Research Highlight


Figure: OVCAR-5 cells in 3D static culture (A). OVCAR-5 cells cultured under flow in microfluidic platform (B) [1]. Expression of EGFR in flow and non-flow models. EGFR expression is greatly upregulated in the flow model. (C). Graph shows the percent of viable area of tumor nodule in cells treated with carboplatin only, PDT only, and PDT+ carboplatin. The data supports the synergistic effect of PDT+ carboplatin on tumor nodules (D) [3]. Depiction of a PIC being irradiated with light (hv). (E). Combination of PDT/PIT+ chemotherapy has a promising outlook in treatment of ovarian cancer.

PDT and PIT with Chemotherapy for Treatment of 3D Ovarian Cancer Nodules Under Flow and Static Conditions

Metastases in ovarian cancer are associated with the poorest outcomes for patients. The cancer is able to spread to distant sites in the body by route of natural fluidic movement, resulting in aggressive disease that is hard to treat. A key biomarker in advanced ovarian cancer is the epidermal growth factor receptor (EGFR). Upregulation of EGFR has been shown in metastatic ovarian cancer with high proliferation and survival, and its effects on other factors enhance metastatic progression, resulting in poorer clinical outcome [1]. A microfluidic platform was developed to culture cells in 3D under flow conditions. The flow model showed an increase in EGFR expression when compared to the static culture, indicating a more aggressive phenotype. Photodynamic therapy (PDT) is a photochemical approach that uses a light-activated photosensitizer (PS) and illumination by an appropriate wavelength of light to induce cytotoxicity of target cells by formation of a reactive oxygen species, or singlet oxygen [2]. Combining a benzoporphyrin derivative (BPD) PS with an antibody creates a photo-immuno-conjugate (PIC) and thus initiates photo-immunotherapy (PIT). Specificity of killing is increased when PDT is performed with a PIC rather than a free photosensitizer. It is proven that the addition of chemotherapy drugs such as carboplatin to PIT greatly synergizes the anti-tumor and anti-metastatic effects of chemotherapeutics [3]. OVCAR5 cells will be cultured in 3D nodules to investigate the effects of PDT, PIT, and PIT with chemotherapeutics on ovarian cancer cells under flow and non-flow conditions. The cells will be fluorescently labeled with mCherry, which will indicate presence of cells upon imaging. PDT will be performed with free photosensitizer (BPD), and PIT with the BPD photosensitizer coupled with an antibody. The PIC/PIT will include chemotherapeutic drugs as well. The overarching goal is to use 3D tumor models to show the effect of PDT/PIT + chemotherapy as effective in the treatment of metastatic ovarian cancer. References 1. Rizvi, I., et al., Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules. Proceedings of the National Academy of Sciences, 2013. 110(22): p. E1974-E1983. 2. Celli, J.P., et al., Imaging and photodynamic therapy: mechanisms, monitoring, and optimization. Chemical reviews, 2010. 110(5): p. 2795-2838. 3. Rizvi, I., et al., Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer. Cancer research, 2010. 70(22): p. 9319-9328.

 

 


Trainee Research

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:

Radiotherapeutic synergism of thermogelling cisplatin-loaded polymers for cervical cancer treatment

Quantification of SPION accumulation in tumors using positive-contrast MRI

Codelivery of tumor suppressor mRNA and anti-cancer drug in cancer treatment

Pharmacokinetic analysis of changes in temozolomide distribution after antiangiogenic treatment of glioblastoma

Creating Animal Models of High-grade Serous Ovarian Cancer Cells

Co-delivery of protective substrate and chemotherapy drugs via lipid Bilayer Mesoporous Silica Nanoparticles

RHAMM splicing in multiple myeloma (MM) and its implications for immunotherapy

Nanoencapsulation of tyrosine kinase inhibitors and their effects on pathway inhibition

Assessment of Atherosclerotic Changes using Ferumoxytol as MRI Contrast Agent

T1-weighted imaging of primary pancreatic adenocarcinoma using magnetic ferumoxytol nanoparticles

Radiation enhancement in cancer cells using gold and gadolinium nanoparticles

Development of PSMA-targeting nanoparticles for positron emitting tomography imaging in prostate cancer using animal models

Development of a novel nanogel for non-invasive transdermal delivery of cancer vaccines using hyaluronic acid

Uptake and localization of nanoparticles in prostate and lung cancer cells as a function of time and nanoparticle type

Detection of low-level mutations in DNA obtained from cancer patients, using PCR and nano-PCR

Synthesis of DFO-Lys(PEG30k)-Cys(Cy3) to examine macropinocytosis in human and mouse cancers in vitro

Small T Antigen Effect on Mitotic Proteins B-Myb and FOXM1

Nanomedicine for Safe Healing of Bone Trauma

Using smart biomaterials with immunoadjuvants to treat metastatic breast cancer

Identification of novel therapeutic targets of the Notch1 signaling pathway

Analysis of DREAM and E2F1 Competition for Cell Cycle Promoters during G1.

Assessing sufficiency of the Tip60/p400 complex in inducing transcription of Merkel Cell Polyomavirus Small T antigen target genes.

Combined delivery of targeted liposomal chemotherapeutics and photodynamic therapy to treat pancreatic cancer

Quantitative Multimodal Imaging of Tumor Response to Radiation

Software with built-in neuroanatomy atlas provides insight into cancer treatment


Soleil Doggett (Biology, '16) talks to her fellow peers about her research on oxygenating tumors to stimulate the anti-tumor immune response.

 


Trainee e-portfolios

Photo credit: Tom Kates Photography

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!


Trainee Publications

Our Trainees have published 22 peer-reviewed since January 2015.  A full list of Trainee publications is found below.

  1. Patrick Sheedy, Zdravka Medarova. The fundamental role of miR-10b in metastatic cancer. Am J Cancer Res 2018;8(9):1674-1688. Link
  2. 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
  3. 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
  4. Application of the BLADE Sequence in Upper Abdominal MR Imaging. Krebill C.  Radiol Technol. 2018 May;89(5):495-497. PMID:29793909 Link
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Yoo B, Ann-Marie, Billig, Medarova Z. “Guidelines for Rational Cancer Therapeutics. Frontiers in Oncology Journal”. Front Oncol. 2017 Dec 12;7:310. PMC5732930
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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