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Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture

Ja Hye Myung, Michael J. Eblan, Joseph M Caster, sinjung park, Michael J Poellmann, Kyle Wang, Joel E Tepper, Kevin A Tam, Seth M Miller, Colette Shen, Ronald C Chen, Tian Zhang, Bhishamjit Chera, Andrew Z Wang and Seungpyo Hong

Abstract

Purpose: We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in cancer patients undergoing radiotherapy (RT) treatment. Experimental Design: Patients with histologically confirmed primary carcinoma undergoing RT, with or without chemotherapy, were eligible for enrollment. Peripheral blood was collected prospectively at up to 5 time points, including prior to RT, at the first week, mid-point and final week of treatment, as well as 4 to 12 weeks after completion of RT. CTC capture was accomplished using a nanotechnology-based assay (CapioCyte) functionalized with aEpCAM, aHER-2, and aEGFR. Results: CapioCyte was able to detect CTCs in all 24 cancer patients enrolled. Multivalent binding via poly(amidoamine) dendrimers further improved capture sensitivity. We also showed that cell rolling effect can improve CTC capture specificity (% of captured cells that are CK+/CD45-/DAPI+) up to 38%. Among the 18 patients with sequential CTC measurements, the median CTC decreased from 113 CTCs/mL before RT to 32 CTCs/mL at completion of RT (p = 0.001). CTCs declined throughout RT in patients with complete clinical and/or radiographic response, in contrast to an elevation in CTCs at mid or post-RT in the 2 patients with known pathologic residual disease. Conclusions: Our study demonstrated that multivalent binding and cell rolling can improve the sensitivity and specificity of CTC capture compared to multivalent binding alone, allowing reliable monitoring of CTC changes during and after treatment.

  • Received October 17, 2017.

  • Revision received February 2, 2018.

  • Accepted March 8, 2018.

  • Copyright ©2018, American Association for Cancer Research.

doi: 10.1158/1078-0432.CCR-17-3078

Noncatalytic Endosialidase Enables Surface Capture of Small-Cell Lung Cancer Cells Utilizing Strong Dendrimer-Mediated Enzyme-Glycoprotein Interactions

Hao-jui Hsu†, Helena Palka-Hamblin‡, Gaurang P. Bhide‡, Ja-Hye Myung†, Michael Cheong†, Karen J. Colley*‡ , and Seungpyo Hong*†§∥ 

†Departments of Biopharmaceutical Sciences and ‡Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60612, United States

§ Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States

∥ Division of Integrated Science and Engineering, Underwood International College, Yonsei University, Seoul, Korea03706

Anal. Chem., 2018, 90 (6), pp 3670–3675

DOI: 10.1021/acs.analchem.8b00427

Publication Date (Web): February 23, 2018

Copyright © 2018 American Chemical Society

Abstract

Enumeration of circulating tumor cells (CTCs) of small-cell lung cancer (SCLC) patients has been shown to predict the disease progress and long-term survival. Most CTC detection methods rely on epithelial surface markers, such as epithelial cell adhesion molecule (EpCAM). However, this marker in SCLC is reported to be often downregulated after a variety of phenotypic changes, which impairs the reliability of EpCAM-based CTC detections. In this regard, the development of an alternative CTC detection method involving different CTC surface markers is in demand. In this study, we evaluated, for the first time to our knowledge, the feasibility of detecting SCLC CTCs using a noncatalytic endosialidase (EndoN Trap, EndoNt). This noncatalytic enzyme was chosen due to its high affinity to polysialic acid (polySia), a cell-surface glycan, that is highly expressed by SCLC tissue. Furthermore, this enzyme-based system was integrated into our dendrimer-mediated CTC capture platform to further enhance the capture efficiency via multivalent binding. We found that the EndoNt-immobilized surfaces could specifically capture polySia-positive SCLC cells and the binding between SCLC cells and EndoNt surfaces was further stabilized by dendrimer-mediated multivalent binding. When compared to the EpCAM-based capture, EndoNt significantly improved the capture efficiency of polySia-positive SCLC cells under flow due to its higher binding affinity (lower dissociation rate constants). These findings suggest that this enzyme-based CTC capture strategy has the potential to be used as a superior alternative to the commonly used EpCAM-based methods, particularly for those types of cancer that overexpress polySia.

DOI: 10.1021/acs.analchem.

Integration of biomimicry and nanotechnology for significantly improved detection of circulating tumor cells (CTCs)

 Myung JH1, Park SJ1, Wang AZ2, Hong S3.

1 Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, United States.

2 Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, United States.

3 Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, United States; Division of Integrated Science and Engineering, Underwood International College, Yonsei University, Seoul 03706, Republic of Korea. Electronic address: seungpyo.hong@wisc.edu.

Abstract

Circulating tumor cells (CTCs) have received a great deal of scientific and clinical attention as a biomarker for diagnosis and prognosis of many types of cancer. Given their potential significance in clinics, a variety of detection methods, utilizing the recent advances in nanotechnology and microfluidics, have been introduced in an effort of achieving clinically significant detection of CTCs. However, effective detection and isolation of CTCs still remain a tremendous challenge due to their extreme rarity and phenotypic heterogeneity. Among many approaches that are currently under development, this review paper focuses on a unique, promising approach that takes advantages of naturally occurring processes achievable through application of nanotechnology to realize significant improvement in sensitivity and specificity of CTC capture. We provide an overview of successful outcome of this biomimetic CTC capture system in detection of tumor cells from in vitro, in vivo, and clinical pilot studies. We also emphasize the clinical impact of CTCs as biomarkers in cancer diagnosis and predictive prognosis, which provides a cost-effective, minimally invasive method that potentially replaces or supplements existing methods such as imaging technologies and solid tissue biopsy. In addition, their potential prognostic values as treatment guidelines and that ultimately help to realize personalized therapy are discussed.

 

KEYWORDS:

Cell rolling; Circulating tumor cells (CTCs); Dendrimer; Liquid biopsy; Multivalent binding; Nanotechnology

 

PMID: 29247765 DOI: 10.1016/j.addr.2017.12.005

Effective Capture of Circulating Tumor Cells from a Transgenic Mouse Lung Cancer Model using Dendrimer Surfaces Immobilized with anti-EGFR

 Ja Hye Myung,1 Monic Roengvoraphoj,2 Kevin A. Tam,1 Tian Ma,3 Vincent A. Memoli,4 Ethan Dmitrovsky,2,3,5 Sarah J. Freemantle,3 and Seungpyo Hong1,6,*

 

1 Department of Biopharmaceutical Sciences, College of Pharmacy, The University of Illinois , Chicago, Illinois 60612, United States.

2 Department of Medicine, Dartmouth Hitchcock Medical Center , Lebanon, New Hampshire 03756, United States.

3 Departments of Thoracic/Head and Neck Medical Oncology and Cancer Biology, The University of Texas MD Anderson Cancer Center , Houston, Texas 77030, United States.

4 Integrated Science and Engineering Division, Underwood International College, Yonsei University , Incheon 406-840, Korea.



Abstract
The lack of an effective detection method for lung circulating tumor cells (CTCs) presents a substantial challenge to elucidate the value of CTCs as a diagnostic or prognostic indicator in lung cancer, particularly in nonsmall cell lung cancer (NSCLC). In this study, we prepared a capture surface exploiting strong multivalent binding mediated by poly(amidoamine) (PAMAM) dendrimers to capture CTCs originating from lung cancers. Given that 85% of the tumor cells from NSCLC patients overexpress epidermal growth factor receptor (EGFR), anti-EGFR was chosen as a capture agent. Following in vitro confirmation using the murine lung cancer cell lines (ED-1 and ED1-SC), cyclin E-overexpressing (CEO) transgenic mice were employed as an in vivo lung tumor model to assess specificity and sensitivity of the capture surface. The numbers of CTCs in blood from the CEO transgenic mice were significantly higher than those from the healthy controls (on average 75.3 ± 14.9 vs 4.4 ± 1.2 CTCs/100 μL of blood, p < 0.005), indicating the high sensitivity and specificity of our surface. Furthermore, we found that the capture surface also offers a simple, effective method for monitoring treatment responses, as observed by the significant decrease in the CTC numbers from the CEO mice upon a treatment using a novel anti-miR-31 locked nucleic acid (LNA), compared to a vehicle treatment and a control-LNA treatment (p < 0.05). This in vivo evaluation study confirms that our capture surface is highly efficient in detecting in vivo CTCs and thus has translational potential as a diagnostic and prognostic tool for lung cancer. 

 

PMID: 26312815 . PMCID: PMC4734638  DOI: 10.1021/acs.analchem.5b02766  Free PMC Article

Anal Chem. 2014 Jun 17;86(12):6088-94. doi: 10.1021/ac501243a. Epub 2014 Jun 3.

Differential detection of tumor cells using a combination of cell rolling, multivalent binding, and multiple antibodies.

Myung JH1, Gajjar KAChen JMolokie REHong S.

Author information

1 Department of Biopharmaceutical Sciences and §Department of Medicine, University of Illinois , Chicago, Illinois 60612, United States.

Abstract

Effective quantification and in situ identification of circulating tumor cells (CTCs) in blood are still elusive because of the extreme rarity and heterogeneity of the cells. In our previous studies, we developed a novel platform that captures tumor cells at significantly improved efficiency in vitro using a unique biomimetic combination of two physiological processes: E-selectin-induced cell rolling and poly(amidoamine) (PAMAM) dendrimer-mediated strong multivalent binding. Herein, we have engineered a novel multifunctional surface, on the basis of the biomimetic cell capture, through optimized incorporation of multiple antibodies directed to cancer cell-specific surface markers, such as epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor-2 (HER-2), and prostate specific antigen (PSA). The surfaces were tested using a series of tumor cells, MDA-PCa-2b, MCF-7, and MDA-MB-361, both in mixture in vitro and after being spiked into human blood. Our multifunctional surface demonstrated highly efficient capture of tumor cells in human blood, achieving up to 82% capture efficiency (∼10-fold enhancement than a surface with the antibodies alone) and up to 90% purity. Furthermore, the multipatterned antibodies allowed differential capturing of the tumor cells. These results support that our multifunctional surface has great potential as an effective platform that accommodates virtually any antibodies, which will likely lead to clinically significant, differential detection of CTCs that are rare and highly heterogeneous.

PMID: 24892731  PMCID: PMC4066911  DOI: 10.1021/ac501243a Free PMC Article

Langmuir. 2010 Jun 1;26(11):8589-96. doi: 10.1021/la904678p.

Enhanced tumor cell isolation by a biomimetic combination of E-selectin and anti-EpCAM: implications for the effective separation of circulating tumor cells (CTCs).

Myung JH1, Launiere CAEddington DTHong S.

Author information

1 Department of Biopharmaceutical Sciences, University of Illinois, Chicago, Illinois 60612, USA.

Abstract

The selective detection of circulating tumor cells (CTCs) is of significant clinical importance for the clinical diagnosis and prognosis of cancer metastasis. However, largely because of the extremely low number of CTCs (as low as 1 in 10(9) hematologic cells) in the blood of patients, effective detection and separation of the rare cells remain a tremendous challenge. Cell rolling is known to play a key role in physiological processes such as the recruitment of leukocytes to sites of inflammation and selectin-mediated CTC metastasis. Furthermore, because CTCs typically express the epithelial-cell adhesion molecule (EpCAM) on the surface whereas normal hematologic cells do not, substrates with immobilized antibody against EpCAM may specifically interact with CTCs. In this article, we created biomimetic surfaces functionalized with P- and E-selectin and anti-EpCAM that induce different responses in HL-60 (used as a model of leukocytes in this study) and MCF-7 (a model of CTCs) cells. HL-60 and MCF-7 cells showed different degrees of interaction with P-/E-selectin and anti-EpCAM at a shear stress of 0.32 dyn/cm(2). HL-60 cells exhibited rolling on P-selectin-immobilized substrates at a velocity of 2.26 +/- 0.28 microm/s whereas MCF-7 cells had no interaction with the surface. Both cell lines, however, had interactions with E-selectin, and the rolling velocity of MCF-7 cells (4.24 +/- 0.31 microm/s) was faster than that of HL-60 cells (2.12 +/- 0.15 microm/s). However, only MCF-7 cells interacted with anti-EpCAM-coated surfaces, forming stationary binding under flow. More importantly, the combination of the rolling (E-selectin) and stationary binding (anti-EpCAM) resulted in substantially enhanced separation capacity and capture efficiency (more than 3-fold enhancement), as compared to a surface functionalized solely with anti-EpCAM that has been commonly used for CTC capture. Our results indicate that cell-specific detection and separation may be achieved through mimicking the biological processes of combined dynamic cell rolling and stationary binding, which will likely lead to a CTC detection device with significantly enhanced specificity and sensitivity without a complex fabrication process.

PMID: 20155985 . PMCID: PMC2877147  DOI: 10.1021/la904678p Free PMC Article

Angew Chem Int Ed Engl. Author manuscript; available in PMC 2013 Jan 20.


Published in final edited form as:
Angew Chem Int Ed Engl. 2011 Dec 2; 50(49): 11769–11772.
Published online 2011 Oct 19. doi:  10.1002/anie.201105508


PMCID: PMC3549433    NIHMSID: NIHMS405685


Dendrimer-mediated Multivalent Binding for Enhanced Capture of Tumor Cells**


Ja Hye Myung, Khyati A. Gajjar, Jelena Saric, Prof. David T. Eddington, and Prof. Seungpyo Hong corresponding author

Ja Hye Myung, Department of Biopharmaceutical Sciences, University of Illinois at Chicago, 833 South Wood St., Room 335, Chicago, IL, 60612;

The publisher's final edited version of this article is available at Angew Chem Int Ed Engl

Multivalent binding, the simultaneous binding of multiple ligands to multiple receptors, has played a central role in a number of pathological processes, including the attachment of viral, parasitic, mycoplasmal, and bacterial pathogens.[1] These biological activities have been extensively investigated to promote targeting of specific cell types, [2] and biological multivalent inhibitors have yielded significant increases in binding avidities by 1–9 orders of magnitude.[3] In particular, nano-scale poly(amidoamine) (PAMAM) dendrimers have been reported to be an excellent mediator for facilitated multivalent effect due to their capability to pre-organize/orient ligands and easy deformability of the polymer chains.[2a] ...read more....

Publications List

  1. "Multivalent binding and biomimetic cell rolling improves the sensitivity and specificity of circulating tumor cell capture" Ja Hye Myung, Michael J. Eblan, Joseph M Caster, sinjung park, Michael J Poellmann, Kyle Wang, Joel E Tepper, Kevin A Tam, Seth M Miller, Colette Shen, Ronald C Chen, Tian Zhang, Bhishamjit Chera, Andrew Z Wang and Seungpyo Hong. doi: 10.1158/1078-0432.CCR-17-3078

  2. "Noncatalytic Endosialidase Enables Surface Capture of Small-Cell Lung Cancer Cells Utilizing Strong Dendrimer-Mediated Enzyme-Glycoprotein Interactions" Hao-jui Hsu†, Helena Palka-Hamblin‡, Gaurang P. Bhide‡, Ja-Hye Myung†, Michael Cheong†, Karen J. Colley*‡ , and Seungpyo Hong*†§∥. Anal. Chem., 2018, 90 (6), pp 3670–3675 DOI: 10.1021/acs.analchem.8b00427

  3. "Integration of biomimicry and nanotechnology for significantly improved detection of circulating tumor cells (CTCs)" Myung JH, Park SJ, Wang AZ, Hong S. Adv. Drug Deliv. Rev. (2017), https://doi.org/10.1016/j.addr.2017.12.005

  4. “Recent Advances in Nanotechnology-based Detection and Separation of Circulating Tumor Cells” J.H. Myung, K.A. Tam, S.-j. Park, A. Cha, and S. Hong*, WIREs Nanomedicine & Nanobiotechnology 2016, 8(2), 223-239. 

  5. “Microfluidic Devices to Enrich and Isolate Circulating Tumor Cells” J.H. Myung and S. Hong*, Lab on a Chip 2015, 15, 4500-4511.

  6. “Effective Capture of Circulating Tumor Cells from a Transgenic Mouse Lung Cancer Model using Dendrimer Surfaces Immobilized with anti-EGFR” J.H. Myung, M. Roengvoraphoj, K.A. Tam, T. Ma, V.A. Memoli, E. Dmitrovsky, S.J. Freemantle, and S. Hong*, Analytical Chemistry 2015, 87(19), 10096-100102.

  7. “Differential Detection of Tumor Cells using A Combination of Cell Rolling, Multivalent Binding, and Multiple Antibodies” J.H. Myung, K.A. Gajjar, J. Chen, R.E. Molokie, and S. Hong*, Analytical Chemistry 2014, 86(12), 6088-6094.

  8. “Epithelia-Mesenchymal Transition Enhances Nano-scale Actin Filament Dynamics of Ovarian Cancer Cells” S. Lee, Y. Yang, D. Fishman, M.M. Banaszak Holl, and S. Hong*, Journal of Physical Chemistry B 2013, 117(31), 9233-9240.

  9. “The Role of Polymers in Detection and Isolation of Circulating Tumor Cells” J.H. Myung, K.A. Gajjar, Y.E. Han, and S. Hong*, Polymer Chemistry 2012, 3(9), 2336-2341.

  10. “Channel Surface Patterning of Alternating Biomimetic Protein Combinations for Enhanced Microfluidic Tumor Cell Isolation” C.A. Launiere, M. Gaskill, G. Czaplewski, J.H. Myung, S. Hong, and D.T. Eddington*, Analytical Chemistry 2012, 84(9):4022-8.

  11. “Dendrimer-mediated Multivalent Binding for Enhanced Capture of Tumor Cells” J.H. Myung, K.A. Gajjar, J. Saric, D.T. Eddington, and S. Hong*, Angewandte Chemie International Edition 2011, 50(49), 11769-11772.

  12. “Rheologically Biomimetic Cell Suspensions for Decreased Cell Settling in Microfluidic Devices” C.A. Launiere, G.J. Czaplewski, J.H. Myung, S. Hong, and D.T. Eddington*, Biomedical Microdevices 2011, 13(3), 549-557.

  13. “Direct Measurements on CD24-Mediated Rolling of Human Breast Cancer MCF-7 Cells on E-selectin” J.H. Myung, K.A. Gajjar, R.M. Pearson, C.A. Launiere, D.T. Eddington, and S. Hong*, Analytical Chemistry 2011, 83(3), 1078-1083.

  14. “Enhanced Tumor Cell Isolation by a Biomimetic Combination of E-selectin and anti-EpCAM: Implication for Effective Separation of Circulating Tumor Cells (CTCs)” J.H. Myung, C.A. Launiere, D.T. Eddington, and S. Hong*, Langmuir 2010, 26(11), 8589-8596.