title: Rationally Designed 2-in-1 Nanoparticles Can Overcome Adaptive Resistance in Cancer.
abstract: 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.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, United States.|Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.|Harvard Digestive Diseases Center , Boston, Massachusetts 02115, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goldman
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, United States.|Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Department of Applied Mathematics, University of Waterloo , Waterloo, ON N2L 3G1, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kohandel
authors.affiliation: India Innovation Research Center, Invictus Oncology, New Delhi 92, India.
authors.forename: Prithvi
authors.initials: P
authors.lastname: Pandey
authors.affiliation: Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.
authors.forename: Poornima
authors.initials: P
authors.lastname: Rao
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Natarajan
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Venkata
authors.initials: V
authors.lastname: Sabbisetti
authors.affiliation: Department of Medicine, Harvard Medical School , Boston, Massachusetts 02115, United States.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, United States.|Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, United States.|Dana Farber Cancer Institute , Boston, Massachusetts 02115, United States.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D050997:Nanomedicine; D053758:Nanoparticles; D009369:Neoplasms
chemical_list: D000970:Antineoplastic Agents
keywords: drug delivery; drug resistance; nanotechnology; targeted therapy; tumor heterogeneity