Transformable liquid-metal nanomedicine

To date, numerous inorganic nanocarriers have been explored for drug delivery systems (DDSs). However, the clinical application of inorganic formulations has often been hindered by their toxicity and failure to biodegrade. We describe here a transformable liquid-metal nanomedicine, based on a core–shell nanosphere composed of a liquid-phase eutectic gallium-indium core and a thiolated polymeric shell. This formulation can be simply produced through a sonication-mediated method with bioconjugation flexibility. The resulting nanoparticles loaded with doxorubicin (Dox) have an average diameter of 107 nm and demonstrate the capability to fuse and subsequently degrade under a mildly acidic condition, which facilitates release of Dox in acidic endosomes after cellular internalization. Equipped with hyaluronic acid, a tumour-targeting ligand, this formulation displays enhanced chemotherapeutic inhibition towards the xenograft tumour-bearing mice. This liquid metal-based DDS with fusible and degradable behaviour under physiological conditions provides a new strategy for engineering theranostic agents with low toxicity.

[1]  Andrew L. Ferguson,et al.  Investigating the optimal size of anticancer nanomedicine , 2014, Proceedings of the National Academy of Sciences.

[2]  B. Keppler,et al.  Gallium in cancer treatment. , 2002, Critical reviews in oncology/hematology.

[3]  Kaushal Rege,et al.  Inorganic nanoparticles for cancer imaging and therapy. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[4]  Charles M. Lieber,et al.  Three-Dimensional, Flexible Nanoscale Field-Effect Transistors as Localized Bioprobes , 2010, Science.

[5]  Kai Yang,et al.  In vivo pharmacokinetics, long-term biodistribution, and toxicology of PEGylated graphene in mice. , 2011, ACS nano.

[6]  R. Elliott,et al.  Doxorubicin-gallium-transferrin conjugate overcomes multidrug resistance: evidence for drug accumulation in the nucleus of drug resistant MCF-7/ADR cells. , 2000, Anticancer research.

[7]  Hak Soo Choi,et al.  Design considerations for tumour-targeted nanoparticles. , 2010, Nature nanotechnology.

[8]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[9]  José Luis de la Pompa,et al.  Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo , 1998, Cell.

[10]  G. Takemura,et al.  Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. , 2007, Progress in cardiovascular diseases.

[11]  Robert Langer,et al.  Near-infrared–actuated devices for remotely controlled drug delivery , 2014, Proceedings of the National Academy of Sciences.

[12]  Chenjie Xu,et al.  Dumbbell-like Au-Fe3O4 nanoparticles for target-specific platin delivery. , 2009, Journal of the American Chemical Society.

[13]  Dong Choon Hyun,et al.  Engineered nanoparticles for drug delivery in cancer therapy. , 2014, Angewandte Chemie.

[14]  J. Muth,et al.  3D Printing of Free Standing Liquid Metal Microstructures , 2013, Advanced materials.

[15]  C. Cray,et al.  Reference values for serum proteins of common laboratory rodent strains. , 2009, Journal of the American Association for Laboratory Animal Science : JAALAS.

[16]  M. Bawendi,et al.  Renal clearance of quantum dots , 2007, Nature Biotechnology.

[17]  Zhen Gu,et al.  Stimuli-responsive nanomaterials for therapeutic protein delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[18]  Samir Mitragotri,et al.  Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies , 2014, Nature Reviews Drug Discovery.

[19]  K. Toh,et al.  Precise engineering of siRNA delivery vehicles to tumors using polyion complexes and gold nanoparticles. , 2014, ACS nano.

[20]  M. Zöller CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? , 2011, Nature Reviews Cancer.

[21]  Monty Liong,et al.  Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. , 2008, ACS nano.

[22]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[23]  W. Chan,et al.  DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination , 2014, Nature nanotechnology.

[24]  Zhen Gu,et al.  ATP-triggered anticancer drug delivery , 2014, Nature Communications.

[25]  C Haanen,et al.  A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. , 1995, Journal of immunological methods.

[26]  P. Weiss,et al.  Directing substrate morphology via self-assembly: ligand-mediated scission of gallium-indium microspheres to the nanoscale. , 2011, Nano letters.

[27]  G. Whitesides,et al.  Self-assembled monolayers of thiolates on metals as a form of nanotechnology. , 2005, Chemical reviews.

[28]  Michael D. Dickey,et al.  Emerging Applications of Liquid Metals Featuring Surface Oxides , 2014, ACS applied materials & interfaces.

[29]  Mark E. Davis,et al.  Cyclodextrin-based pharmaceutics: past, present and future , 2004, Nature Reviews Drug Discovery.

[30]  Rebecca K. Kramer,et al.  Mechanically Sintered Gallium–Indium Nanoparticles , 2015, Advanced materials.

[31]  M. Dickey,et al.  A study of the production and reversible stability of EGaIn liquid metal microspheres using flow focusing. , 2012, Lab on a Chip.

[32]  I. Stamenkovic,et al.  CD44 is the principal cell surface receptor for hyaluronate , 1990, Cell.

[33]  A. Goga,et al.  Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment , 2011, Science Translational Medicine.

[34]  Sarah Hurst Petrosko,et al.  Accelerating the Translation of Nanomaterials in Biomedicine. , 2015, ACS nano.

[35]  Michael D. Dickey,et al.  Giant and switchable surface activity of liquid metal via surface oxidation , 2014, Proceedings of the National Academy of Sciences.

[36]  C. Mirkin,et al.  Defining rules for the shape evolution of gold nanoparticles. , 2012, Journal of the American Chemical Society.