Ultrasmall inorganic cages directed by surfactant micelles

Functional silica nanoparticles have become highly relevant materials in the fields of biology and medicine. Ultrasmall fluorescent silica nanoparticles developed in our group (Cdots) have now reached phase 2 of clinical trials for cancer diagnostics. Nevertheless, modern nanomedicine techniques and their increasing complexity today are still in demand for more efficient and multifunctional tools for advanced applications such as theranostics. To this end, important developments have been made in order for these nanoparticles to achieve their full potential, including chemical modification of their matrix to improve their optical properties, and new synthetic strategies for multifunctional nanoparticles via a surface modification approach with various functional groups. In parallel, new alternative particle geometries have been investigated for targeted drug delivery applications. In this contribution, we will review some of the recent progress made in our group that ultimately led to the discovery of highly symmetrical dodecahedral silica nanocages, or ‘silicages’ [1]. Ultrasmall (< 10 nm) silica nanoparticles with tunable geometries can be obtained through their templating with surfactant micelles. The self-assembly of silica clusters on these micelles gives rise to unique and well defined structures. The dodecahedral cage structure in particular is of great fundamental importance. It is the simplest of a set of Voronoi polyhedra suggested to form the smallest structural units of multiple forms of mesoporous silica, yet such highly symmetrical silica cages had never been isolated before. In order to resolve the actual structure of these ultrasmall objects, single-particle 3D reconstruction from tens of thousands of cryo-electron microscopy images was performed using a custom-built ‘Hetero’ machine learning algorithm. We will finally show that cage formation is not limited to silica, but has been observed for other materials including metals and transition metal oxides. The chemical and practical value of this polyhedral structure may prove immense. Given the versatility of silica surface chemistry one can readily conceive of cage derivatives of many kinds, which may exhibit unusual properties and be useful in applications ranging from catalysis to drug delivery. For example, given recent success in the clinical translation of ultrasmall fluorescent silica nanoparticles with similar particle sizes and surface properties to these cages, one can envisage a range of new diagnostic and therapeutic probes with drugs hidden inside the cages. Reference: [1] K. Ma, Y. Gong, T. Aubert, M. Z. Turker, T. Kao, P. C. Doerschuk, U. Wiesner, Nature 2018, DOI: 10.1038/s41586-018-0221-0

Self-assembly of highly symmetrical, ultrasmall inorganic cages directed by surfactant micelles

Nanometre-sized objects with highly symmetrical, cage-like polyhedral shapes, often with icosahedral symmetry, have recently been assembled from DNA(1-3), RNA(4) or proteins(5,6) for applications in biology and medicine. These achievements relied on advances in the development of programmable self-assembling biological materials(7-10), and on rapidly developing techniques for generating three-dimensional (3D) reconstructions from cryo-electron microscopy images of single particles, which provide high-resolution structural characterization of biological complexes(11-13). Such single-particle 3D reconstruction approaches have not yet been successfully applied to the identification of synthetic inorganic nanomaterials with highly symmetrical cage-like shapes. Here, however, using a combination of cryo-electron microscopy and single-particle 3D reconstruction, we suggest the existence of isolated ultrasmall (less than 10 nm) silica cages ('silicages') with dodecahedral structure. We propose that such highly symmetrical, self-assembled cages form through the arrangement of primary silica clusters in aqueous solutions on the surface of oppositely charged surfactant micelles. This discovery paves the way for nanoscale cages made from silica and other inorganic materials to be used as building blocks for a wide range of advanced functional-materials applications

Bimodal Morphology Transition Mechanism In The Synthesis Of Two Different Silica Nanoparticles

Morphology transitions in the surfactant directed synthesis of mesoporous silica nanoparticles are of great interest as these materials are interesting for applications in catalysis, separation, and drug delivery. The nature of the transition mechanisms often remains unknown, but is vital to understanding of better-designed materials. We investigate a bimodal transition mechanism in the synthesis of single pore silica nanoparticles of two different shapes synthesized through micelle templating. Introducing pore expander trimethylbenzene (TMB) to the system at varying concentrations results in a transition from pure thicker single-pore particles to pure thinner single-pore particles. In the transition region both particles have stable pore and particle sizes while after the transition region an increase in the size of the thinner particles is observed. The bimodal nature of the transition is verified by a combination of gel permeation chromatography (GPC), fluorescence correlation spectroscopy (FCS), dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques

TOPOLOGICAL ENGINEERING AND SURFACE CHEMISTRY OF ULTRASMALL FLUORESCENT SILICA NANOPARTICLES FOR CANCER NANOMEDICINES

In the evolution of life on earth, complex biological molecules, viruses, and microorganisms have first emerged. The fascinating complexity of these biological structures at the nanoscale, with topologies varying from spheres to icosahedral objects to rings and with different surface chemistries, have always been an inspiration to scientists from a number of disciplines. Although the role of such topologies and respective surface chemistries on modulating biological response is still an open question, there have been numerous efforts in both synthesizing such nanoscale structures and their applications in medicine, particularly cancer diagnostics and therapeutics. In this dissertation, ultrasmall fluorescent silica nanoparticles with diameters around 10 nm and spherical, dodecahedral, and torus-type topologies are investigated. First, orthogonal pathways for surface functionalization of inside and outside surfaces of torus-shaped ultrasmall silica nanoparticles are explored using high-performance liquid chromatography (HPLC). Second, the formation mechanisms of ultrasmall spherical silica nanoparticles are investigated in order to minimize surface chemical heterogeneities as detected by HPLC that result from incomplete covalent encapsulation of fluorescent dye molecules. Finally, in-vivo studies in mice elucidate the effects of nanoparticle topology on pharmacokinetics and biodistribution. Results suggest synthetic pathways to next generation nanomaterials for advanced applications in bioimaging and nanomedicine

Early formation pathways of surfactant micelle directed ultrasmall silica ring and cage structures

By combining a surfactant, an organic pore expander, a silane, and poly(ethylene glycol) (PEG), we have observed the formation of a previously unknown set of ultrasmall silica structures in aqueous solutions. At appropriate concentrations of reagents, similar to 2 nm primary silica clusters arrange around surfactant micelles to form ultrasmall silica rings, which can further evolve into cage like structures. With increasing concentration, these rings line up into segmented worm-like one-dimensional (1D) structures, an effect that can be dramatically enhanced by PEG addition. PEG adsorbed 1D striped cylinders further arrange into higher order assemblies in the form of two-dimensional (2D) sheets or three-dimensional (3D) helical structures. Results provide insights into synergies between deformable noncovalent organic molecule assemblies and covalent inorganic network formation as well as early transformation pathways from spherical soft materials into 1D, 2D, and 3D silica solution structures, hallmarks of mesoporous silica materials formation. The ultrasmall silica ring and cage structures may prove useful in nanomedicine and other nanotechnology based applications

Block Copolymer Directed Nanostructured Surfaces as Templates for Confined Surface Reactions

Despite advances in nanomaterials synthesis, the bottom-up preparation of nanopatterned films as templates for spatially confined surface reactions remains a challenge. We report an approach to fabricating nanoscale thin film surface structures with periodicities on the order of 20 nm and with the capacity to localize reactions with small molecules and nanoparticles. A block copolymer (BCP) of polystyrene-<i>block</i>-poly­[(allyl glycidyl ether)-<i>co</i>-(ethylene oxide)] (PS-<i>b</i>-P­(AGE-<i>co</i>-EO)) is used to prepare periodically ordered, reactive thin films. As proof-of-principle demonstrations of the versatility of the chemical functionalization, a small organic molecule, an amino acid, and ultrasmall silica nanoparticles are selectively attached via thiol–ene click chemistry to the exposed P­(AGE-<i>co</i>-EO) domains of the BCP thin film. Our approach employing click chemistry on the spatially confined reactive surfaces of a BCP thin film overcomes solvent incompatibilities typically encountered when synthetic polymers are functionalized with water-soluble molecules. Moreover, this post-assembly functionalization of a reactive thin film surface preserves the original patterning reduces the amount of required reactant, and leads to short reaction times. The demonstrated approach is expected to provide a new materials platform in applications including sensing, catalysis, pattern recognition, or microelectronics