title: Multi-modal strategies for overcoming tumor drug resistance: hypoxia, the Warburg effect, stem cells, and multifunctional nanotechnology.
abstract: Inefficiencies in systemic drug delivery and tumor residence as well as micro-environmental selection pressures contribute to the development of multidrug resistance (MDR) in cancer. Characteristics of MDR include abnormal vasculature, regions of hypoxia, up-regulation of ABC-transporters, aerobic glycolysis, and an elevated apoptotic threshold. Nano-sized delivery vehicles are ideal for treating MDR cancer as they can improve the therapeutic index of drugs and they can be engineered to achieve multifunctional parameters. The multifunctional ability of nanocarriers makes them more adept at treating heterogeneous tumor mass than traditional chemotherapy. Nanocarriers also have preferential tumor accumulation via the EPR effect; this accumulation can be further enhanced by actively targeting the biological profile of MDR cells. Perhaps the most significant benefit of using nanocarrier drug delivery to treat MDR cancer is that nanocarrier delivery diverts the effects of ABC-transporter mediated drug efflux; which is the primary mechanism of MDR. This review discusses the capabilities, applications, and examples of multifunctional nanocarriers for the treatment of MDR. This review emphasizes multifunctional nanocarriers that enhance drug delivery efficiency, the application of RNAi, modulation of the tumor apoptotic threshold, and physical approaches to overcome MDR.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Milane
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesh
authors.forename: Shruti
authors.initials: S
authors.lastname: Shah
authors.forename: Zhen-Feng
authors.initials: ZF
authors.lastname: Duan
authors.forename: Mansoor
authors.initials: M
authors.lastname: Amiji
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003131:Combined Modality Therapy; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D036103:Nanotechnology; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D000255:Adenosine Triphosphate