Tumor -Targeting Chemotherapeutic Agents

Summary

Principal Investigator: Iwao Ojima
Abstract: Cancer is the second major cause of death (the No. 1 cause of death for age 85 or younger population) in the U.S. Despite the significant progress in the development of cancer detection, prevention, surgery and therapy, there is still no common cure for patients with malignant diseases. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects such as hair loss, damages to liver, kidney and bone marrow. Therefore, various drug delivery protocols and systems have been explored in the last three decades. In general, a tumor-targeting drug delivery system consists of a tumor recognition moiety and a cytotoxic warhead connected directly or through a suitable linker to form a conjugate. The conjugate, which can be regarded as "guided molecular missile", should be systemically non-toxic. This means that the linker must be stable in blood circulation. Upon internalization into the cancer cell the conjugate should be readily cleaved to regenerate the active cytotoxic warhead. A rapidly growing tumor requires various nutrients and vitamins. Therefore, tumor cells overexpress many tumor-specific receptors, which can be used as targets to deliver cytotoxic agents into tumors. We have successfully targeted tumor xenografts in animal models by employing monoclonal antibodies and polyunsaturated fatty acids. In the next funding period, we plan to use vitamins (biotin and folic acid), hyaluronic acids and aptamers as the guiding modules to construct "guided molecular missiles" for tumor- targeting chemotherapy. We will use mechanism-based linkers that are stable in blood circulation, but readily cleavable inside tumor cells. As the vehicle or platform for the novel tumor-targeting agents bearing multiple guiding modules as well as warheads, we will explore the high potentials of single-walled carbon nanotubes (SWNTs), ultra-short SWNTs and dendrimers, as well as drug conjugates with small-molecule splitter modules. Drug conjugates with dual targeting modules and/or dual warheads will also be studied. Imaging of the tumor-targeting process and drug release in vitro and in vivo will be investigated by means of confocal fluorescence microscopy, MRI and PET. For that purpose, drug conjugates with ultra-short SWNTs encapsulating gadolinium ions as well as [11C]-labeled warheads will be synthesized. PUBLIC HEALTH RELEVANCE: Statement One of the long-standing problems of chemotherapy is the lack of tumor-specific treatments, i.e., traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, the development of new and efficient tumor-specific drug delivery systems with potent anticancer agents is an urgent need in the 21st century chemotherapy to dramatically enhance the efficacy and eliminate undesirable side effects. This proposal deals with novel tumor-targeting drug delivery systems to address these urgent medical issues.
Funding Period: 1990-03-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents
    Larissa Kuznetsova
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794 3400, USA
    Bioorg Med Chem Lett 16:974-7. 2006
  2. pmc New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells
    Galina I Botchkina
    Department of Pathology, SUNY Stony Brook, NY, USA
    Mol Cancer 9:192. 2010
  3. pmc Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel
    Liang Sun
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794 3400, USA
    Bioorg Med Chem 18:7101-12. 2010
  4. ncbi Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes
    Berta Otová
    Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital Charles University, 128 00, Prague, Czech Republic
    Invest New Drugs 30:991-1002. 2012
  5. pmc Targeted and armed oncolytic adenovirus via chemoselective modification
    Partha S Banerjee
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, NY 11790, USA
    Bioorg Med Chem Lett 21:4985-8. 2011
  6. pmc Tumor-targeting drug delivery of new-generation taxoids
    Iwao Ojima
    Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 3400, USA
    Future Med Chem 4:33-50. 2012
  7. pmc Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology
    Iwao Ojima
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794 3400, USA
    J Org Chem 78:6358-83. 2013
  8. pmc Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release
    Shuyi Chen
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 3400, USA
    Bioconjug Chem 21:979-87. 2010
  9. pmc Cell death induced by novel fluorinated taxanes in drug-sensitive and drug-resistant cancer cells
    Jana Voborilova
    Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruska 87, 10000, Prague 10, Czech Republic
    Invest New Drugs 29:411-23. 2011
  10. pmc Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents
    Qing Huang
    Department of Chemistry, State University of New York at Stony Brook, New York 11794 3400, USA
    J Med Chem 49:463-6. 2006

Research Grants

Detail Information

Publications24

  1. ncbi Syntheses and evaluation of novel fatty acid-second-generation taxoid conjugates as promising anticancer agents
    Larissa Kuznetsova
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794 3400, USA
    Bioorg Med Chem Lett 16:974-7. 2006
    ..Two of the new conjugates, DHA-SB-T-1214 and DHA-SB-T-1213, were found to achieve the total regression of drug-resistant and drug-sensitive tumors, respectively, in the animal models with substantially reduced systemic toxicity...
  2. pmc New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells
    Galina I Botchkina
    Department of Pathology, SUNY Stony Brook, NY, USA
    Mol Cancer 9:192. 2010
    ....
  3. pmc Design and synthesis of de novo cytotoxic alkaloids by mimicking the bioactive conformation of paclitaxel
    Liang Sun
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794 3400, USA
    Bioorg Med Chem 18:7101-12. 2010
    ..The latter may account for the large difference in potency, and provides critical information for possible improvement in the future design of paclitaxel mimics...
  4. ncbi Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes
    Berta Otová
    Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital Charles University, 128 00, Prague, Czech Republic
    Invest New Drugs 30:991-1002. 2012
    ..In conclusion, SB-T-1214, SB-T-12854 and IDN5109 are good candidates for further study...
  5. pmc Targeted and armed oncolytic adenovirus via chemoselective modification
    Partha S Banerjee
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, NY 11790, USA
    Bioorg Med Chem Lett 21:4985-8. 2011
    ..Conjugation was enabled via the metabolic incorporation of non-canonical monosaccharides (O-GlcNAz) and amino acids (homopropargylglycine), which served as sites for chemoselective modification...
  6. pmc Tumor-targeting drug delivery of new-generation taxoids
    Iwao Ojima
    Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 3400, USA
    Future Med Chem 4:33-50. 2012
    ..This review describes our groups' research on the molecular approaches to the design and development of a novel drug-delivery system bearing highly potent new-generation taxoids for tumor-targeting chemotherapy in our laboratory...
  7. pmc Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology
    Iwao Ojima
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794 3400, USA
    J Org Chem 78:6358-83. 2013
    ....
  8. pmc Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release
    Shuyi Chen
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 3400, USA
    Bioconjug Chem 21:979-87. 2010
    ..This mechanism-based tumor-targeting drug delivery system will find a range of applications...
  9. pmc Cell death induced by novel fluorinated taxanes in drug-sensitive and drug-resistant cancer cells
    Jana Voborilova
    Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruska 87, 10000, Prague 10, Czech Republic
    Invest New Drugs 29:411-23. 2011
    ..Therefore, new generation of taxanes, either non-fluorinated or fluorinated, are excellent candidates for further and detailed studies...
  10. pmc Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents
    Qing Huang
    Department of Chemistry, State University of New York at Stony Brook, New York 11794 3400, USA
    J Med Chem 49:463-6. 2006
    ..Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation...
  11. pmc Design, synthesis, and biological evaluation of new-generation taxoids
    Iwao Ojima
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794 3400, USA
    J Med Chem 51:3203-21. 2008
    ..Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice...
  12. pmc Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids
    Liang Sun
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794 3400, USA
    J Org Chem 73:9584-93. 2008
    ..The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed...
  13. pmc Recent advances in the chemistry and biology of new generation taxoids
    Iwao Ojima
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 3400, USA
    J Nat Prod 72:554-65. 2009
    ..This account describes our work on the design, synthesis, and biological evaluation of these novel taxoids, which has led to the discovery of very promising candidates for further preclinical studies...
  14. pmc Recent advances in the study of the bioactive conformation of taxol
    Liang Sun
    Department of Chemistry and Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 3400, USA
    ChemMedChem 4:719-31. 2009
    ..The bioactive conformation of paclitaxel is important since it could provide critical information that would allow the design of novel analogues with simpler structures and/or increased potency against cancer...
  15. pmc Novel C-seco-taxoids possessing high potency against paclitaxel-resistant cancer cell lines overexpressing class III beta-tubulin
    Antonella Pepe
    Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794 3400, USA
    Bioorg Med Chem Lett 19:3300-4. 2009
    ....
  16. pmc Functionalized single-walled carbon nanotubes as rationally designed vehicles for tumor-targeted drug delivery
    Jingyi Chen
    Condensed Matter Physics and Materials Science Department, Brookhaven National Laboratory, Upton, New York 11973, USA
    J Am Chem Soc 130:16778-85. 2008
    ..Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development...
  17. pmc Comparison of cell death-inducing effect of novel taxane SB-T-1216 and paclitaxel in breast cancer cells
    Jan Kovar
    Department of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Ruska 87, 10000 Prague 10, Czech Republic
    Anticancer Res 29:2951-60. 2009
    ..In this study, the effect of novel taxane SB-T-1216 and paclitaxel on sensitive MDA-MB-435 and resistant NCI/ADR-RES human breast cancer cells was compared...
  18. ncbi Drug discovery targeting cell division proteins, microtubules and FtsZ
    Iwao Ojima
    Department of Chemistry, Stony Brook University, Stony Brook, NY 11794 3400, USA Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794 3400, USA Electronic address
    Bioorg Med Chem 22:5060-77. 2014
    ..This review describes an account of our research on these two fronts in drug discovery, targeting eukaryotic as well as prokaryotic cell division. ..

Research Grants30

  1. Engineered intelligent micelle for tumor pH targeting
    You Han Bae; Fiscal Year: 2013
    ..The research also plans to investigate more multidrug resistant models relevant to clinical setting and pharmacokinetic analysis at cellular and tissue levels. ..
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..