title: Mechanistic modeling identifies drug-uptake history as predictor of tumor drug resistance and nano-carrier-mediated response.
abstract: A quantitative understanding of the advantages of nanoparticle-based drug delivery vis-à-vis conventional free drug chemotherapy has yet to be established for cancer or other diseases despite numerous investigations. Here, we employ first-principles cell biophysics, drug pharmaco-kinetics, and drug pharmaco-dynamics to model the delivery of doxorubicin (DOX) to hepatocellular carcinoma (HCC) tumor cells and predict the resultant experimental cytotoxicity data. The fundamental, mechanistic hypothesis of our mathematical model is that the integrated history of drug uptake by the cells over time of exposure, which sets the cell death rate parameter, and the uptake rate are the sole determinants of the dose response relationship. A universal solution of the model equations is capable of predicting the entire, nonlinear dose response of the cells to any drug concentration based on just two separate measurements of these cellular parameters. This analysis reveals that nanocarrier-mediated delivery overcomes resistance to the free drug because of improved cellular uptake rates, and that dose response curves to nanocarrier mediated drug delivery are equivalent to those for free-drug, but "shifted to the left;" that is, lower amounts of drug achieve the same cell kill. We then demonstrate the model's general applicability to different tumor and drug types, and cell-exposure time courses by investigating HCC cells exposed to cisplatin and 5-fluorouracil, breast cancer MCF-7 cells exposed to DOX, and pancreatic adenocarcinoma PANC-1 cells exposed to gemcitabine. The model will help in the optimal design of nanocarriers for clinical applications and improve the current, largely empirical understanding of in vivo drug transport and tumor response.
authors.affiliation: Department of Pathology, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pascal
authors.affiliation: Biotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, CA 94551-0969, USA.|Cancer Research and Treatment Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Carlee E
authors.initials: CE
authors.lastname: Ashley
authors.affiliation: Department of Pathology, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Chemical and Nuclear Engineering, and Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Terisse A
authors.initials: TA
authors.lastname: Brocato
authors.affiliation: Department of Chemical and Nuclear Engineering, and Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Butner
authors.affiliation: Nanobiology Department, Sandia National Laboratories, Albuquerque, CA 87185-1349.|Department of Chemical and Nuclear Engineering, and Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM 87131, USA.|Cancer Research and Treatment Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Carnes
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.|Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Koay
authors.affiliation: Department of Chemical and Nuclear Engineering, and Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM 87131, USA.|Center for Micro-Engineered Materials, The University of New Mexico, Albuquerque, NM 87131, USA.|Cancer Research and Treatment Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|Department of Molecular Genetics and Microbiology, the University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|Self-Assembled Materials Department, Sandia National Laboratories, Albuquerque, NM 87185-1349, USA.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.affiliation: Department of Pathology, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.|Department of Chemical and Nuclear Engineering, and Center for Biomedical Engineering, The University of New Mexico, Albuquerque, NM 87131, USA.|Cancer Research and Treatment Center, The University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Cristini
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy*; D008962:Models, Theoretical; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D003841:Deoxycytidine; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil; D000093542:Gemcitabine