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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103314-21
Application #
8225354
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fu, Yali
Project Start
1990-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
21
Fiscal Year
2012
Total Cost
$314,565
Indirect Cost
$114,205
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Botchkina, Galina I; Zuniga, Edison S; Das, Manisha et al. (2010) New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells. Mol Cancer 9:192

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