Nearly all cancer therapies are limited by their ability to precisely deliver a lethal dose of a therapeutic agent to tumor cells while sparing normal tissue. Recent progress in nanotechnology has resulted in nanomaterials with remarkable biological and material properties that can be leveraged for enhanced cancer diagnosis and therapy. These include targeting of tumors via ligands that direct nanoparticles to receptors in the tumor microenvironment, providing electromagnetic properties for imaging and sensing tumors, and delivery chemotherapeutic agents to tumor cells in vivo. RNA interference offers an attractive means to silence expression of genes with extraordinary specificity, particularly for the subset of genes considered """"""""undruggable"""""""". However, systemic delivery of siRNAs has been challenging due to pharmacokinetic properties resulting from their small size, the requirement for delivery of these agents into the cytosol of target cells, and their susceptibility to serum nucleases. To date, approaches for delivery of siRNAs have primarily focused on chemical modifications, carrier development using polymers, antibodies, aptamers, and peptides with limited success. The goal of this project is to assemble a multidisciplinary team to improve the management of ovarian cancer by delivering therapeutic siRNAs. As the most lethal gynecologic malignancy with 31% five-year survival rates, new therapies are desperately needed. This malignancy disseminates in the peritoneal cavity and delivery of therapeutic agents to this compartment has shown to prolong survival. siRNAs can be designed to silence most, if not all genes and thus could be used to block pathways that induce cell death in cancer cells as compared to normal cells. We propose to continue the development and testing of nanoparticles for the delivery of siRNAs to treat ovarian cancer.
The specific aims are: 1 Identification and testing by nanoparticle delivery of siRNAs to specific genes that when silenced induce cell death of subsets of ovarian cancer cells in the peritoneal cavity, 2 Development of modular nanomaterials that will target the delivery of siRNAs to ovarian tumors and 3 Development of safe and effective nanoparticles composed of novel biomaterials to deliver siRNA to ovarian cancer cells in the peritoneal cavity.

Public Health Relevance

New treatments for ovarian cancer are desparately needed. This project brings together a mulfidisciplinary team to focus on novel biomaterials, targeting strategies, and methods of cancer inhibition via RNA interference, all formulated into nanoparticles that can access ovarian tumors.and deliver the therapeutic cargo to the cytosol of tumor cells where it acts. This project also includes a trans-CCNE collaboration.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
United States
Zip Code
Bartelt, Alexander; Widenmaier, Scott B; Schlein, Christian et al. (2018) Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 24:292-303
Lim, Jong-Min; Cai, Truong; Mandaric, Stefan et al. (2018) Drug loading augmentation in polymeric nanoparticles using a coaxial turbulent jet mixer: Yong investigator perspective. J Colloid Interface Sci 538:45-50
Lo, Justin H; Hao, Liangliang; Muzumdar, Mandar D et al. (2018) iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer. Mol Cancer Ther 17:2377-2388
Chertok, Beata; Langer, Robert (2018) Circulating Magnetic Microbubbles for Localized Real-Time Control of Drug Delivery by Ultrasonography-Guided Magnetic Targeting and Ultrasound. Theranostics 8:341-357
Mitchell, Michael J; Webster, Jamie; Chung, Amanda et al. (2017) Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis. Nat Commun 8:14179
Corbo, Claudia; Molinaro, Roberto; Tabatabaei, Mateen et al. (2017) Personalized protein corona on nanoparticles and its clinical implications. Biomater Sci 5:378-387
Shi, Jinjun; Kantoff, Philip W; Wooster, Richard et al. (2017) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17:20-37
Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:
Bertrand, Nicolas; Grenier, Philippe; Mahmoudi, Morteza et al. (2017) Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics. Nat Commun 8:777
Behzadi, Shahed; Serpooshan, Vahid; Tao, Wei et al. (2017) Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev 46:4218-4244

Showing the most recent 10 out of 170 publications