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Phenotypically Screened Carbon Nanoparticles for Enhanced Combinatorial Therapy in Triple Negative Breast Cancer

Abstract

Introduction

Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer with high resistance to current standard therapies. We demonstrate that phenotypically stratified carbon nanoparticle is highly effective in delivering a novel combinatorial triple drug formulation for synergistic regression of TNBC in vitro and in vivo.

Method

The combinatorial formulation is comprised of repurposed inhibitors of STAT3 (nifuroxazide), topoisomerase-II-activation-pathway (amonafide) and NFκb (pentoxifylline). Synergistic effect of drug combination was established in a panel of TNBC-lines comprising mesenchymal-stem-like, mesenchymal and basal-like cells along with non-TNBC-cells. The delivery of combinatorial drug formulation was achieved using a phenotypically screened carbon nanoparticles for TNBC cell lines.

Results

Results indicated a remarkable five-fold improvement (IC50-6.75 µM) from the parent drugs with a combinatorial index <1 in majority of the TNBC cells. Multi-compartmental carbon nanoparticles were then parametrically assessed based on size, charge (positive/negative/neutral) and chemistry (functionalities) to study their likelihood of crossing endocytic barriers from phenotypical standpoint in TNBC lines. Interestingly, a combination of clathrin mediated, energy and dynamin dependent pathways were predominant for sulfonated nanoparticles, whereas pristine and phospholipid particles followed all the investigated endocytic pathways.

Conclusions

An exactitude ‘omics’ approach helps to predict that phospholipid encapsulated-particles will predominantly accumulate in TNBC comprising the drug-‘cocktail’. We investigated the protein expression effects inducing synergistic effect and simultaneously suppressing drug resistance through distinct mechanisms of action.

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Acknowledgments

Materials characterizations were done at Frederick Seitz Materials Research Laboratory, UIUC. We would like to thank Fatemeh Ostadhossein and Enrique Daza for help with the biodegradability studies.

Funding

Funding from UIUC, National Science Foundation, Michael Reese Foundation and Children’s Discovery Institute are acknowledged.

Conflict of Interest

Prof. Pan has received research grants from NIH, NSF, American Heart Association, Children’s Discovery Institute, Michael Reese Foundation and other agencies. Prof. Pan is the founder or co-founder of three start-up companies. None of these entities supported this research. Taylor Kampert, Indrajit Srivastava and Santosh Misra declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Correspondence to Dipanjan Pan.

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Prof. Dipanjan Pan, MS, PhD, is a recognized expert in nanomedicine, molecular imaging and drug delivery. He is an Associate Professor in Bioengineering and Materials Science and Engineering and Institute of Sustainability in Energy and Environment in University of Illinois, Urbana-Champaign. He holds a full faculty position with Beckman Institute for Advanced Science and Technology, University of Illinois Cancer Center and Carle Foundation Hospital. Administratively he directs the Professional Masters in Engineering Program in Bioengineering in the College of Engineering. He is also a course director for the newly founded engineering inspired medical school at the University of Illinois. Prior to coming to Illinois, he was an Assistant Professor in Medicine, Research in Washington University School of Medicine, St Louis. His research is highly collaborative and interdisciplinary centering on the development of novel materials for biomedical applications and targeted therapies for stem-like cancer cell and phenotypically screened nanomedicine platforms. Over the years, this research has resulted in more than 100 high impact peer reviewed publications in scientific journals, numerous conference abstracts and has been supported by external funding from NIH, NSF, DoD, American Heart Association and other sources. Prof. Pan edited and co-written two books published from Taylor and Francis (Nanomedicine: A Soft Matter Perspective, ISBN-13: 978-1466572829) and Springer (Personalized Medicine with a Nanochemistry Twist: Nanomedicine (Topics in Medicinal Chemistry, ISBN-13: 978-3319335445). He holds multiple patents, several ongoing clinical trials and is the founder of three University based early start-ups. He is the CEO/President for a biotechnology start-up Vitruvian Biotech dedicated to develop novel image guided therapies. He also co-founded InnSight Technologies dedicated to nanotechnology based application for ocular diseases. His other company Kalocyte, which he cofounded with his clinical collaborators, develops oxygen therapeutics. Technology developed in his laboratories has been licensed for commercial development multiple times. He serves frequently as study section review board member for NIH, CDMRP (DoD) and multiple review committee member for American Heart Association. In 2016 he received Nano-Micro Letter (NML) Researcher award. He is an elected fellow of Royal Society of Chemistry, and a Fellow of American Heart Association. Professor Pan is an editorial board member of Scientific Reports (Nature Publishing) and an editorial advisory board member of Molecular Pharmaceutics (ACS)

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This article is part of the 2017 CMBE Young Innovators special issue.

Associate Editor Michael R. King oversaw the review of this article.

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Kampert, T., Misra, S.K., Srivastava, I. et al. Phenotypically Screened Carbon Nanoparticles for Enhanced Combinatorial Therapy in Triple Negative Breast Cancer. Cel. Mol. Bioeng. 10, 371–386 (2017). https://doi.org/10.1007/s12195-017-0490-y

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Keywords

  • Carbon Nanoparticles
  • Triple-negative Breast Cancer
  • Amonafide (AMF)
  • Nifuroxazide (NIFU)
  • TNBC Cells