Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer

被引:69
作者
Goldman, Aaron [1 ,2 ,3 ,4 ]
Kulkarni, Ashish [1 ,2 ,3 ]
Kohandel, Mohammad [5 ]
Pandey, Prithvi [6 ]
Rao, Poornima [3 ]
Natarajan, Siva Kumar [1 ]
Sabbisetti, Venkata [1 ]
Sengupta, Shiladitya [1 ,2 ,3 ,7 ]
机构
[1] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[2] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA
[3] Brigham & Womens Hosp, Dept Med, Div Biomed Engn, 75 Francis St, Boston, MA 02115 USA
[4] Harvard Digest Dis Ctr, Boston, MA 02115 USA
[5] Univ Waterloo, Dept Appl Math, Waterloo, ON N2L 3G1, Canada
[6] India Innovat Res Ctr, Invictus Oncol, New Delhi 92, India
[7] Dana Farber Canc Inst, Boston, MA 02115 USA
关键词
drug resistance; tumor heterogeneity; nanotechnology; drug delivery; targeted therapy; BREAST-CANCER; ANTITUMOR EFFICACY; ANTICANCER DRUGS; DELIVERY-SYSTEM; CO-DELIVERY; IN-VITRO; CELLS; CHEMOTHERAPY; COMBINATION; CISPLATIN;
D O I
10.1021/acsnano.6b00320
中图分类号
O6 [化学];
学科分类号
070301 [无机化学];
摘要
The development of resistance is the major cause of mortality in cancer. Combination chemotherapy is used clinically to reduce the probability of evolution of resistance. A similar trend toward the use of combinations of drugs is also emerging in the application of cancer nanomedicine. However, should a combination of two drugs be delivered from a single nanoparticle or should they be delivered in two different nanoparticles for maximal efficacy? We explored these questions in the context of adaptive resistance, which emerges as a phenotypic response of cancer cells to chemotherapy. We studied the phenotypic dynamics of breast cancer cells under cytotoxic chemotherapeutic stress and analyzed the data using a phenomenological mathematical model. We demonstrate that cancer cells can develop adaptive resistance by entering into a predetermined transitional trajectory that leads to phenocopies of inherently chemoresistant cancer cells. Disrupting this deterministic program requires a unique combination of inhibitors and cytotoxic agents. Using two such combinations, we demonstrate that a 2-in-1 nanomedicine can induce greater antitumor efficacy by ensuring that the origins of adaptive resistance are terminated by deterministic spatially constrained delivery of both drugs to the target cells. In contrast, a combination of free-form drugs or two nanoparticles, each carrying a single payload, is less effective, arising from a stochastic distribution to cells. These findings suggest that 2-in-1 nanomedicines could emerge as an important strategy for targeting adaptive resistance, resulting in increased antitumor efficacy.
引用
收藏
页码:5823 / 5834
页数:12
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