Combinatorial therapy for triple negative breast cancer and the effect of nanoscale surfaces

Combinatorial;nanosurface;triple negative breast cancer;carbon nanoparticles;therapy

Kampert, Taylor ; Pan ; Dipanjan

关键词: Combinatorial;    nanosurface;    triple negative breast cancer;    carbon nanoparticles;    therapy;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/101367/KAMPERT-THESIS-2018.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

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, wedemonstratethat phenotypicallystratified carbon nanoparticleishighlyeffectiveindeliveringanovel combinatorialtripledrugformulationforsynergisticregressionofTNBC 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 combinationwasestablishedinapanel 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 parentdrugswithacombinatorialindex< 1in majorityoftheTNBC 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, acombinationofclathrinmediated,energyanddynamindependentpathwayswere predominantforsulfonatednanoparticles,whereas pristineand phospholipidparticles followed all the investigated endocytic pathways. Anexactitude‘omics’approachhelpstopredictthatphospholipid encapsulated-particleswillpredominantlyaccumulateinTNBCcomprisingthedrug ‘cocktail’. Thus, our efforts might generate a novel triple drug combination as an answer to current TNBC related shortcomings.