Ovarian cancer is the fifth leading cause of cancer-related deaths in women. The majority of patients is diagnosed at late stages of disease due to inadequate detection methods, and is treated with surgery followed by chemotherapy. Due to the advanced stage of disease at diagnosis, there is a high rate of recurrence. The five-year survival rate of ovarian cancer is 20% below the average five-year survival rate for all cancer combined, highlighting the need for innovative therapies for ovarian cancer. Rapid and inexpensive sequencing technology has allowed for the ongoing efforts to profile individual cancer genomes and subsequent identification of new therapeutic candidates. However, the development of small molecule inhibitors against newly identified targets is expensive, slow, and many targets are undruggable. RNAi therapy offers an attractive course of treatment: siRNA against new targets can be rapidly synthesized and can target specific isoforms which may not be possible by small molecule therapy. However, at this stage, efficient delivery of siRNA into the cytosol of diseased cells remains a major challenge. We propose utilizing primary ovarian cancer cells as a clinically relevant model of disease to optimize siRNA delivery vehicles for ovarian cancer therapy. There are several mouse models utilized to develop therapeutics for ovarian cancer, including genetically engineered mouse models and xenografts of ex vivo propagated cell lines. Although useful, these models may not represent the human etiology of high-grade ovarian cancer, the greater majority of which originate from the fallopian tube. Primary ovarian cells isolated from the ascites of human patients may more accurately represent disease development and the heterogeneity of cancer cells, and therefore may be more useful in evaluating the response to therapy. Characterization of primary ovarian cancers may provide insights to develop therapeutics that will be ultimately translated into humans. The purpose of this proposal is the development of siRNA delivery carriers to clinically relevant models of ovarian cancer. We will fine-tune our first generation carrier which includes (1) a peptide for targeting ectopically expressed p32 and (2) a peptide for mediating endosomal escape of internalized siRNA. First, we will characterize primary ovarian cancer cells for surface representation of the cognate receptor of our targeting peptide. Next, targeting peptide will be optimized for internalization and delivery of siRNA in primary ovarian cancer cells in vitro, as well as optimal biodistribution in vivo. These optimized vehicles will then be applied for therapeutic delivery of siRNA in primary ovarian cancer xenograft models. A multi-component peptide siRNA delivery vehicle has broad applicability to other cancer subtypes via interchanging targeting moieties and cargo.

Public Health Relevance

The five-year survival rate of patients with ovarian cancer is 20% below that of average cancer survival rates, highlighting the necessity for innovation in ovarian cancer therapy. The purpose of this project is to develop synthetic carriers to deliver therapeutic siRNA for the treatment of ovarian cancer. We will incorporate several peptides to mediate efficient trafficking and optimize the vehicles for delivery to primary ovarian cancer cell isolated from human patients in vitro and in a mouse model.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA177094-02
Application #
8820072
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakowlew, Sonia B
Project Start
2014-02-01
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
Kwon, Ester J; Dudani, Jaideep S; Bhatia, Sangeeta N (2017) Ultrasensitive tumour-penetrating nanosensors of protease activity. Nat Biomed Eng 1:
Kwon, Ester J; Skalak, Matthew; Bertucci, Alessandro et al. (2017) Porous Silicon Nanoparticle Delivery of Tandem Peptide Anti-Infectives for the Treatment of Pseudomonas aeruginosa Lung Infections. Adv Mater 29:
Kang, Jinyoung; Joo, Jinmyoung; Kwon, Ester J et al. (2016) Self-Sealing Porous Silicon-Calcium Silicate Core-Shell Nanoparticles for Targeted siRNA Delivery to the Injured Brain. Adv Mater 28:7962-7969
Kwon, Ester J; Skalak, Matthew; Lo Bu, Riana et al. (2016) Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries. ACS Nano 10:7926-33
Lo, Justin H; Kwon, Ester J; Zhang, Angela Q et al. (2016) Comparison of Modular PEG Incorporation Strategies for Stabilization of Peptide-siRNA Nanocomplexes. Bioconjug Chem 27:2323-2331