More than 50% of cancer patients receive radiation therapy at some point during their care. Previous and ongoing studies have demonstrated that metallic nanoparticles like gold nanoparticles, can amplify the radiation dose by facilitating the ejection of low-energy (short range) photoelectrons. This radiation enhancement leads to increased DNA double strand breaks (DSBs) in nearby cells. When molecular targeting methods are employed, the increased DNA damage can be confined to specific subpopulations (e.g. cancer cells, tumor vasculature, etc.). Single strand breaks (SSBs) are normally repaired by base excision repair (BER). Poly ADP ribose polymerase (PARP) is a key component of BER and PARP inhibition leads, therefore, to persistence of SSBs. A replication fork may encounter a persistent SSB during DNA replication, which causes the replication fork to collapse or the formation of a double strand break. Previous studies have shown that agents such as PARP inhibitors (PARPi) can inhibit and prevent the repair of DNA double strand breaks caused by radiation damage. By inhibiting DSB repair, PARPi can amplify the effects of radiation therapy. My project will explore a strategy to combine the radiosensitizing ability of gold nanoparticles (AuNPs) in synergy with the DNA-repair inhibiting ability of PARPi. The hypothesis is that combining these treatments will lead to a greater therapeutic effect than each alone. To test this hypothesis, I will a) synthesize a liposomal formulation encapsulating functionalized gold nanoparticles in the aqueous core and PARPi in the lipid bilayer of the liposomes (Figure 1), b) characterize and test their in vitro efficacy in non-small cell lung cancer (NSCLC) cell line Calu 6, and c) evaluate the in vivo benefit of combined PARP inhibition and nanoparticle-amplified radiation therapy in mouse models of lung cancer. Standard assays to evaluate the cytotoxity (MTT), cell proliferation (clonogenic survival) and DNA double strand break (gamma-H2aX staining) will be carried out.
CaNCURE provides trainees with a 6-month hands-on research experience and one-on-one mentoring by leading researchers in cancer nanomedicine. Projects performed by current and past participants include:
While on co-op, trainees document their research in an e-portfolio. This gives trainees the opportunity to provide regular updates on their research progress, reflect on training they are receiving, and explain how their research fits within the field of cancer nanomedicine. These research e-portfolios can be accessed through individual trainee profiles. The complete collection may be found here.
Presentation at CaNCURE Nanomedicine Day
At the completion of their co-op, trainees are provided with the opportunity to present their research to a wider audience. For our June CaNCURE Nanomedicine Day, trainees prepare interactive, digital posters to display on electronic poster boards. Over 100 faculty, students, and researchers attend this annual event!
Check out the news article about our first CaNCURE Day!
Our Trainees have published 22 peer-reviewed since January 2015. A full list of Trainee publications is found below.
- Patrick Sheedy, Zdravka Medarova. The fundamental role of miR-10b in metastatic cancer. Am J Cancer Res 2018;8(9):1674-1688. Link
- Chen X, Ling X, Zhao L, Xiong F, Hollett G, Kang Y, Barrett A, Wu J. “Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultrahigh Paclitaxel Payloads for Specific and Robust Chemotherapy.” ACS Appl Mater Interfaces. 2018 Sep 25. doi: 10.1021/acsami.8b11571. PMID: 30203956 Link
- Hedgire S, Krebill C, Wojtkiewicz GR, Oliveira I, Ghoshhajra BB, Hoffmann U, Harisinghani MG. “Ultrasmall superparamagnetic iron oxide nanoparticle uptake as noninvasive marker of aortic wall inflammation on MRI: proof of concept study.” Br J Radiol. 2018 Sep 12:20180461. doi: 10.1259/bjr.20180461. PMID: 30160173 Link
- Application of the BLADE Sequence in Upper Abdominal MR Imaging. Krebill C. Radiol Technol. 2018 May;89(5):495-497. PMID:29793909 Link
- Torrado-Carvajal A, Vera-Olmos J, Izquierdo-Garcia D1, Catalano OA, Morales MA, Margolin J, Soricelli A, Salvatore M, Malpica N, Catana C1. Dixon-VIBE Deep Learning (DIVIDE) Pseudo-CT Synthesis for Pelvis PET/MR Attenuation Correction. J Nucl Med. 2018 Aug 30. pii: jnumed.118.209288. doi: 10.2967/jnumed.118.209288. PMID: 30166357 Link
- Xiaoyuan Ji, Jie Wang, Lin Mei, Wei Tao, Austin Barrett, Zhiguo Su, Shaomin Wang. Guanghui Ma, Jinjun Shi, Songping Zhang. Artificial Photosynthesis: Porphyrin/SiO2 /Cp*Rh(bpy)Cl Hybrid Nanoparticles Mimicking Chloroplast with Enhanced Electronic Energy Transfer for Biocatalyzed Artificial Photosynthesis. Advanced Functional Materials. Link
- Yang KS, Im H, Hong S, Pergolini I, Del Castillo AF, Wang R, Clardy S, Huang CH, Craig Pille, Ferrone, Yang R, Castro CM, Lee H, Del Castillo CF, Weissleder R. Multiparametric plasma EV profiling facilitates diagnosis of pancreatic malignancy. Sci Transl Med. 2017; 9(391): eaal3226. PMC5846089
- Zhu X, Ji X, Kong N, Chen Y, Mahmoudi M, Xu X, Ding L, Tao W, Cai T, Li Y, Gan T, Austin Barrett, Bharwani Z, Chen H, Farokhzad OC. Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy. ACS Nano. 2018 Mar 27;12(3):2922-2938. PMC6097229
- Miller MA1, Kim E, Cuccarese MF, Alec Plotkin, Prytyskach M, Kohler RH, Pittet MJ, Weissleder R. “Near infrared imaging of Mer tyrosine kinase (MERTK) using MERi-SiR reveals tumor associated macrophage uptake in metastatic disease.” Chem Commun. 2017 Dec 19;54(1):42-45. PMC5736449
- Ding L, Zhu X, Wang Y, Shi B, Ling X, Chen H, Nan W, Austin Barrett, Guo Z, Tao W, Wu J, Shi X. “Intracellular Fate of Nanoparticles with Polydopamine Surface Engineering and a Novel Strategy for Exocytosis-Inhibiting, Lysosome Impairment-Based Cancer Therapy”. Nano Lett. 2017 Nov 8;17(11):6790-6801. PMC6071871
- Yoo B, Ann-Marie, Billig, Medarova Z. “Guidelines for Rational Cancer Therapeutics. Frontiers in Oncology Journal”. Front Oncol. 2017 Dec 12;7:310. PMC5732930
- Gharagouzloo C, Timms L, Qiao J, Fang Z, Joseph Nneji, Pandya A, Kulkarni P, van de Ven AL, Ferris C, Sridhar S. “Neural circuits and brain function: New insights using quantitative vascular mapping of the rat.” Neuroimage, 2017. 16C:24-33 PMC5824692
- Gharagouzloo C, Timms L, Qiao J, Fang Z, Joseph Nneji, Pandya A, Kulkarni P, van de Ven AL, Ferris C, Sridhar S. “Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge”. Data in Brief, 2018. 17:393-396. Link
- Qin L, Li A, Qu J, Reinshagen K, Li X, Cheng S, Annie Bryant, Young GS. Normalization of ADC does not improve correlation with overall survival in patients with high-grade glioma (HGG). J Neurooncol. 2018 Apr;137(2):313-319. PMC6071871
- Belz J, Kumar R, Baldwin P, Noelle Castilla Ojo, Leal AS, Royce DB, Di Zhang D, van de Ven AL, Liby K, Sridhar S. “Sustained-release Talazoparib implants for localized treatment of BRCA1-deficient breast cancer”. Theranostics, 7(17): 4340-4349. PMC5695017
- Qin L, Li X, Amanda Stroiney, Qu J, Helgager J, Reardon DA, Young GS. “Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma.” 2017 Feb;59(2):135-145. PMC6097616
- Jodi Belz, Noelle Castilla Ojo,Srinivas Sridhar, Rajiv Kumar. Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer, In Cancer Nanotechnology. Reema Zeineldin (Ed). Series: Methods in Molecular Biology. Springer Press. Methods Mol Biol. 2017; 1530:403-409. PMC5531609
- Christian Berrios, Megha Padi, Mark A. Keibler, Donglim Esther Park, Vadim Molla, Gregory Stephanopoulos, John Quackenbush, James A. DeCaprio. “Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation”. 2016 Nov 23;12(11):e1006020. PMC5120958
- Song C, Liu Y, Rachel Fontana, Makrigiorgos A, Mamon H, Kulke MH, G. Mike Makrigiorgos. “Elimination of unaltered DNA in mixed clinical samples via nuclease-assisted minor-allele enrichment”. 2016 Nov 2;44(19):e146. PMC5100565
- Andrew L. Hong, Yuen-Yi Tseng, Glenn S. Cowley, Oliver Jonas, Jaime H. Cheah, Bryan D. Kynnap, Mihir B. Doshi, Coyin Oh, Stephanie C. Meyer, Alanna J. Church, Shubhroz Gill, Craig M. Bielski, Paula Keskula, Alma Imamovic, Sara Howell, Gregory V. Kryukov, Paul A. Clemons, Aviad Tsherniak, Francisca Vazquez, Brian D. Crompton, Alykhan F. Shamji, Carlos Rodriguez-Galindo, Katherine A. Janeway, Charles W. M. Roberts, Kimberly Stegmaier, Paul van Hummelen, Michael J. Cima, Robert S. Langer, Levi A. Garraway, Stuart L. Schreiber, David E. Root, William C. Hahn, & Jesse S. Boehm. “Integrated genetic and pharmacologic interrogation of rare cancers”. Nat Commun. 2016 Jun 22;7:11987. PMC4917959
- Wang P, Yoo B, Sherman S, Mukherjee P, Ross A, Pantazopoulos P, Petkova V, Farrar C, Medarova Z, Moore A. “Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer.” Int J Cancer. 2016 Aug 1;139(3):712-8. PMCID: PMC4925171
- Nazila Kamaly, Gabrielle Fredman, Jhalique J. Fojas, Manikandan Subramanian, Won II Choi, Katherine Zepeda, Cristian Vilos, Mikyung Yu, Suresh Gadde, Jun Wu, Jaclyn Milton, Renata Leitao, Livia Rosa, Moaraj Hasan, Huayi Gao, Vance Nguyen, Jordan Harris, Ira Tabas, and Omid C. Farokhzad. “Interleukin-10 Targeted Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis”. ACS Nano. 2016 May 24;10(5):5280-92. PMC5199136