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Title:Combinatorial therapy for triple negative breast cancer and the effect of nanoscale surfaces
Author(s):Kampert, Taylor
Advisor(s):Pan, Dipanjan
Department / Program:Bioengineering
Discipline:Bioengineering
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:M.S.
Genre:Thesis
Subject(s):Combinatorial
nanosurface
triple negative breast cancer
carbon nanoparticles
therapy
Abstract:Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer with urgent clinical need for effective therapies. Resistance to standard clinical therapies with metastatic TNBC pushed the researchers to explore combinatorial therapy regime. A combination of STAT-3 specific inhibitor, reported to act synergistically with metformin in reducing cell growth and inducing apoptosis in TNBCs and agents targeting DNA repair, can produce a new approach to TNBC therapy. Towards this aim, we have generated a combinatorial drug formulation comprising DNA damage repair agents, along with inhibitors for STAT-3 for an optimized effect. The combinatorial formulation includes nifuroxazide, a known STAT-3 inhibitor, and amonafide, an agent known to exert its effect through topoisomerase-II activation pathways. An additional incorporation of pentoxifylline, a methylxanthine derivative known for anti-metastatic effects in breast cancers, could further improve the efficiency. We used drug combination of nifuroxazide, amonafide and pentoxifylline in MDA-MB-231, HCC1806, HCC1143 and BT-549 TNBCs along with normal breast cells, MCF-7 and SkBr3, to find the combinatorial index of the drug cocktail. It was found that combination of pentoxifylline, nifuroxazide and amonafide resulted in a combinatorial index of 0.82 in HCC1806 cells. We also investigated the gene and protein expression effects exerted by combination of drugs responsible to induce synergistic effect and simultaneously suppressing drug resistance through distinct mechanisms of action. Next, 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. The combinatorial formulation is comprised of repurposed inhibitors of STAT3 (nifuroxazide), topoisomerase-II-activation-pathway (amonafide) and NFb (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 indicated a remarkable five-fold improvement (IC50-6.75μM) 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. An exactitude ‘omics’ approach helps to predict that phospholipid encapsulated-particles will predominantly accumulate in TNBC comprising the drug ‘cocktail’. Thus, our efforts might generate a novel triple drug combination as an answer to current TNBC related shortcomings.
Issue Date:2018-04-25
Type:Thesis
URI:http://hdl.handle.net/2142/101367
Rights Information:Copyright 2018 Taylor Kampert
Date Available in IDEALS:2018-09-04
Date Deposited:2018-05


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