TY - JOUR
T1 - Phenotypically Screened Carbon Nanoparticles for Enhanced Combinatorial Therapy in Triple Negative Breast Cancer
AU - Kampert, Taylor
AU - Misra, Santosh K.
AU - Srivastava, Indrajit
AU - Tripathi, Indu
AU - Pan, Dipanjan
N1 - Funding Information:
Funding from UIUC, National Science Foundation, Michael Reese Foundation and Children’s Discovery Institute are acknowledged.
Funding Information:
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.
Funding Information:
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).
Publisher Copyright:
© 2017, Biomedical Engineering Society.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019953557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019953557&partnerID=8YFLogxK
U2 - 10.1007/s12195-017-0490-y
DO - 10.1007/s12195-017-0490-y
M3 - Article
C2 - 31719869
AN - SCOPUS:85019953557
VL - 10
SP - 371
EP - 386
JO - Cellular and Molecular Bioengineering
JF - Cellular and Molecular Bioengineering
SN - 1865-5025
IS - 5
ER -