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

Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer. ACS Nano, 2016; DOI: 10.1021/acsnano.6b00320

Math, biology and nanotechnology are becoming strange, yet effective bed-fellows in the fight against cancer treatment resistance. Researchers have engineered a revolutionary new approach to cancer treatment that pits a lethal combination of drugs together into a single nano particle.

Math, biology and nanotechnology are becoming strange, yet effective bed-fellows in the fight against cancer treatment resistance. Researchers at the University of Waterloo and Harvard Medical School have engineered a revolutionary new approach to cancer treatment that pits a lethal combination of drugs together into a single nanoparticle. The approach the bioengineers took was to build a single nanoparticle, inspired by computer models, that exploit a technique known as supramolecular chemistry. This nanotechnology enables scientists to build cholesterol-tethered drugs together from “tetris-like” building blocks that self-assemble, incorporating multiple drugs into stable, individual nano-vehicles that target tumors through the leaky vasculature. This 2-in-1 strategy ensures that resistance to therapy never has a chance to develop, bringing together the right recipe to destroy surviving cancer cells. https://www.sciencedaily.com/releases/2016/06/160623150159.htm

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 anti tumorefficacy.

http://pubs.acs.org/doi/abs/10.1021/acsnano.6b00320