Multi-drug resistance (MDR) of cancer is one of the major challenges for curing cancer. Exosomes play an essential role in this activity by expulsion of drug and signaling biomolecules, and have attracted significant research interests as they may also imply important biomarkers for cancer and therapy. Nanoparticles, an emerging technology to encapsulate and deliver drugs, are demonstrated to overcome MDR, by potentially interfering the production and composition of exosomes. We hypothesize that treatment by nanoparticles helps shedding drugs from exosome efflux to overcome MDR of cancer. To test this hypothesis and identify the underlying mechanism, our proposed research will focus on inducing MDR suppression with nanoparticle encapsulation and analyzing the quantitative and compositional variation of cancer-secreted exosomes. We plan to treat in vitro culture of the multidrug resistant cancer cells with nanoparticle encapsulated paclitaxel or doxorubicin to overcome MDR. To extract and purify the subsequently-secreted exosomes, we plan utilize our proprietary ciliated micropillar array, a novel nanowire-on-micropillar structure, which allows rapid, efficient, and non-invasive isolation of exosome. Recently, our group developed a microfluidic device consisting of ciliated micropillars, and demonstrated that it can preferentially trap exosome-like liposomes, while simultaneously filtering protein molecules and larger cell debris. This technique is temperature- stable, immediate accessible, and cost-effective. With the enhancement of exosome antibody, it allows rapid and non-invasive isolation of specific exosomes of high purity, therefore providing opportunity for on-site and high-throughput assay. The isolated exosomes will firstly be quantitated for their secretion rate under various treatment conditions of MDR up/down regulation. Exosomal constituents, especially ABC transporter proteins, will be further extracted for biomarker analysis. The result will be evaluated to track exosomal compositional variation and to identify the existence of potential biomarkers. With completion of above research, we expect to provide a powerful nanotechnology platform for rapid and efficient analysis of intact cancer derived exosomes, which can improve our understanding of cancer MDR and nanoparticle involvement. The outcome would also benefit the discovery of useful drug-resistant cancer biomarkers, thus leading to more efficient cancer nanotherapy.

Public Health Relevance

Multi-drug resistance (MDR) of cancer is one of the major challenges for anti- cancer chemotherapy, and nanoparticles, the emerging technology to encapsulate drug, are demonstrated to overcome MDR, by potentially interfering the generation and secretion of exosomes, the cancer-derived microvesicles that are essential in MDR mechanism. The objective of this proposal is to study the exosomes responding to nanoparticle treatments of two MDR breast cancer models, and measure the quantitative and compositional variation of secreted exosomes corresponding to nanotherapy. This research will significantly speed up the exosome analysis; help to acquire more accurate biological information of their cancer-mediating role, which can further improve our understanding of MDR mechanism, thus leading to more efficient cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA190024-01A1
Application #
9036062
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2015-12-01
Project End
2017-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030