Phenotypically Screened Carbon Nanoparticles for Enhanced Combinatorial Therapy in Triple Negative Breast Cancer
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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.
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 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.
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.
- 2.Andersson, B. S., M. Beran, M. Bakic, L. E. Silberman, R. A. Newman, and L. A. Zwelling. In vitro toxicity and DNA cleaving capacity of benzisoquinonlinedione (nafimide; NSC 308847) in human leukemia. Cancer Res. 1987:47, 1040.Google Scholar
- 4.Brana, M. F., and A. M. Sanz. Synthesis and cytostatic activity of benz[de]isoqinolin-1,3-diones. Structure-activity relationships. Eur. J. Med. Chem. 16:207, 1981.Google Scholar
- 10.Cho, E. C., J. W. Xie, P. A. Wurm, and Y. N. Xia. Understanding the role of surface charges in cellular adsorption versus internalization by selectively removing gold nanoparticles on the cell surface with I2/KI etchant. Nano Lett. 2009:9, 1080.Google Scholar
- 12.Crown, J., J. O’Shaughnessy, and G. Gullo. Emerging targeted therapies in triple-negative breast cancer. Ann. Oncol. 23(vi5):6, 2012.Google Scholar
- 19.He, H., L. A. Pham-Huy, P. Dramou, D. Xiao, P. Zuo, and C. Pham-Huy. Carbon nanotubes: applications in pharmacy and medicine. BioMed Res. Int., 2013Google Scholar
- 21.Kim, J. S., T. J. Yoon, K. N. Yu, M. S. Noh, M. Woo, B. G. Kim, K. H. Lee, B. H. Sohn, S. B. Park, J. K. Lee, and M. H. Cho. Selective targeting of gold nanorods at the mitochondria of cancer cells: implications of cancer therapy. J. Vet. Sci. 11:772, 2006.Google Scholar
- 23.Kostarelos, K., L. Lacerda, G. Pastorin, W. Wi, S. Wieckowski, J. Luangsivilay, S. Godefroy, D. Pantarotto, J. P. Briand, S. Muller, M. Prato, and A. Bianco. Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell type. Nat. Nanotechnol. 2:108, 2007.CrossRefGoogle Scholar
- 29.Madani, S. Y., N. Naderi, O. Dissanayake, A. Tan, and A. M. Seifalian. A new era of cancer treatmemt: carbon nanotubes as drug delivery tools. Int. J. Nanomed. 6:2963–2979, 2011.Google Scholar
- 30.Matsumura, Y., and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agents smancs. Cancer Res. 46:6387, 1986.Google Scholar
- 32.Michael, M. D., B. C. Christopher, B. Jessica, S. Kelly, W. Linda, S. K. Gary, F. Vita, G. David, G. Robert, and H. Chris. Optimized high-throughtput microRNA expression profiling provides novel biomarker assessment of clinical prostrate and breast cancer biopsies. Mol. Cancer 5:24, 2006.CrossRefGoogle Scholar
- 34.Misra, S. K., J. Kus, S. Kim, and D. Pan. Nanoscopic poly-DNA-cleaver for breast cancer regression with induced oxidative damage. Mol. Pharm. 2014:33, 1976.Google Scholar
- 40.Mukherjee, P., S. K. Misra, M. C. Gryka, H.-H. Chang, S. Tiwari, W. L. Wilson, J. W. Scott, R. Bhargava, and D. Pan. Tunable luminescent carbon nanospheres with well-defined nanoscale chemistry for synchronized imaging and therapy. Small 36:4691, 2016.Google Scholar
- 58.Ye, T., Y. Xiong, Y. Yan, Y. Xia, X. Song, L. Liu, D. Li, N. Wang, L. Zhang, Y. Zhu, J. Zeng, Y. Wei, and L. Yu. Comparison of RNA-Seq and microarray in transcriptome profiling of activated T cells. PLoS ONE 9:P1, 2014.Google Scholar