The multifunctional micelle-based targeting nanotherapeutics to be developed in this project offer an opportunity to deliver high concentration of cytotoxic drugs (e.g. doxorubicine), molecularly targeted drugs (e.g. bortezomib [Velcade(R)], a proteosome inhibitor) as well as therapeutic radionuclides such as 131I to the tumor sites while sparing normal organs, thus greatly enhance the anti-tumor effects and lessen the systemic side effects of these drugs. As a result, we expect patients with advanced non- Hodgkin lymphoma (both T- and B-cell type) or solid tumors will benefit from such novel nanotherapies. In addition, such multifunctional nanoplatform can also be used as tumor imaging agents. Our nanotherapeutic platform is unique and comprised of oligocholic acid based micelles with drugs loaded inside and cancer targeting ligands decorating the micelle surface. We believe the addition of LLP2A, a lymphoma targeting ligand, to the nanotherapeutics can facilitate the intracellular delivery of the nanocarrier to the tumor cells in vivo and therefore will greatly enhance their anti-tumor efficacies. In this proposed research, biodistribution properties (imaging) and therapeutic efficacies of such targeting nanoparticles will be evaluated in both transgenic mouse lymphoma models and spontaneous canine lymphoma. This research will lead to the development of more efficacious and less toxic multifunctional targeting nanoformulations of bortexomib (a proteasome inhibitor), doxorubicin (a DNA intercalate), and therapeutic radionuclide 131I, all of which are expected to be useful in the treatment of many cancer types including non-Hodgkin lymphoma (NHL). If successful, this therapeutic approach can be applied to many other cancer types as well and therefore will have a great impact in the survival of cancer patients in the United States and around the world.

Public Health Relevance

The multifunctional micelle-based targeting nanotherapeutics to be developed in this project offer an opportunity to deliver high concentration of cytotoxic drugs, molecularly targeted drugs as well as therapeutic radionuclides such as 131I to the tumor sites while sparing normal organs, thus greatly enhance the anti-tumor effects and lessen the systemic side effects of these drugs. Amphiphilic polymers will be designed, synthesized, and optimized for efficient loading of bortezomib or doxorubicin to form nanoparticles. These nanotherapeutics will be evaluated for their anti-tumor efficacies in transgenic mouse lymphoma model and in companion dogs with spontaneous lymphomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB012569-02
Application #
8247714
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Zullo, Steven J
Project Start
2011-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$596,201
Indirect Cost
$204,882
Name
University of California Davis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Li, Yuanpei; Xiao, Kai; Zhu, Wei et al. (2014) Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers. Adv Drug Deliv Rev 66:58-73
Li, Yuanpei; Lin, Tzu-yin; Luo, Yan et al. (2014) A smart and versatile theranostic nanomedicine platform based on nanoporphyrin. Nat Commun 5:4712
Xiao, Kai; Suby, Nell; Li, Yuanpei et al. (2013) Telodendrimer-based nanocarriers for the treatment of ovarian cancer. Ther Deliv 4:1279-92
Xiao, Kai; Li, Yuanpei; Lee, Joyce S et al. (2012) "OA02" peptide facilitates the precise targeting of paclitaxel-loaded micellar nanoparticles to ovarian cancer in vivo. Cancer Res 72:2100-10
Li, Yuanpei; Xiao, Wenwu; Xiao, Kai et al. (2012) Well-defined, reversible boronate crosslinked nanocarriers for targeted drug delivery in response to acidic pH values and cis-diols. Angew Chem Int Ed Engl 51:2864-9
Xiao, Kai; Luo, Juntao; Li, Yuanpei et al. (2011) PEG-oligocholic acid telodendrimer micelles for the targeted delivery of doxorubicin to B-cell lymphoma. J Control Release 155:272-81