PEGylated liposomal doxorubicin (Doxil, PLD) is used clinically to treat ovarian cancer (OC) and breast cancer (BC); however, the response rates of PLD treatment in both diseases need to be improved. Based on strong preliminary data, we propose a novel simple strategy to increase the efficacy of PLD treatment by promoting the release of the active ingredient (doxorubicin, (Dox)) from the liposomal particles directly within the tumor matrix, whil concurrently sensitizing this tumor to the drug. In this strategy, amphiphilic Pluronic block copolymers (poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), PEO-PPO-PEO) are intravenously (IV) administered after the PLD treatment, when the concentration of the liposomal drug within the tumor reaches its maximum. We posit, the copolymer then depots into tumors, incorporates into the PLD particles, and promotes the encapsulated drug release, thus increasing drug bioavailability and improving the tumor response. Moreover, a combination of Dox and Pluronic generated within tumors is highly potent in eliminating multidrug resistant (MDR) and tumor-initiating cells (TIC) that can further improve the therapeutic outcomes in cancer. Our objectives are: to determine mechanism by which administration of Pluronic after the PLD increases the anti-tumor activity; provide proof of principle using genetically engineered mouse models (GEMMs) of OC and BC that closely represent biology and microenvironment of solid tumors in patients; and select Pluronic compositions and treatment regimen to maximize the translational and clinical outcomes.
The aims will: 1) determine in vitro release kinetics of Dox from PLD and in vivo pharmacokinetics (PK) of Pluronic to select the best Pluroinic composition, doses and schedule; 2) evaluate PK of PLD alone and in combination with the selected Pluronic(s) to determine the amount of Dox released from liposomes in plasma and drug exposure in tumor; 3) evaluate the anti-tumor activity and safety of the proposed treatments; and 4) determine whether administration of Pluronic after PLD results in depletion of TIC, and decreases tumorigenicity and aggressiveness of cancer cells. The proposed combination therapy if successful has high potential for translation to clinical studies, since it is simple, can improve efficacy of clinically available PD (such as Doxil(r)), and is likely to be safe, since Pluronics were shown to be safe in clinical trils of non-liposomal Dox/Pluronic formulation, SP1049C.

Public Health Relevance

PEGylated liposomal doxorubicin is used clinically to treat ovarian cancer and breast cancer; however, the response rates in both diseases need to be improved. We propose a novel simple strategy to increase the efficacy of the treatment by promoting the release of the active ingredient (doxorubicin) from the liposomal particles directly within the tumor, while concurrently increasing the drug ability to kill cancer cells resistant to chemotherapy. The approach has high potential for translation to clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA184088-05
Application #
9618122
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Fu, Yali
Project Start
2015-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Petschauer, Jennifer S; Madden, Andrew J; Kirschbrown, Whitney P et al. (2015) The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents. Nanomedicine (Lond) 10:447-63