Journal
ACS NANO
Volume 10, Issue 6, Pages 5823-5834Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.6b00320
Keywords
drug resistance; tumor heterogeneity; nanotechnology; drug delivery; targeted therapy
Categories
Funding
- DoD BCRP Collaborative Innovator Grant [W81XWH-09-1-0700]
- NIH [1R01CA135242-01A2]
- DoD Breakthrough Award [BC132168]
- American Lung Association Innovation Award [LCD-259932-N]
- IUSSTF
- American Cancer Society [122854-PF-12-226-01-CDD]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available