Research Highlight


Figure: Schematic of tri-block co-polymer gel (PLGA-PEG-PLGA) loaded with Cisplatin and BMN-673. The hydrophilic Cisplatin (orange circles) is held by the hydrophilic PEG regions (red lines) of the gel while the hydrophobic BMN-673 (blue stars) is held by the hydrophobic PLGA pockets (green lines). The dual nature of the gel allows for the potential to load both a hydrophobic drug and a hydrophilic drug. Source: (Qiao et al. 2005)

Use of a Triblock Copolymer Hydrogel for Controlled Release of Cisplatin and BMN-673

This project is working toward the optimization of the treatment of cervical cancer by using the chemotherapy drug, and known radiosensitizer, Cisplatin in conjunction with radiation therapy and PARP inhibitor BMN-673 in a novel manner. Cisplatin is generally administered to patients systemically, resulting in devastating side effects to the patient, including vomiting, hair loss, and nausea. The radiosensitizing effects of Cisplatin are not tissue specific, and as a result, the negative side effects of systemic radiation on healthy tissues can also be devastating for patients. Working in collaboration with Northeastern University, the Dana Farber Cancer Institute, and the Brigham and Women’s Hospital, I will be experimenting with a biologically engineered hydrogel designed to hold a dose of Cisplatin that will be injected into a tumor in the same clinical procedure as brachytherapy so that Cisplatin is delivered to the tumor with minimal harm to healthy tissues in the body. The hydrogel involved in our testing will be a tri-block co-polymer made up of PLGA-PEG-PLGA. The hydrophobic and hydrophilic pocketing of the gel affords us with the opportunity to also experiment with the incorporation of hydrophobic PARP inhibitor BMN-673 as a second drug to be loaded in the gel with hydrophilic Cisplatin. Previous research with this hydrogel as a drug delivering agent has shown that it is non-toxic, biodegradable, capable of gelling at body temperature, and also, capable of drug release over a two week period with optimal release in the first 72 hours. Moving forward with this project I will be working with the hydrogel in vitro and in vivo to characterize and attempt to optimize its effectiveness in Cisplatin uptake and targeted, sustained delivery. Methods for evaluating the hydrogel performance will include evaluating its ability to provide prolonged release of Cisplatin/BMN-673, its capacity to be biodegradable, how thoroughly drugs are released throughout the tumor, and the amount tumor reduction in hydrogel-treated mice as compared to other treatments and a control.

 

 

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

Enhanced delivery of camptothecin and doxorubicin conjugates with hyaluronic acid for the treatment of Glioblastoma using microbubble-mediated focused ultrasound

Integrated diffraction-based diagnostic for point-of-care screening

Investigating the use of Feraheme to monitor the immune response by PET in general inflammation and specific immune cell populations

Protein-encapsulated nanoparticles for oral delivery of anti-mitotic agents in prostate cancer

Combined Cisplatin and Olaparib nanoparticles for ovarian cancer therapy

Nanoparticle-aided radio-immunotherapy

Assessment of Atherosclerotic Changes using Ferumoxytol as MRI Contrast Agent

Identifying genomic and compound dependencies in undifferentiated sarcomas

Use of CT Texture Analysis for Characterization and Prognostication of Incidental Adnexal Lesions

Optimization of macrophage-targeted nanoparticles for positron emission tomography imaging in cancer

Mechanistic and modeling studies of lipid nanoemulsions impact on oral lapatinib absorption

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

Expression of anti-apoptotic proteins in pancreatic cancers: A potential barrier to photodynamic killing

Implementation of novel MR-based attenuation correction in PET/MR pelvic scans

In vivo imaging of targeted drug delivery to HER2 positive cancer cells

Surface-targeting, ligand-switching nanoparticles for mitochondrial drug delivery in prostate cancer

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

Nanomedicine for Safe Healing of Bone Trauma

Discovering the Genetic Mechanism of Enhanced Metastatic Colonization in SMAD4 Mutant Tumors

Assessing the reproducibility of MRI-based brain tumor measurements between both observers and MRI vendors

Development of Smart INCeRT Brachytherapy Spacers via PLGA and Docetaxel for Combined Chemo-Radiation Therapies in Prostate Cancer

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

Tracking pancreatic adenocarcinoma response to treatment using targeted, multi-modal nanoparticles

Iron-chelating PEG-like nanoprobes as therapeutic and 89Zr/PET imaging agents

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