Kapoor M.,University of Connecticut |
Burgess D.J.,University of Connecticut |
Patil S.D.,Millennium: The Takeda Oncology Company
International Journal of Pharmaceutics | Year: 2012
siRNA based therapeutics is an emerging class of molecules with a high potential for fulfilling the promise of gene medicine. The high selectivity of siRNAs for their targets and subsequent gene ablation has been effectively demonstrated in a wide range of pre-clinical models. siRNA delivery in vivo has been most successfully achieved using lipid-based drug delivery systems. These lipid based formulations are designed to entrap siRNA molecules, ensure stability in in vitro and in vivo milieu, facilitate uptake, enhance cellular targeting, and facilitate delivery in the desired intracellular compartment. As more siRNA-based therapeutics enters the clinic with the associated regulatory scrutiny, there is a clear need to develop well-characterized systems that ensure consistent quality and thus reliable performance. Early clinical trials can be conducted using formulations with limited short-term stability manufactured on a small scale. However, a thorough understanding of the factors that influence the structure and stability of these particulate formulations is required to prevent any issues with optimization of large-scale industrial manufacturing, scale-up, and long-term shelf-life required to support large clinical trials and eventual market use. As newer targets for siRNA are identified and novel lipids are synthesized to optimize their in vivo efficiency, concomitant development of bio-physical methodologies that can improve understanding of the assembly and stability of these complex systems is critical. Along with bio-physical characterization, these assays are also required to reliably design, screen, develop and optimize formulations. Physicochemical characterization thus forms the basis of developing an effective analytical control strategy for siRNA delivery systems. In this review, analytical techniques used to characterize lipid-based siRNA delivery systems are discussed in detail. The importance of these physicochemical characterization techniques and analytical assays is explained. Case studies illustrating their use in siRNA formulation development and optimization are presented. © 2011 Elsevier B.V. All rights reserved.
Zhuang X.-M.,Beijing Institute of Pharmacology and Toxicology |
Shen G.-L.,Beijing Institute of Pharmacology and Toxicology |
Xiao W.-B.,Beijing Institute of Pharmacology and Toxicology |
Tan Y.,Beijing Institute of Pharmacology and Toxicology |
And 2 more authors.
Drug Metabolism and Disposition | Year: 2013
Triptolide (TP), a main bioactive component of Tripterygium wilfordii Hook F., is a promising agent for treatment of autoimmune diseases. However, a high incidence of dose-limiting hepatotoxicity was observed in the clinic. Sandwich-cultured rat hepatocyte model was used in this study to identify the involvement of P-glycoprotein (P-gp) in TP disposition and to evaluate TP-induced hepatotoxicity after modulation of P-gp by the known inhibitors, ritonavir and tariquidar, and known inducers, phenobarbital, quercetin, and H2O2. Our data showed that biliary clearance of TP reduced 73.7% and 84.2% upon treatment of ritonavir (25 μM) and tariquidar (5 μM), respectively. In contrast, increases of 346%, 280%, and 273% in biliary clearance of TP were observed with treatment of phenobarbital (1.0 mM), quercetin (20 μM), and H2O2 (0.5 mM), respectively. The TP-induced hepatotoxicity increased by twofold when CYP activity was blocked by 1-aminobenzotriazole, suggesting that CYP and P-gp may both contribute to the detoxification of TP in the SCRH model. In addition, hepatotoxicity and the expression of apoptosis proteins Bax and Bcl-2 were correlated qualitatively with the TP exposure duration and its intracellular concentration, which, in turn, can be modulated by P-gp inhibitors or inducers. Our results for the first time demonstrated that in addition to CYP-mediated metabolism, P-gp also plays an important role in the disposition of TP and TP-induced hepatotoxicity. Thus, the modulation of canalicular P-gp has a potential to cause drug-drug interaction between TP and the coadministered P-gp inhibitors or inducers in the clinic. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Weiser J.R.,Cornell University |
Zawaneh P.N.,Cornell University |
Zawaneh P.N.,Millennium: The Takeda Oncology Company |
Putnam D.,Cornell University
Biomacromolecules | Year: 2011
The synthesis of new polymeric biomaterials using biocompatible building blocks is important for the advancement of the biomedical field. We report the synthesis of statistically random poly(carbonate-ester)s derived from lactic acid and dihydroxyacetone by ring-opening polymerization. The monomer mole feed ratio and initiator concentration were adjusted to create various copolymer ratios and molecular weights. A dimethoxy acetal protecting group was used to stabilize the dihydroxyacetone and was removed using elemental iodine and acetone at reflux to produce the final poly(lactide-co-dihydroxyacetone) copolymers. The characteristics of the copolymers in their protected and deprotected forms were characterized by 1H NMR, 13C NMR, GPC, TGA, and DSC. Hydrolytic degradation of the deprotected copolymers was tracked over an 8-week time frame. The results show that faster degradation occurred with increased carbonate content in the copolymer backbone. The degradation pattern of the copolymers was visualized using SEM and revealed a trend toward surface erosion as the primary mode of degradation. © 2011 American Chemical Society.
Kothari K.,University of Minnesota |
Kothari K.,Millennium: The Takeda Oncology Company |
Ragoonanan V.,University of Minnesota |
Ragoonanan V.,DuPont Company |
Suryanarayanan R.,University of Minnesota
Molecular Pharmaceutics | Year: 2015
We investigated the influence of drug-polymer hydrogen bonding interactions on molecular mobility and the physical stability in solid dispersions of nifedipine with each of the polymers polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMCAS), and poly(acrylic acid) (PAA). The drug-polymer interactions were monitored by FT-IR spectroscopy, the molecular mobility was characterized using broadband dielectric spectroscopy, and the crystallization kinetics was evaluated by powder X-ray diffractometry. The strength of drug-polymer hydrogen bonding, the structural relaxation time, and the crystallization kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed polymer concentration, the fraction of the drug bonded to the polymer was the highest with PVP. Addition of 20% w/w polymer resulted in ∼65-fold increase in the relaxation time in the PVP dispersion and only ∼5-fold increase in HPMCAS dispersion. In the PAA dispersions, there was no evidence of drug-polymer interactions and the polymer addition did not influence the relaxation time. Thus, the strongest drug-polymer hydrogen bonding interactions in PVP solid dispersions translated to the longest structural relaxation times and the highest resistance to drug crystallization. © 2014 American Chemical Society.
Blair D.,Chestnut Hill College |
Blair D.,Millennium: The Takeda Oncology Company |
Dufort F.J.,Chestnut Hill College |
Chiles T.C.,Chestnut Hill College
Biochemical Journal | Year: 2012
Signals derived from the BCR (B-cell antigen receptor) control survival, development and antigenic responses. One mechanism by which BCR signals may mediate these responses is by regulating cell metabolism. Indeed, the bioenergetic demands of naïve B-cells increase following BCR engagement and are characterized by a metabolic switch to aerobic glycolysis; however, the signalling pathways involved in this metabolic reprogramming are poorly defined. The PKC (protein kinase C) family plays an integral role in B-cell survival and antigenic responses. Using pharmacological inhibition and mice deficient in PKCβ, we demonstrate an essential role of PKCβ in BCR-induced glycolysis in B-cells. In contrast, mice deficient in PKCδ exhibit glycolytic rates comparable with those of wild-type B-cells following BCR cross-linking. The induction of several glycolytic genes following BCR engagement is impaired in PKCβ-deficient B-cells. Moreover, blocking glycolysis results in decreased survival of B-cells despite BCR engagement. The results establish a definitive role for PKCβ in themetabolic switch to glycolysis following BCR engagement of naïve B-cells. © The Authors Journal compilation © 2012 Biochemical Society.
Huang S.-C.,Millennium: The Takeda Oncology Company |
Korlipara V.L.,St. John's University
Expert Opinion on Therapeutic Patents | Year: 2010
Importance of the field: Substance P is involved in mediating a number of biological effects such as emesis, pain, inflammation, bronchoconstriction, antitumor activity, and regulation of gastrointestinal and CNS function by binding to the neurokinin-1 (NK1) receptor. Antagonists of this receptor have the potential to be useful in the treatment of various disease conditions. Areas covered in this review: More than 300 patents have been filed by nearly 20 companies and 2 academic institutions in the past 2 decades. This review provides an overview of the patenting activity in the NK1 antagonist field over the last 20 years. What the reader will gain: Chemically diverse non-peptide NK1 receptor antagonists have been identified since the discovery of CP-96,345 by Pfizer in 1991. Representative examples of patented ligands and their biological activities are presented in a company-wise approach. Take home message: The NK1 receptor research has led to the clinical introduction of aprepitant in 2003 and its water soluble injectable form, fosaprepitant dimeglumine, in 2009 by Merck for the prevention of postoperative nausea and vomiting and for inhibiting chemotherapy-induced nausea and vomiting. In addition, maropitant citrate received approval in 2007 for veterinary use. © Informa UK Ltd.
Neel N.F.,University of North Carolina at Chapel Hill |
Stratford J.K.,University of North Carolina at Chapel Hill |
Shinde V.,Millennium: The Takeda Oncology Company |
Ecsedy J.A.,Millennium: The Takeda Oncology Company |
And 3 more authors.
Molecular Cancer Therapeutics | Year: 2014
The high prevalence of KRAS mutations and importance of the RalGEF-Ral pathway downstream of activated K-ras in pancreatic ductal adenocarcinoma (PDAC emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought to evaluate the AAKselective inhibitor MLN8237 as a potential indirect anti-RalA-targeted therapy for PDAC. We used a sitespecific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatmentmaybe effective for a subset of patients with PDAC independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment. © 2013 American Association for Cancer Research.
News Article | October 13, 2014
Millennium: The Takeda Oncology Company combines the innovative science of a leading American biopharmaceutical company with the global assets – both intellectual and fiscal – of Japan's largest pharmaceutical company. Our mission is to deliver extraordinary medicines to patients with cancer worldwide through our science, innovation, and passion. Millennium Pharmaceuticals, Inc., was established in 1993 as a genomics company applying world-class recombinant technology to the discovery and development of innovative new therapies in a broad spectrum of diseases. In May, 2008, Millennium was acquired by Takeda Pharmaceutical Company Limited. Millennium brings a strong oncology commercial presence and holds responsibility for the promotion of VELCADE within the United States. The commercial team at Millennium offers services including full scale reimbursement assistance, patient advocacy, liaisons with global medical affairs as well as health system and oncology based specialists.
News Article | December 14, 2012
—The last of the year’s major medical conferences, the American Society of Hematology annual meeting in Atlanta, was held this week (Dec. 8-11), and several biotechs reported promising clinical data results. Ariad Pharmaceuticals (NASDAQ: ARIA), in Cambridge, MA, said on Monday that 56 percent of 444 chronic myeloid leukemia patients treated with its drug ponatinib, all of whom had been heavily pretreated with other medicines, had a major response after one year, with minimal side effects. Ariad’s stock has been climbing all week as a result, from $22.07 last Friday to $23.88 this Thursday. —Celgene (NASDAQ:CELG), based in Summit, NJ, also announced good results at ASH for pomalidomide, its multiple myeloma drug scheduled for a decision from the FDA by Feb. 10. Patients who were given the drug and steroids lived a median of 3.6 months without their disease progressing, twice as long as those given steroids alone. And Cambridge, MA-based Millennium: The Takeda Oncology Company, reported that the oral version of Velcade, its top-selling multiple myeloma drug, proved safe and effective in an early stage clinical trial, and so warrants further study. —Arsenal Medical of Watertown, MA, said on Monday that it won a $15.5 million contract from the Defense Advanced Research Projects Agency to continue developing its foam-based product to control abdominal bleeding in soldiers injured on the battlefield. The foam is meant to be injected into the abdominal cavity, where it can control bleeding for at least an hour, Arsenal says. —Polaris Ventures Partners in Waltham, MA, and Arch Ventures Partners got a nice Christmas present on Tuesday when Amgen (NASDAQ: AMGN) announced it will buy deCode Genetics of Iceland for $415 million. As my colleague Luke Timmerman reported, the two VC firms paid $14 million less than three years ago to acquire deCode’s assets out of bankruptcy.