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

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• 作者：Aaron Goldman ; Ashish Kulkarni ; Mohammad Kohandel ; Prithvi Pandey ; Poornima Rao ; Siva Kumar Natarajan ; Venkata Sabbisetti ; Shiladitya Sengupta
• 刊名：ACS Nano
• 出版年：2016
• 出版时间：June 28, 2016
• 年：2016
• 卷：10
• 期：6
• 页码：5823-5834
• 全文大小：700K
• 年卷期：0
• ISSN：1936-086X

文摘

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.