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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University New York Stony Brook
Schools of Arts and Sciences
Stony Brook
United States
Zip Code
Ojima, Iwao; Wang, Xin; Jing, Yunrong et al. (2018) Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery. J Nat Prod 81:703-721
Jelínek, Michael; Balušíková, Kamila; Daniel, Petr et al. (2018) Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel. Toxicol Appl Pharmacol 347:79-91
Ahmad, Gulzar; Gattacecca, Florence; El Sadda, Rana et al. (2018) Biodistribution and Pharmacokinetic Evaluations of a Novel Taxoid DHA-SBT-1214 in an Oil-in-Water Nanoemulsion Formulation in Naïve and Tumor-Bearing Mice. Pharm Res 35:91
Yang, Chia-Ping Huang; Wang, Changwei; Ojima, Iwao et al. (2018) Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of ?-Tubulin and the Multidrug Resistance Associated P-Glycoprotein. J Nat Prod 81:600-606
Zheng, Xiaowei; Wang, Changwei; Xing, Yuanming et al. (2017) SB-T-121205, a next-generation taxane, enhances apoptosis and inhibits migration/invasion in MCF-7/PTX cells. Int J Oncol 50:893-902
Ojima, Iwao (2017) Strategic Incorporation of Fluorine into Taxoid Anticancer Agents for Medicinal Chemistry and Chemical Biology Studies. J Fluor Chem 198:10-23
Zong, Yao; Shea, Christie; Maffucci, Katherine et al. (2017) Computational Design and Synthesis of Novel Fluoro-Analogs of Combretastatins A-4 and A-1. J Fluor Chem 203:193-199
Ahmad, Gulzar; El Sadda, Rana; Botchkina, Galina et al. (2017) Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth. Cancer Lett 406:71-80
Ojima, Iwao; Lichtenthal, Brendan; Lee, Siyeon et al. (2016) Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 26:1-20
He, Zhijian; Schulz, Anita; Wan, Xiaomeng et al. (2015) Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation. J Control Release 208:67-75

Showing the most recent 10 out of 43 publications