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1.  Design and Evaluation of a PEGylated Lipopeptide Equipped with Drug-Interactive Motifs as an Improved Drug Carrier 
The AAPS Journal  2013;16(1):114-124.
Micelles are attractive delivery systems for hydrophobic drugs due to their small size and the ease of application. However, the limited drug loading capacity and the intrinsic poor stability of drug-loaded formulations represent two major issues for some micellar systems. In this study, we designed and synthesized a micelle-forming PEG-lipopeptide conjugate with two Fmoc groups located at the interfacial region, and two oleoyl chains as the hydrophobic core. The significance of Fmoc groups as a broadly applicable drug-interactive motif that enhances the carrier–drug interaction was examined using eight model drugs of diverse structures. Compared with an analogue without carrying a Fmoc motif, PEG5000-(Fmoc-OA)2 demonstrated a lower value of critical micelle concentration and three-fold increases of loading capacity for paclitaxel (PTX). These micelles showed tubular structures and small particle sizes (∼70 nm), which can be lyophilized and readily reconstituted with water without significant changes in particle sizes. Fluorescence quenching study illustrated the Fmoc/PTX π–π stacking contributes to the carrier/PTX interaction, and drug-release study demonstrated a much slower kinetics than Taxol, a clinically used PTX formulation. PTX/PEG5000-(Fmoc-OA)2 mixed micelles exhibited higher levels of cytotoxicity than Taxol in several cancer cell lines and more potent inhibitory effects on tumor growth than Taxol in a syngeneic murine breast cancer model (4T1.2). We have further shown that seven other drugs can be effectively formulated in PEG5000-(Fmoc-OA)2 micelles. Our study suggests that micelle-forming PEG-lipopeptide surfactants with interfacial Fmoc motifs may represent a promising formulation platform for a broad range of drugs with diverse structures.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9536-9) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-013-9536-9
PMCID: PMC3889538  PMID: 24281690
drug-interactive motif; micelle; paclitaxel; slow release
2.  Pharmacodynamic Model of Parathyroid Hormone Modulation by a Negative Allosteric Modulator of the Calcium-Sensing Receptor 
The AAPS Journal  2011;13(2):265-273.
In this study, a pharmacodynamic model is developed, based on calcium–parathyroid hormone (PTH) homeostasis, which describes the concentration–effect relationship of a negative allosteric modulator of the calcium-sensing receptor (CaR) in rats. Plasma concentrations of drug and PTH were determined from plasma samples obtained via serial jugular vein sampling following single subcutaneous doses of 1, 5, 45, and 150 mg/kg to male Sprague–Dawley rats (n = 5/dose). Drug pharmacokinetics was described by a one-compartment model with first-order absorption and linear elimination. Concentration-time profiles of PTH were characterized using a model in which the compound allosterically modulates Ca+2 binding to the CaR that, in turn, modulates PTH through a precursor-pool indirect response model. Additionally, negative feedback was incorporated to account for tolerance observed at higher dose levels. Model fitting and parameter estimation were conducted using the maximum likelihood algorithm. The proposed model well characterized the data and provided compound specific estimates of the Ki and cooperativity constant (α) of 1.47 ng/mL and 0.406, respectively. In addition, the estimated model parameters for PTH turnover were comparable to that previously reported. The final generalized model is capable of characterizing both PTH–Ca+2 homeostasis and the pharmacokinetics and pharmacodynamics associated with the negative allosteric CaR modulator. As such, the model provides a simple platform for analysis of drugs targeting the PTH–Ca+2 system.
doi:10.1208/s12248-011-9266-9
PMCID: PMC3085713  PMID: 21437757
allosteric; bone; calcium sensing receptor; ionized calcium; osteoporosis; parathyroid hormone; pharmacodynamics; pharmacokinetics
3.  Nonviral Gene Delivery: Principle, Limitations, and Recent Progress 
The AAPS Journal  2009;11(4):671-681.
Gene therapy is becoming a promising therapeutic modality for the treatment of genetic and acquired disorders. Nonviral approaches as alternative gene transfer vehicles to the popular viral vectors have received significant attention because of their favorable properties, including lack of immunogenicity, low toxicity, and potential for tissue specificity. Such approaches have been tested in preclinical studies and human clinical trials over the last decade. Although therapeutic benefit has been demonstrated in animal models, gene delivery efficiency of the nonviral approaches remains to be a key obstacle for clinical applications. This review focuses on existing and emerging concepts of chemical and physical methods for delivery of therapeutic nucleic acid molecules in vivo. The emphasis is placed on discussion about problems associated with current nonviral methods and recent efforts toward refinement of nonviral approaches.
doi:10.1208/s12248-009-9143-y
PMCID: PMC2782077  PMID: 19834816
gene delivery; gene therapy; lipoplex; nonviral vectors; polyplex; transfection
4.  Targeted Delivery of Nucleic Acid-Based Therapeutics to the Pulmonary Circulation 
The AAPS Journal  2009;11(1):23-30.
Targeted delivery of functional nucleic acids (genes and oligonucleotides) to pulmonary endothelium may become a novel therapy for the treatment of various types of lung diseases. It may also provide a new research tool to study the functions and regulation of novel genes in pulmonary endothelium. Its success is largely dependent on the development of a vehicle that is capable of efficient pulmonary delivery with minimal toxicity. This review summarizes the recent progress that has been made in our laboratory along these research directions. Factors that affect pulmonary nucleic acids delivery are also discussed.
doi:10.1208/s12248-008-9073-0
PMCID: PMC2664874  PMID: 19132538
delivery; endothelial cells; genes; lung; oligonucleotides; pulmonary circulation; siRNA; targeting
5.  Nonviral gene delivery: What we know and what is next 
The AAPS Journal  2007;9(1):E92-E104.
Gene delivery using nonviral approaches has been extensively studied as a basic tool for intracellular gene transfer and gene therapy. In the past, the primary focus has been on application of physical, chemical, and biological principles to development of a safe and efficient method that delivers a transgene into target cells for appropriate expression. This review summarizes the current status of the most commonly used nonviral methods, with an emphasis on their mechanism of action for gene delivery, and their advantages and limitations for gene therapy applications. The technical aspects of each delivery system are also reviewed, with a focus on how to achieve optimal delivery efficiency. A brief discussion of future development and further improvement of the current systems is intended to stimulate new ideas and encourage rapid advancement in this new and promising field.
doi:10.1208/aapsj0901009
PMCID: PMC2751307  PMID: 17408239
Gene delivery; gene therapy; nonviral vectors; transfection

Results 1-5 (5)