The development of multi-drug resistance (MDR) is a major cause of failure in chemotherapeutic management of cancer. In breast cancer, for instance, more than 50% of the patients relapse due to acquired resistance to standard chemotherapy regimens. Novel strategies to overcome MDR in a clinically meaningful way that does not expose the patients to significant toxicity are urgently needed. In the proposed study, our strategy to overcome MDR in vivo relies on a multifunctional approach to optimize delivery of pro-apoptotic drugs to the tumor mass, increase the intracellular drug concentrations, and reverse cellular resistance by modulating ceramide levels. The preliminary studies show that we can prepare tumor-targeted biodegradable polymer-based engineered nanocarriers (PENS) for encapsulation of hydrophobic pro-apoptotic drugs, like paclitaxel. We have also found that increasing intracellular ceramide concentrations by delivery from exogenous source or inhibiting the metabolism results in significant enhancement of cytotoxicity in sensitive and resistant tumor cells. C6-ceramide and tamoxifen, a potent inhibitor of ceramide metabolism, were co-administered with paclitaxel for synergistic activity in tumor cells and in vivo. Based on these preliminary findings, we are confident that PENS, developed using engineering design criteria, can be made to efficiently deliver multiple therapeutic agents to the tumor mass.
The specific aims of the proposal are: (1) to develop, characterize, and optimize long-circulating, biodegradable polymeric nanocarriers with encapsulated paclitaxel, ceramide, and tamoxifen, either alone or in combination, (2) to evaluate the uptake, distribution, intracellular concentrations of paclitaxel, ceramide, and tamoxifen, cytotoxicity, and apoptotic activity in culture of sensitive and resistant tumor cells, (3) to examine the biodistribution and pharmacokinetic profiles of drugs administered in the control and nanocarrier formulations in sensitive and resistant xenograft tumor models established in nude mice, (4) to determine the antitumor efficacy of single and combination therapy in PENS in sensitive and resistant xenograft models, and (5) use mathematical modeling to improve the design of nanocarriers for tumor-targeted delivery of single and combination drug therapy. The results of this study would be extremely valuable in the treatment of refractory tumors using a multifunctional nanotherapeutic approach that efficiently delivers the drug and can overcome cellular resistance. The multimodal nanocarrier strategy proposed here would provide a translatable approach to overcome MDR in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119617-02
Application #
7127627
Study Section
Special Emphasis Panel (ZCA1-SRRB-C (O1))
Program Officer
Grodzinski, Piotr
Project Start
2005-09-30
Project End
2009-07-31
Budget Start
2006-09-12
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$360,523
Indirect Cost
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Mattheolabakis, George; Ling, Dandan; Ahmad, Gulzar et al. (2016) Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer. Pharm Res 33:2943-2953
Talekar, Meghna; Ouyang, Qijun; Goldberg, Michael S et al. (2015) Cosilencing of PKM-2 and MDR-1 Sensitizes Multidrug-Resistant Ovarian Cancer Cells to Paclitaxel in a Murine Model of Ovarian Cancer. Mol Cancer Ther 14:1521-31
Chernenko, Tatyana; Buyukozturk, Fulden; Miljkovic, Milos et al. (2013) Label-Free Raman Microspectral Analysis for Comparison of Cellular Uptake and Distribution between Non-Targeted and EGFR-Targeted Biodegradable Polymeric Nanoparticles. Drug Deliv Transl Res 3:
Milane, Lara; Duan, Zhen-feng; Amiji, Mansoor (2011) Pharmacokinetics and biodistribution of lonidamine/paclitaxel loaded, EGFR-targeted nanoparticles in an orthotopic animal model of multi-drug resistant breast cancer. Nanomedicine 7:435-44
Susa, Michiro; Milane, Lara; Amiji, Mansoor M et al. (2011) Nanoparticles: a promising modality in the treatment of sarcomas. Pharm Res 28:260-72
Milane, Lara; Ganesh, Shanthi; Shah, Shruti et al. (2011) Multi-modal strategies for overcoming tumor drug resistance: hypoxia, the Warburg effect, stem cells, and multifunctional nanotechnology. J Control Release 155:237-47
Milane, Lara; Duan, Zhenfeng; Amiji, Mansoor (2011) Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells. Mol Pharm 8:185-203
Yang, Cao; Choy, Edwin; Hornicek, Francis J et al. (2011) Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines. Anticancer Res 31:1115-23
Yang, Cao; Choy, Edwin; Hornicek, Francis J et al. (2011) Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells. Cancer Chemother Pharmacol 67:439-46
Milane, Lara; Duan, Zhenfeng; Amiji, Mansoor (2011) Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer. PLoS One 6:e24075

Showing the most recent 10 out of 38 publications