title: Mechanism-independent optimization of combinatorial nanodiamond and unmodified drug delivery using a phenotypically driven platform technology.
abstract: Combination chemotherapy can mediate drug synergy to improve treatment efficacy against a broad spectrum of cancers. However, conventional multidrug regimens are often additively determined, which have long been believed to enable good cancer-killing efficiency but are insufficient to address the nonlinearity in dosing. Despite improved clinical outcomes by combination treatment, multi-objective combination optimization, which takes into account tumor heterogeneity and balance of efficacy and toxicity, remains challenging given the sheer magnitude of the combinatorial dosing space. To enhance the properties of the therapeutic agents, the field of nanomedicine has realized novel drug delivery platforms that can enhance therapeutic efficacy and safety. However, optimal combination design that incorporates nanomedicine agents still faces the same hurdles as unmodified drug administration. The work reported here applied a powerful phenotypically driven platform, termed feedback system control (FSC), that systematically and rapidly converges upon a combination consisting of three nanodiamond-modified drugs and one unmodified drug that is simultaneously optimized for efficacy against multiple breast cancer cell lines and safety against multiple control cell lines. Specifically, the therapeutic window achieved from an optimally efficacious and safe nanomedicine combination was markedly higher compared to that of an optimized unmodified drug combination and nanodiamond monotherapy or unmodified drug administration. The phenotypically driven foundation of FSC implementation does not require any cellular signaling pathway data and innately accounts for population heterogeneity and nonlinear biological processes. Therefore, FSC is a broadly applicable platform for both nanotechnology-modified and unmodified therapeutic optimizations that represent a promising path toward phenotypic personalized medicine.
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Hann
authors.initials: H
authors.lastname: Wang
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Lee
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Kai-Yu
authors.initials: KY
authors.lastname: Chen
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Jing-Yao
authors.initials: JY
authors.lastname: Chen
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Kangyi
authors.initials: K
authors.lastname: Zhang
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Aleidy
authors.initials: A
authors.lastname: Silva
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Ho
authors.affiliation: †Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, ‡Division of Oral Biology and Medicine, School of Dentistry, §The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, ∥California NanoSystems Institute, ⊥Jonsson Comprehensive Cancer Center, #Department of Chemical and Biomolecular Engineering, and ¶Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Ho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D058612:Nanodiamonds / Q000737:chemistry*; D050997:Nanomedicine / Q000379:methods*; D010641:Phenotype; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D058612:Nanodiamonds
keywords: biocompatibility; breast cancer; drug delivery; nanodiamond; nanomedicine; optimization