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.
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.
|Corbo, Claudia; Molinaro, Roberto; Tabatabaei, Mateen et al. (2017) Personalized protein corona on nanoparticles and its clinical implications. Biomater Sci 5:378-387|
|Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906|
|Mou, Haiwei; Smith, Jordan L; Peng, Lingtao et al. (2017) CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion. Genome Biol 18:108|
|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:|
|Mitchell, Michael J; Webster, Jamie; Chung, Amanda et al. (2017) Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis. Nat Commun 8:14179|
|Shi, Jinjun; Kantoff, Philip W; Wooster, Richard et al. (2017) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17:20-37|
|Quadir, Mohiuddin A; Morton, Stephen W; Mensah, Lawrence B et al. (2017) Ligand-decorated click polypeptide derived nanoparticles for targeted drug delivery applications. Nanomedicine 13:1797-1808|
|Doloff, Joshua C; Veiseh, Omid; Vegas, Arturo J et al. (2017) Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nat Mater 16:671-680|
|Behzadi, Shahed; Serpooshan, Vahid; Tao, Wei et al. (2017) Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev 46:4218-4244|
|Rowlands, Christopher J; Park, Demian; Bruns, Oliver T et al. (2017) Wide-field three-photon excitation in biological samples. Light Sci Appl 6:e16255|
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