At the present, a high potential of epigallocatechin-3-gallate (EGCG) as a new preventive and therapeutic agent in oncol. and several other indications is well established.EGCG exerts its antitumor activity through induction of cell cycle arrest and apoptosis, inhibition of tumor angiogenesis, migration and metastasis due to its ability to interact with multiple targets in cancer cell.Unfortunately, very low oral bioavailability of EGCG prevents its efficient development as novel medicine.In this work, we have developed a polymer based nano-formulation of EGCG that significantly improved its oral bioavailability by increasing systemic exposure of the compound by about 8-fold.This formulation comprises a well-known inactive ingredient non-ionic block copolymer Pluronic F127 that has recently been successfully used to increase bioavailability of another promising phytonutrient, 3,3'-diindolylmethane.The pharmacokinetic parameters established in the present study revealed that AUC and Cmax of the new formulation dosed at 500 mg/kg were 578.5 ± 73.8 μg·h/mL and 49.3 ± 2.9 μg/mL, while in the case of control EGCG administered in the equivalent dose AUC and Cmax were 72.9 ± 14.7 μg·h/mL, and 10.7 ± 1.1 μg/mL.

2010-05-10·Journal of controlled release : official journal of the Controlled Release Society1区 · 医学

Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers

1区 · 医学

Article

作者: Nan Gong ; Amit K. Sharma ; Elena V. Batrakova ; Howard E. Gendelman ; Valery Yu Alakhov ; Alexander V. Kabanov ; Shu Li ; Michael Boska ; Anna M. Brynskikh ; Yili Li ; R. Lee Mosley

Cancer chemotherapy is believed to be impeded by multidrug resistance (MDR). Pluronic (triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), PEO-b-PPO-b-PEO) were previously shown to sensitize MDR tumors to antineoplastic agents. This study uses animal models of Lewis lung carcinoma (3LL-M27) and T-lymphocytic leukemia (P388/ADR and P388) derived solid tumors to delineate mechanisms of sensitization of MDR tumors by Pluronic P85 (P85) in vivo. First, non-invasive single photon emission computed tomography (SPECT) and tumor tissue radioactivity sampling demonstrate that intravenous co-administration of P85 with a Pgp substrate, 99Tc-sestamibi, greatly increases the tumor uptake of this substrate in the MDR tumors. Second, 31P magnetic resonance spectroscopy (31P-MRS) in live animals and tumor tissue sampling for ATP suggest that P85 and doxorubicin (Dox) formulations induce pronounced ATP depletion in MDR tumors. Third, these formulations are shown to increase tumor apoptosis in vivo by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and reverse transcription polymerase chain reaction (RT-PCR) for caspases 8 and 9. Altogether, formulation of Dox with P85 results in increased inhibition of the growth solid tumors in mice and represents novel and promising strategy for therapy of drug resistant cancers.

2008-11-01·Journal of controlled release : official journal of the Controlled Release Society1区 · 医学

Prevention of MDR development in leukemia cells by micelle-forming polymeric surfactant

1区 · 医学

Article

作者: Valery Yu Alakhov ; Amit K. Sharma ; Li Zhang ; Alexander V. Kabanov ; Elena V. Batrakova ; David Lee Kelly ; Shu Li

Doxorubicin (Dox) incorporated in nanosized polymeric micelles, SP1049C, has shown promise as monotherapy in patients with advanced esophageal carcinoma. The formulation contains amphiphilic block copolymers, Pluronics, that exhibit the unique ability to chemosensitize multidrug resistant (MDR) tumors by inhibiting P-glycoprotein (Pgp) drug efflux system and enhancing pro-apoptotic signaling in cancer cells. This work evaluates whether a representative block copolymer, Pluronic P85 (P85) can also prevent development of Dox-induced MDR in leukemia cells. For in vitro studies murine lymphocytic leukemia cells (P388) were exposed to increasing concentrations of Dox with/without P85. For in vivo studies, BDF1 mice bearing P388 ascite were treated with Dox or Dox/P85. The selected P388 cell sublines and ascitic tumor-derived cells were characterized for Pgp expression and functional activity (RT-PCR, Western Blot, rhodamine 123 accumulation) as well as Dox resistance (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). The global gene expression was determined by oligonucleotide gene microarrays. We demonstrated that P85 prevented development of MDR1 phenotype in leukemia cells in vitro and in vivo as determined by Pgp expression and functional assays of the selected cells. Cells selected with Dox in the presence of P85 in vitro and in vivo exhibited some increases in IC(50) values compared to parental cells, but these values were much less than IC(50) in respective cells selected with the drug alone. In addition to mdr1, P85 abolished alterations of genes implicated in apoptosis, drug metabolism, stress response, molecular transport and tumorigenesis. In conclusion, Pluronic formulation can prevent development of MDR in leukemia cells in vitro and in vivo.

项与 Supratek Pharma, Inc. 相关的新闻（医药）

2008-04-01

·BioSpace

Supratek Pharma Inc.'s Lead Compound SP1049C is Granted Orphan Drug Designation for the Treatment of Gastric Cancer

MONTREAL, April 1 /PRNewswire/ - Supratek Pharma Inc. announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to SP1049C for the treatment of gastric cancer. Orphan drug refers to a product that is intended for use in a disease or condition that affects fewer than 200,000 individuals in the United States. According to the US National Cancer Institute it is estimated that 21,500 new cases of gastric cancer will be diagnosed in USA in 2008. Throughout the world, however, gastric cancer is the second leading cause of cancer-related deaths. Last year Supratek Pharma obtained FDA clearance for its Investigational New Drug application for SP1049C for the treatment of metastatic adenocarcinoma of the upper gastrointestinal tract. Recently Supratek has also reached an agreement with the FDA for the design of SP1049C pivotal Phase III study protocol under the Special Protocol Assessment process. A randomized Phase III pivotal clinical trial will compare SP1049C plus Best Supportive Care (BSC) versus BSC alone for the treatment of patients with metastatic adenocarcinoma of esophagus, gastroesophageal junction and stomach who have failed adjuvant or 1st or 2nd line chemotherapy. Supratek Pharma will direct the clinical development program. Oleg Romar, President and Chief Executive Officer, said, "Acquiring an orphan drug designation in gastric cancer is a welcome milestone for the SP1049C program". "Orphan drug designation provides multiple incentives for Supratek Pharma to continue its development of SP1049C for metastatic adenocarcinoma of the upper gastrointestinal tract. Our experience to date with SP1049C has been very encouraging and we look forward to the initiation of our Phase III pivotal clinical trial", added Dr. Christopher E. Newman, Vice-President and Chief Medical Officer of Supratek. About SP1049C ------------- SP1049C, Supratek's proprietary lead anticancer drug candidate, is a Biotransport(TM) nano-composition of block copolymers and one of the most potent cytotoxic drugs, doxorubicin. In pre-clinical and clinical development, SP1049C has been shown to have a strong activity and a novel mechanism of action against chemoresistant tumors, in which conventional chemotherapeutics are inactive. In 2005 SP1049C has also obtained an orphan drug designation from the FDA for the treatment of esophageal carcinoma. About Supratek Pharma Inc. -------------------------- Supratek Pharma is an emerging pharmaceutical company focused on the treatment of drug resistant and metastatic cancers. The company has seven clinical-stage proprietary products in its pipeline. The next product in line for clinical development is SP-MET-X1. It is based on the Company's potential breakthrough discovery of a new biochemical pathway and target consistently involved in metastasis formation and cancer progression. SP-MET-X1, the first drug developed in this new therapeutic class. Late-stage metastatic cancers account for the majority of cancer deaths and represent one of the major unmet medical needs world-wide. CONTACT: Dr. Christopher E. Newman, Vice-President and Chief Medical Officer, Supratek Pharma Inc., Phone: (514) 849-6094, e-mail: chris.newman@supratek.com

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