"Manganese Extraction" Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles.

Biodegradability of inorganic nanoparticles is one of the most critical issues in their further clinical translations. In this work, a novel "metal ion-doping" approach has been developed to endow inorganic mesoporous silica-based nanoparticles with tumor-sensitive biodegradation and theranostic functions, simply by topological transformation of mesoporous silica to metal-doped composite nanoformulations. "Manganese extraction" sensitive to tumor microenvironment was enabled in manganese-doped hollow mesoporous silica nanoparticles (designated as Mn-HMSNs) to fast promote the disintegration and biodegradation of Mn-HMSNs, further accelerating the breakage of Si-O-Si bonds within the framework. The fast biodegradation of Mn-HMSNs sensitive to mild acidic and reducing microenvironment of tumor resulted in much accelerated anticancer drug releasing and enhanced T1-weighted magnetic resonance imaging of tumor. A high tumor-inhibition effect was simultaneously achieved by anticancer drug delivery mediated by PEGylated Mn-HMSNs, and the high biocompatibility of composite nanosystems was systematically demonstrated in vivo. This is the first demonstration of biodegradable inorganic mesoporous nanosystems with specific biodegradation behavior sensitive to tumor microenvironment, which also provides a feasible approach to realize the on-demand biodegradation of inorganic nanomaterials simply by "metal ion-doping" strategy, paving the way to solve the critical low-biodegradation issue of inorganic drug carriers.

[1]  Patrick Couvreur,et al.  Stimuli-responsive nanocarriers for drug delivery. , 2013, Nature materials.

[2]  Jianan Liu,et al.  NIR-triggered anticancer drug delivery by upconverting nanoparticles with integrated azobenzene-modified mesoporous silica. , 2013, Angewandte Chemie.

[3]  Linlin Li,et al.  Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery , 2012, Advanced materials.

[4]  Katie R. Hurley,et al.  Critical Considerations in the Biomedical Use of Mesoporous Silica Nanoparticles. , 2012, The journal of physical chemistry letters.

[5]  Zhen Guo,et al.  Multifunctional Fe3O4@C@Ag hybrid nanoparticles as dual modal imaging probes and near-infrared light-responsive drug delivery platform. , 2013, Biomaterials.

[6]  Cecilia Sahlgren,et al.  Nanoparticles in targeted cancer therapy: mesoporous silica nanoparticles entering preclinical development stage. , 2012, Nanomedicine.

[7]  Yufang Zhu,et al.  Rattle-type Fe(3)O(4)@SiO(2) hollow mesoporous spheres as carriers for drug delivery. , 2010, Small.

[8]  L. J. Mueller,et al.  pH-responsive nanogated ensemble based on gold-capped mesoporous silica through an acid-labile acetal linker. , 2010, Journal of the American Chemical Society.

[9]  Zongxi Li,et al.  Mesoporous silica nanoparticles in biomedical applications. , 2012, Chemical Society reviews.

[10]  Lianzhou Wang,et al.  Break‐up of Two‐Dimensional MnO2 Nanosheets Promotes Ultrasensitive pH‐Triggered Theranostics of Cancer , 2014, Advanced materials.

[11]  Victor S-Y Lin,et al.  A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules. , 2003, Journal of the American Chemical Society.

[12]  Chung-Yuan Mou,et al.  Mesoporous silica nanoparticles as nanocarriers. , 2011, Chemical communications.

[13]  V. S. Lin,et al.  Mesoporous silica nanoparticle-based double drug delivery system for glucose-responsive controlled release of insulin and cyclic AMP. , 2009, Journal of the American Chemical Society.

[14]  Feng Chen,et al.  Hollow/rattle-type mesoporous nanostructures by a structural difference-based selective etching strategy. , 2010, ACS nano.

[15]  Yaping Li,et al.  Controlled intracellular release of doxorubicin in multidrug-resistant cancer cells by tuning the shell-pore sizes of mesoporous silica nanoparticles. , 2011, ACS nano.

[16]  P. Cullis,et al.  Drug Delivery Systems: Entering the Mainstream , 2004, Science.

[17]  G. Pauletti,et al.  Rapidly disassembling nanomicelles with disulfide-linked PEG shells for glutathione-mediated intracellular drug delivery. , 2011, Chemical communications.

[18]  Qianjun He,et al.  An anticancer drug delivery system based on surfactant-templated mesoporous silica nanoparticles. , 2010, Biomaterials.

[19]  Jianlin Shi,et al.  Mesoporous silica nanoparticle based nano drug delivery systems: synthesis, controlled drug release and delivery, pharmacokinetics and biocompatibility , 2011 .

[20]  Juan L. Vivero-Escoto,et al.  Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. , 2008, Advanced drug delivery reviews.

[21]  Elise C. Kohn,et al.  The microenvironment of the tumour–host interface , 2001, Nature.

[22]  S. Bauer,et al.  Amphiphilic TiO2 nanotube arrays: an actively controllable drug delivery system. , 2009, Journal of the American Chemical Society.

[23]  Guowu Zhan,et al.  Mesoporous bubble-like manganese silicate as a versatile platform for design and synthesis of nanostructured catalysts. , 2015, Chemistry.

[24]  S. Mann,et al.  Interfacial synthesis of hollow microspheres of mesostructured silica. , 2001, Chemical communications.

[25]  Ichio Aoki,et al.  Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations , 2004, NMR in biomedicine.

[26]  Demin Liu,et al.  Nanoscale metal-organic frameworks for biomedical imaging and drug delivery. , 2011, Accounts of chemical research.

[27]  Woo-Sik Kim,et al.  pH-triggered release of manganese from MnAu nanoparticles that enables cellular neuronal differentiation without cellular toxicity. , 2015, Biomaterials.

[28]  Shreya Mukherjee,et al.  Redox-activated manganese-based MR contrast agent. , 2013, Journal of the American Chemical Society.

[29]  G. Lin,et al.  Controllable drug release and simultaneously carrier decomposition of SiO2-drug composite nanoparticles. , 2013, Journal of the American Chemical Society.

[30]  Taeghwan Hyeon,et al.  Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery. , 2010, Journal of the American Chemical Society.

[31]  Dusan Losic,et al.  Self-ordered nanopore and nanotube platforms for drug delivery applications , 2009, Expert opinion on drug delivery.

[32]  T. Hyeon,et al.  Synthesis of Nanorattles Composed of Gold Nanoparticles Encapsulated in Mesoporous Carbon and Polymer Shells , 2002 .

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

[34]  Marc Vendrell,et al.  Intracellular glutathione detection using MnO(2)-nanosheet-modified upconversion nanoparticles. , 2011, Journal of the American Chemical Society.

[35]  Wenru Zhao,et al.  Fabrication of uniform magnetic nanocomposite spheres with a magnetic core/mesoporous silica shell structure. , 2005, Journal of the American Chemical Society.

[36]  Taeghwan Hyeon,et al.  Mesoporous Silica-Coated Hollow Manganese Oxide Nanoparticles as Positive T1 Contrast Agents for Labeling and MRI Tracking of Adipose-Derived Mesenchymal Stem Cells , 2011, Journal of the American Chemical Society.

[37]  S. Nie,et al.  In vivo cancer targeting and imaging with semiconductor quantum dots , 2004, Nature Biotechnology.

[38]  Yu Chen,et al.  Biocompatibility, MR imaging and targeted drug delivery of a rattle-type magnetic mesoporous silica nanosphere system conjugated with PEG and cancer-cell-specific ligands , 2011 .

[39]  Afonso C. Silva,et al.  In vivo neuronal tract tracing using manganese‐enhanced magnetic resonance imaging , 1998, Magnetic resonance in medicine.

[40]  Yang Sun,et al.  Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells. , 2012, Biomaterials.

[41]  Ming Ma,et al.  Au capped magnetic core/mesoporous silica shell nanoparticles for combined photothermo-/chemo-therapy and multimodal imaging. , 2012, Biomaterials.

[42]  V. S. Lin,et al.  Structurally ordered mesoporous carbon nanoparticles as transmembrane delivery vehicle in human cancer cells. , 2008, Nano letters.

[43]  Brian G. Trewyn,et al.  Mesoporous Silica Nanoparticles for Drug Delivery and Biosensing Applications , 2007 .

[44]  Jianghua Feng,et al.  Understanding the metabolic fate and assessing the biosafety of MnO nanoparticles by metabonomic analysis , 2013, Nanotechnology.

[45]  Weihong Tan,et al.  Activatable fluorescence/MRI bimodal platform for tumor cell imaging via MnO2 nanosheet-aptamer nanoprobe. , 2014, Journal of the American Chemical Society.

[46]  A. Kummel,et al.  Iron(III)-doped, silica nanoshells: a biodegradable form of silica. , 2012, Journal of the American Chemical Society.

[47]  W. Cai,et al.  Chemical-template synthesis of micro/nanoscale magnesium silicate hollow spheres for waste-water treatment. , 2010, Chemistry.

[48]  Wendelin J Stark,et al.  Nanoparticles in biological systems. , 2011, Angewandte Chemie.

[49]  Xiaohua Huang,et al.  Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. , 2006, Journal of the American Chemical Society.

[50]  Yu Chen,et al.  Core/shell structured hollow mesoporous nanocapsules: a potential platform for simultaneous cell imaging and anticancer drug delivery. , 2010, ACS nano.

[51]  Fredrickson,et al.  Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores , 1998, Science.

[52]  Jinwoo Cheon,et al.  Chemical design of nanoparticle probes for high-performance magnetic resonance imaging. , 2008, Angewandte Chemie.

[53]  Elodie Boisselier,et al.  Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. , 2009, Chemical Society reviews.

[54]  Mark B. Carter,et al.  The Targeted Delivery of Multicomponent Cargos to Cancer Cells via Nanoporous Particle-Supported Lipid Bilayers , 2011, Nature materials.

[55]  H. Zeng,et al.  Nanobubbles within a microbubble: synthesis and self-assembly of hollow manganese silicate and its metal-doped derivatives. , 2014, ACS nano.

[56]  H. Dai,et al.  Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Ling Zhang,et al.  Hierarchically Nanostructured Magnetic Hollow Spheres of Fe3O4 and γ-Fe2O3: Preparation and Potential Application in Drug Delivery , 2008 .

[58]  Yu Chen,et al.  Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles. , 2012, Journal of the American Chemical Society.

[59]  Hyunjun Yoo,et al.  Template-Directed Synthesis of Oxide Nanotubes: Fabrication, Characterization, and Applications† , 2008 .

[60]  Zhichuan J. Xu,et al.  Synthesis, Functionalization, and Biomedical Applications of Multifunctional Magnetic Nanoparticles , 2010, Advanced materials.

[61]  D. Zhao,et al.  Hierarchically Ordered Macro-/Mesoporous Silica Monolith: Tuning Macropore Entrance Size for Size-Selective Adsorption of Proteins , 2011 .

[62]  Ru Cheng,et al.  Intracellular drug release nanosystems , 2012 .

[63]  Baorui Liu,et al.  Entering and Lighting Up Nuclei Using Hollow Chitosan–Gold Hybrid Nanospheres , 2009 .

[64]  Zongxi Li,et al.  Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. , 2010, Small.

[65]  P. Chou,et al.  One-step synthesis of degradable T(1)-FeOOH functionalized hollow mesoporous silica nanocomposites from mesoporous silica spheres. , 2015, Nanoscale.

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