The Application of Micro- and Nanomotors in Classified Drug Delivery.

Micro and nanomotors (MNMs) are micro/nanoscale devices that are able to convert chemical or external energy into mechanical motion. Based on a multitude of propulsion mechanisms, synthetic MNMs have been developed over the past decades for diverse biomedical applications, particularly drug delivery. Herein, we set out the classification of drugs delivered by MNMs, such as small molecules, nucleic acid, peptides, antibodies, and other proteins, and discuss their current limitations and possibilities in in vivo applications. Challenges and future perspectives are also discussed. With the increasing research enthusiasm in this field and the strengthening of multidisciplinary cooperation, intelligent MNMs will appear in the near future, which will have a profound impact on all related fields.

[1]  Kinam Park.  Controlled drug delivery systems: past forward and future back. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[2]  O. Schmidt,et al.  Catalytic microtubular jet engines self-propelled by accumulated gas bubbles. , 2009, Small.

[3]  Zhiguang Wu,et al.  Self-propelled polymer-based multilayer nanorockets for transportation and drug release. , 2013, Angewandte Chemie.

[4]  Letha J. Sooter,et al.  Automated acquisition of aptamer sequences. , 2002, Combinatorial chemistry & high throughput screening.

[5]  Kevin Kaufmann,et al.  Aptamer-Modified Graphene-Based Catalytic Micromotors: Off–On Fluorescent Detection of Ricin , 2016 .

[6]  J. Hao,et al.  Near-Infrared-Light-Responsive Magnetic DNA Microgels for Photon- and Magneto-Manipulated Cancer Therapy. , 2017, ACS applied materials & interfaces.

[7]  D. Wilson,et al.  Supramolecular Adaptive Nanomotors with Magnetotaxis Behavior , 2017, Advanced materials.

[8]  D. Wilson,et al.  High-Throughput Design of Biocompatible Enzyme-Based Hydrogel Microparticles with Autonomous Movement. , 2018, Angewandte Chemie.

[9]  K. Cornetta,et al.  Gene transfer into humans--immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. , 1990, The New England journal of medicine.

[10]  Martin Pumera,et al.  Cooperative Multifunctional Self‐Propelled Paramagnetic Microrobots with Chemical Handles for Cell Manipulation and Drug Delivery , 2018, Advanced Functional Materials.

[11]  Qiang He,et al.  Chemotaxis-Guided Hybrid Neutrophil Micromotors for Targeted Drug Transport. , 2017, Angewandte Chemie.

[12]  A Escarpa,et al.  Multiplexed immunoassay based on micromotors and microscale tags. , 2014, Lab on a chip.

[13]  Jun Chen,et al.  Self-propelled manganese oxide-based catalytic micromotors for drug delivery , 2016 .

[14]  Oliver G Schmidt,et al.  Micro- and nano-motors: the new generation of drug carriers. , 2018, Therapeutic delivery.

[15]  Donglei Fan,et al.  Tunable release of multiplex biochemicals by plasmonically active rotary nanomotors. , 2015, Angewandte Chemie.

[16]  Lixin Dong,et al.  Artificial bacterial flagella: Fabrication and magnetic control , 2009 .

[17]  Weihong Tan,et al.  Magnetically driven single DNA nanomotor. , 2011, Small.

[18]  Qiang He,et al.  Self-propelled polymer multilayer Janus capsules for effective drug delivery and light-triggered release. , 2014, ACS applied materials & interfaces.

[19]  Sirilak Sattayasamitsathit,et al.  Rapid delivery of drug carriers propelled and navigated by catalytic nanoshuttles. , 2010, Small.

[20]  Filiz Kuralay,et al.  Ultrasound-propelled nanoporous gold wire for efficient drug loading and release. , 2014, Small.

[21]  R Maria-Hormigos,et al.  Labs-on-a-chip meet self-propelled micromotors. , 2016, Lab on a chip.

[22]  Ryan Pavlick,et al.  Intelligent, self-powered, drug delivery systems. , 2013, Nanoscale.

[23]  Andre Levchenko,et al.  Sub-Cellular Resolution Delivery of a Cytokine via Precisely Manipulated Nanowires , 2010, Nature nanotechnology.

[24]  M. Dewhirst,et al.  The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors. , 2001, Advanced drug delivery reviews.

[25]  Junbai Li,et al.  Nanorods assembly of polystyrene under theta condition , 2006 .

[26]  Qiang He,et al.  Bioinspired Platform Conjugated Active Drug Delivery. , 2018, Current drug targets.

[27]  Ramin Golestanian,et al.  Self-motile colloidal particles: from directed propulsion to random walk. , 2007, Physical review letters.

[28]  Wei Gao,et al.  Fuel‐Free Synthetic Micro‐/Nanomachines , 2017, Advanced materials.

[29]  Berta Esteban-Fernández de Ávila,et al.  Micromotor-enabled active drug delivery for in vivo treatment of stomach infection , 2017, Nature Communications.

[30]  Ayusman Sen,et al.  Catalytic motors for transport of colloidal cargo. , 2008, Nano letters.

[31]  Metin Sitti,et al.  Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery. , 2017, ACS nano.

[32]  Paula Díez,et al.  Biomedical nanomotors: efficient glucose-mediated insulin release. , 2017, Nanoscale.

[33]  Wei Gao,et al.  Reversible swarming and separation of self-propelled chemically powered nanomotors under acoustic fields. , 2015, Journal of the American Chemical Society.

[34]  Samuel Sánchez,et al.  Motion Control of Urea-Powered Biocompatible Hollow Microcapsules. , 2016, ACS nano.

[35]  Zhiguang Wu,et al.  Biodegradable protein-based rockets for drug transportation and light-triggered release. , 2015, ACS applied materials & interfaces.

[36]  Alberto Escarpa,et al.  RBC micromotors carrying multiple cargos towards potential theranostic applications. , 2015, Nanoscale.

[37]  Wei Gao,et al.  Nanomotor lithography , 2014, Nature Communications.

[38]  E. Fullerton,et al.  Cargo-towing fuel-free magnetic nanoswimmers for targeted drug delivery. , 2012, Small.

[39]  Samuel Sanchez,et al.  Enzyme-Powered Hollow Mesoporous Janus Nanomotors. , 2015, Nano letters (Print).

[40]  R. Forster,et al.  Electrogenerated chemiluminescence. , 2009, Annual review of analytical chemistry.

[41]  Flory Wong,et al.  Progress toward Light-Harvesting Self-Electrophoretic Motors: Highly Efficient Bimetallic Nanomotors and Micropumps in Halogen Media. , 2016, ACS nano.

[42]  Wei Gao,et al.  Functionalized ultrasound-propelled magnetically guided nanomotors: toward practical biomedical applications. , 2013, ACS nano.

[43]  J. Biaglow,et al.  The role of glutathione in the aerobic radioresponse. I. Sensitization and recovery in the absence of intracellular glutathione. , 1986, Radiation research.

[44]  Prabodhika Mallikaratchy,et al.  Evolution of Complex Target SELEX to Identify Aptamers against Mammalian Cell-Surface Antigens , 2017, Molecules.

[45]  Amar H Flood,et al.  Hydrophobic collapse of foldamer capsules drives picomolar-level chloride binding in aqueous acetonitrile solutions. , 2013, Journal of the American Chemical Society.

[46]  Mingli Xu,et al.  Micromotors Spontaneously Neutralize Gastric Acid for pH-Responsive Payload Release. , 2017, Angewandte Chemie.

[47]  Oliver G. Schmidt,et al.  Versatile Approach for Integrative and Functionalized Tubes by Strain Engineering of Nanomembranes on Polymers , 2008 .

[48]  Ali Kemal Yetisen,et al.  Paper-based microfluidic point-of-care diagnostic devices. , 2013, Lab on a chip.

[49]  Lindsay S. Machan,et al.  Self-propelled particles that transport cargo through flowing blood and halt hemorrhage , 2015, Science Advances.

[50]  Susana Campuzano,et al.  Nanomotor-Enabled pH-Responsive Intracellular Delivery of Caspase-3: Toward Rapid Cell Apoptosis. , 2017, ACS nano.

[51]  Liangfang Zhang,et al.  Chemotactic Guidance of Synthetic Organic/Inorganic Payloads Functionalized Sperm Micromotors , 2018 .

[52]  Samuel Sánchez,et al.  Reversed Janus Micro/Nanomotors with Internal Chemical Engine , 2016, ACS nano.

[53]  P. Decuzzi,et al.  TPA Immobilization on Iron Oxide Nanocubes and Localized Magnetic Hyperthermia Accelerate Blood Clot Lysis , 2015 .

[54]  W. Xi,et al.  Self-propelled nanotools. , 2012, ACS nano.

[55]  Lian-Hua Fu,et al.  Catalytic chemistry of glucose oxidase in cancer diagnosis and treatment. , 2018, Chemical Society reviews.

[56]  Alejandro Baeza,et al.  Nanomotors for Nucleic Acid, Proteins, Pollutants and Cells Detection , 2018, International journal of molecular sciences.

[57]  Alberto Escarpa,et al.  Micromotor-based lab-on-chip immunoassays. , 2013, Nanoscale.

[58]  Daniela A Wilson,et al.  Self-Guided Supramolecular Cargo-Loaded Nanomotors with Chemotactic Behavior towards Cells , 2015, Angewandte Chemie.

[59]  Daniel Ahmed,et al.  Acoustic tweezers: patterning cells and microparticles using standing surface acoustic waves (SSAW). , 2009, Lab on a chip.

[60]  A. Caudy,et al.  Role for a bidentate ribonuclease in the initiation step of RNA interference , 2001 .

[61]  Chuanrui Chen,et al.  Magnesium-Based Micromotors: Water-Powered Propulsion, Multifunctionality, and Biomedical and Environmental Applications. , 2018, Small.

[62]  Jiangnan Hu,et al.  Magnetically active Fe3O4 nanorods loaded with tissue plasminogen activator for enhanced thrombolysis , 2016, Nano Research.

[63]  S. Sánchez,et al.  Catalytic Mesoporous Janus Nanomotors for Active Cargo Delivery , 2015, Journal of the American Chemical Society.

[64]  Martin Pumera,et al.  Fuel-Free Light-Powered TiO2/Pt Janus Micromotors for Enhanced Nitroaromatic Explosives Degradation. , 2018, ACS applied materials & interfaces.

[65]  Daniela A Wilson,et al.  Biodegradable Hybrid Stomatocyte Nanomotors for Drug Delivery , 2017, ACS nano.

[66]  Oliver G Schmidt,et al.  Medibots: Dual‐Action Biogenic Microdaggers for Single‐Cell Surgery and Drug Release , 2016, Advanced materials.

[67]  Jianguo Guan,et al.  Secondary growth of hierarchical nanostructures composed only of Nb3O7F single-crystalline nanorods as a new photocatalyst for hydrogen production , 2015 .

[68]  T. Ala‐Nissila,et al.  Propulsion and controlled steering of magnetic nanohelices. , 2017, Soft matter.

[69]  Daniela A Wilson,et al.  Fuel concentration dependent movement of supramolecular catalytic nanomotors. , 2013, Nanoscale.

[70]  Liangfang Zhang,et al.  Artificial Micromotors in the Mouse’s Stomach: A Step toward in Vivo Use of Synthetic Motors , 2014, ACS nano.

[71]  Daniela A Wilson,et al.  Redox‐Sensitive Stomatocyte Nanomotors: Destruction and Drug Release in the Presence of Glutathione , 2017, Angewandte Chemie.

[72]  Mohammad Zarei,et al.  Self-Propelled Micro/Nanomotors for Sensing and Environmental Remediation. , 2018, Small.

[73]  H. Shum,et al.  Self-Propelled Nanomotors Autonomously Seek and Repair Cracks. , 2015, Nano letters.

[74]  Jonathan D Posner,et al.  Synthetic nanomotors in microchannel networks: directional microchip motion and controlled manipulation of cargo. , 2008, Journal of the American Chemical Society.

[75]  R. Lequin.  Enzyme immunoassay (EIA)/enzyme-linked immunosorbent assay (ELISA). , 2005, Clinical chemistry.

[76]  S. Pané,et al.  Hybrid Magnetoelectric Nanowires for Nanorobotic Applications: Fabrication, Magnetoelectric Coupling, and Magnetically Assisted In Vitro Targeted Drug Delivery , 2017, Advanced materials.

[77]  Mieke Uyttendaele,et al.  Immunoquantitative Real-Time PCR for Detection and Quantification of Staphylococcus aureus Enterotoxin B in Foods , 2006, Applied and Environmental Microbiology.

[78]  Wentao Duan,et al.  Synthesis and characterization of silver halide nanowires , 2014 .

[79]  Samuel Sanchez,et al.  Enzyme‐Powered Nanobots Enhance Anticancer Drug Delivery , 2018 .

[80]  Daniela A Wilson,et al.  A peptide functionalized nanomotor as an efficient cell penetrating tool. , 2017, Chemical communications.

[81]  Wentao Duan,et al.  A tale of two forces: simultaneous chemical and acoustic propulsion of bimetallic micromotors. , 2015, Chemical communications.

[82]  C. Kastrup,et al.  Halting hemorrhage with self-propelling particles and local drug delivery , 2016, Thrombosis research.

[83]  Daniela A Wilson,et al.  Autonomous movement of platinum-loaded stomatocytes. , 2012, Nature chemistry.

[84]  Wei Gao,et al.  Ultrasound-modulated bubble propulsion of chemically powered microengines. , 2014, Journal of the American Chemical Society.

[85]  Mara Beltrán-Gastélum,et al.  Micromotor Pills as a Dynamic Oral Delivery Platform. , 2018, ACS nano.

[86]  Alberto Escarpa,et al.  Biosensing Strategy for Simultaneous and Accurate Quantitative Analysis of Mycotoxins in Food Samples Using Unmodified Graphene Micromotors. , 2017, Analytical chemistry.

[87]  Shelley D Minteer,et al.  DNA-functionalized Pt nanoparticles as catalysts for chemically powered micromotors: toward signal-on motion-based DNA biosensor. , 2015, Chemical communications.

[88]  Benjamin J. Carey,et al.  Green Synthesis of Low‐Dimensional Aluminum Oxide Hydroxide and Oxide Using Liquid Metal Reaction Media: Ultrahigh Flux Membranes , 2018, Advanced Functional Materials.

[89]  John G. Gibbs,et al.  Nanopropellers and their actuation in complex viscoelastic media. , 2014, ACS nano.

[90]  Yanyan Cao,et al.  Catalytic nanomotors: autonomous movement of striped nanorods. , 2004, Journal of the American Chemical Society.

[91]  Filiz Kuralay,et al.  Functionalized micromachines for selective and rapid isolation of nucleic acid targets from complex samples. , 2011, Nano letters.

[92]  T. Chiles,et al.  Highly efficient molecular delivery into mammalian cells using carbon nanotube spearing , 2005, Nature Methods.

[93]  Daniela A. Wilson,et al.  Self-destroyed Redox-sensitive Stomatocyte Nanomotor , 2017 .

[94]  Eleanor Stride,et al.  Ultrasound-Propelled Nanocups for Drug Delivery , 2015, Small.

[95]  Chenming Zhang,et al.  Multifunctional Nanosystem for Targeted and Controlled Delivery of Multiple Chemotherapeutic Agents for the Treatment of Drug-Resistant Breast Cancer , 2018, ACS omega.

[96]  Wei Li,et al.  Photonic nanorods with magnetic responsiveness regulated by lattice defects. , 2017, Nanoscale.

[97]  K. G. Rajeev,et al.  Rational design of cationic lipids for siRNA delivery , 2010, Nature Biotechnology.

[98]  Qing Yang,et al.  Precision-Guided Nanospears for Targeted and High-Throughput Intracellular Gene Delivery. , 2018, ACS nano.

[99]  Peixuan Guo,et al.  Viral nanomotors for packaging of dsDNA and dsRNA , 2007, Molecular microbiology.

[100]  Susana Campuzano,et al.  Micromachine-enabled capture and isolation of cancer cells in complex media. , 2011, Angewandte Chemie.

[101]  Chava Angell,et al.  Acoustically Propelled Nanomotors for Intracellular siRNA Delivery. , 2016, ACS nano.

[102]  Mariana Medina-Sánchez,et al.  Medical microbots need better imaging and control , 2017, Nature.

[103]  Mingjun Xuan,et al.  Near Infrared Light-Powered Janus Mesoporous Silica Nanoparticle Motors. , 2016, Journal of the American Chemical Society.

[104]  Bradley J. Nelson,et al.  Magnetic Helical Microswimmers Functionalized with Lipoplexes for Targeted Gene Delivery , 2015 .

[105]  M. Sitti,et al.  Mobile Microrobots for Active Therapeutic Delivery , 2018, Advanced Therapeutics.

[106]  M. Sitti,et al.  Light-Triggered Drug Release from 3D-Printed Magnetic Chitosan Microswimmers. , 2018, ACS nano.

[107]  Susana Campuzano,et al.  Single Cell Real-Time miRNAs Sensing Based on Nanomotors. , 2015, ACS nano.

[108]  Po-Hsun Huang,et al.  Tunable nanowire patterning using standing surface acoustic waves. , 2013, ACS nano.

[109]  Marcus L. Roper,et al.  Microscopic artificial swimmers , 2005, Nature.

[110]  Xingguo Liang,et al.  A light-driven DNA nanomachine for the efficient photoswitching of RNA digestion. , 2010, Angewandte Chemie.