in vivo will also be discussed. Finally, current advances in the targeted delivery of siRNA and their impacts on the field of RNA interference (RNAi)-based therapy will be presented.
doi:10.1208/s12248-009-9140-1
PMCID: PMC2782074  PMID: 19757082
in vivo delivery; liposomes; siRNA

Results 1-25 (63)