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Xie G.,State University of New York at Stony Brook | Wong C.C.,State University of New York at Stony Brook | Cheng K.-W.,State University of New York at Stony Brook | Huang L.,State University of New York at Stony Brook | And 2 more authors.
British Journal of Pharmacology | Year: 2012

BACKGROUND AND PURPOSE Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs). EXPERIMENTAL APPROACH The CYP/FMO-catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach. KEY RESULTS The CYP isoforms catalyse the oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac respectively. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho-sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho-sulindac may be due to their greater lipophilicity, a key parameter for CYP binding. CONCLUSIONS AND IMPLICATIONS CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety. © 2012 The British Pharmacological Society.


Zhu C.,State University of New York at Stony Brook | Cheng K.-W.,State University of New York at Stony Brook | Ouyang N.,State University of New York at Stony Brook | Huang L.,State University of New York at Stony Brook | And 3 more authors.
Stem Cells | Year: 2012

Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferation and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment of mixtures of cultured breast CSCs and breast cancer cells with PS preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p = .06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p < .05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/β-catenin pathway by stimulating the degradation of β-catenin and its relocalization to the cell membrane and also blocked the epithelial-mesenchymal transition and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling. © AlphaMed Press.


Mattheolabakis G.,State University of New York at Stony Brook | Nie T.,State University of New York at Stony Brook | Constantinides P.P.,Medicon, Inc. | Rigas B.,State University of New York at Stony Brook
Pharmaceutical Research | Year: 2012

Purpose: To incorporate phospho-ibuprofen (P-I), a lipophilic, water insoluble novel anti-cancer agent, into pegylated liposomes and upon formulation optimization to evaluate its antitumor activity in vitro and in vivo. Methods: P-I loaded liposomes were prepared using the thin-film hydration method, and characterized for size, zeta potential, drug content and drug release. We examined their physical stability by particle size changes; their lyophilization ability in the presence of cryoprotectants; and their antitumor activity in vitro in human cancer cell lines and in vivo in a xenograft murine model. Results: P-I was successfully loaded into liposomes consisting of soy-PC and PEG 2000-PE. These liposomes were <150 nm in diameter; exhibited prolonged stability in suspension and can be lyophilized using sucrose as cryoprotectant. P-I liposomes inhibited the growth of human cancer cell lines in vitro and in vivo of xenograft in nude mice to a greater extent than free P-I. Conclusions: High levels of P-I can be incorporated into liposomes which can be lyophilized in the presence of sucrose and showed good stability upon storage. Moreover, these drug-incorporating liposomes were capable of inhibiting the growth of xenografted tumors in mice more effectively than free P-I. These results justify further development of the P-I liposomes. © 2011 Springer Science+Business Media, LLC.


Mattheolabakis G.,State University of New York at Stony Brook | Rigas B.,State University of New York at Stony Brook | Constantinides P.P.,Biopharmaceutical and Drug Delivery Consulting LLC | Constantinides P.P.,Medicon, Inc.
Nanomedicine | Year: 2012

Nanotechnology is revolutionizing our approach to drug delivery, a key determinant of drug efficacy. Here, we present cancer drug delivery strategies that exploit nanotechnology, providing first an overview of tumor biology aspects that critically affect the design of drug delivery carriers, namely the enhanced permeability and retention effect, the lower tumor extracellular pH and tumor-specific antigens. In general, nanoscience-based approaches have circumvented limitations in the delivery of cancer therapeutics, related to their poor aqueous solubility and toxicity issues with conventional vehicles and resulted in improved pharmacokinetics and biodistribution. Included in the discussion are promising examples and pharmaceutical perspectives on liposomes, nanoemulsions, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes and magnetic nanoparticles. As the cardinal features of the ideal multifunctional cancer drug nanocarrier are becoming clear, and drug development challenges are proactively addressed, we anticipate that future advances will enhance therapeutic outcomes by refining the delivery and targeting of complex payloads. © 2012 Future Medicine Ltd.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 1.80M | Year: 2012

DESCRIPTION (provided by applicant): The chemoprevention of colon cancer has been hampered by either weak agents or significant side effects. It was recently shown that the combination of sulindac with difluoromethylornithine (DFMO) prevents nearly 70% ofcolon cancer, assessed as colon polyp recurrence. Sulindac, however, has frequent and significant side-effects that make its long-term application to cancer prevention problematic. Our phase I STTR assessed the potential role of our sulindac-like compoundMDC-1231, also known as phosphosulindac (PS), in colon cancer prevention. PS has increased potency and safety compared to sulindac and acts synergistically with DFMO to prevent colon cancer with an efficacy of 91%. Our goal is to replace sulindac with PSin the successful combination with DFMO in order to develop a superior approach to colon cancer prevention. We have accomplished all the goals of the phase I grant. The goal of the present phase II application is to complete the preclinical development ofPS and submit an FDA IND application. We propose five specific aims, some of them will be pursued in parallel and influence each other. Specific Aim #1: Complete the studies on the metabolism; perform PK/PD and biodistribution of the optimized oral formulation of PS. Specific Aim #2: Scale up the synthesis of PS under GMP conditions. Specific Aim #3: Develop an oral formulation of PS and determine its stability. Specific Aim #4: Perform toxicity studies of PS; they include animal toxicity and genotoxicity studies. Specific Aim #5: Prepare an IND protocol and package for FDA submission. The proposed work, if successful, will contribute greatly towards a realistic strategy for human colon cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Colon cancer is a major cause of cancer deaths in the US and worldwide. The prevention of colon cancer using pharmacological agents is now a realistic possibility, but new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, whichis potentially a highly effective and safe chemopreventive agent. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2012

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in the US and worldwide. Given its prevalence, morbidity and mortality, it is clear that in terms of treatment, the lung cancer problem is far from solved; and thatnew agents are urgently needed. Our preliminary data indicate that the novel compound phospho-sulindac (PS) is potentially highly effective against lung cancer. Our hypothesis is that PS is a safe and highly effective agent against lung cancer. To evaluate this hypothesis, we propose the following specific aims: 1) Determine the efficacy and mechanism of action of PS in animal models of lung cancer. PS will be administered to nude mice with xenografts of human lung cancer cells representing the major clinical subcategories and to nude rats with orthotopic xenografted lung cancer and assess the in vivo changes of the signaling pathways already outlined. 2) Perform toxicity studies of PS. We will determine the genotoxicity, maximum tolerated dose and repeateddose/organ toxicity of PS. 3) Study the metabolism, pharmacokinetics and pharmacodynamics of PS. These aims will assess parameters that are essential to the preclinical development of PS: drug efficacy; drug safety; drug metabolism; pharmacokinetics; andpharmacodynamics. The expected results will pave the way towards the completion of PS's preclinical evaluation. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the US and worldwide. Given its prevalence, morbidity and mortality, it is clear that in terms of treatment, the lung cancer problem is far from solved and that new agents are urgently needed. We are proposing to develop a novel compound, phospho-sulindac, which is potentially highly effective against lungcancer. The expected results will pave the way towards the completion of phospho-sulindac's preclinical evaluation, a required step prior to its testing in humans.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.90K | Year: 2010

We propose studies for the preclinical development of BJ-813, a novel agent against breast cancer. BJ-813 has significant activity in vitro (human breast cancer cell lines covering the clinical spectrum of the disease) and in xenograft models of human breast cancer in nude mice. When formulated in liposomes, BJ-813 regresses xenograft tumors. Our hypothesis is that BJ-813 can be developed into an effective therapeutic agent against breast cancer. The fact that the remarkable effect of BJ-813 against breast cancer in tumor animal models is obtained when this drug is formulated in liposomes, suggests that optimizing its formulation will lead to enhanced efficacy and safety.


Novel compounds and pharmaceutical compositions thereof for the treatment and/or prevention of cancer and precancerous conditions, inflammation-related disorders, pain and fever.


The present invention provides novel compounds and pharmaceutical compositions for the prevention and/or treatment of cancer and precancerous conditions thereof, for the treatment of pain and fever, for the treatment of skin disorders, and for treating and/or preventing inflammation-related diseases and/or cardiovascular diseases. The compounds of the invention also have analgesic properties and anti-platelet properties. The compounds of the invention may be provided to animals, including mammals and humans, by administering a suitable pharmaceutical dose in a suitable pharmaceutical dosage form. The compounds of the invention have improved efficacy and safety, including higher potency and/or fewer or less severe side effects, than conventional therapies. The compounds of the invention comprise a biologically active moiety or portion (A) that has, or is modified to have at least one carboxyl group. The moiety A is preferably an aliphatic, aromatic or alkylaryl group, preferably derived from a non-steroidal anti-inflammatory drug or NSAID (A). The moiety A is bound to a linker moiety (B) via the carboxyl of group A and a linking atom that is selected from oxygen, nitrogen, and sulphur, to form a carboxylic ester, and amide, or a thioester, bond (X^(1)) between groups A and B. Moiety B is a single bond, an aliphatic group, a substituted benzene, or an alkylene substituted hydrocarbon chain, which in turn is bound to functional moiety Z, which facilitates access of the compound into cells. The moiety Z can comprise, for example, a phosphorous-containing group, a nitrogen-containing group, or a folic acid residue.


Novel compounds and pharmaceutical compositions thereof administered by the respiratory route for prevention and/or treatment of lung and brain cancer and precancerous conditions thereof.

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