Michael W. Ambrogio

Stimulated Release of Size-Selected Cargos in Succession from Mesoporous Silica Nanoparticles†

Combination drug therapy, a regimen in which multiple drugs with different therapeutic outcomes are used in parallel or in sequence, has become one of the dominant strategies in the clinical treatment of HIV/AIDS, diabetes, and cancer. In cancer therapy, for example, the U.S. Food and Drug Administration (FDA) approved the use in 2006 of Avastin in combination with Carboplatin and Paclitaxel for the initial systemic treatment of patients with lung cancer. Unlike monotherapy, combination therapy maximizes therapeutic efficacy against individual targets and is more likely to overcome drug resistance, while increasing the odds of a positive prognosis and reducing harmful side effects. Drug delivery systems, which administer medically active compounds to diseased cells in a targeted and controlled manner, have gained much attention in the past couple of decades. While polymers, dendrimers, micelles, vesicles, and nanoparticles have all been investigated for their use as possible drug delivery systems, most systems provide either delivery of a single drug or the simultaneous delivery of multiple drugs. Using these systems, however, it is difficult to control the administration order, timing, and dosage of each individual drug in a comprehensive manner. While it is possible to deliver a cocktail of drugs using several different co-administered drug delivery systems, this protocol has disadvantages. For example, it is not easy to expose several co-administered drug delivery systems to the same target at the right time, while also controlling the dosage rates and ratios of each individual drug. In order to administer chemotherapeutic combinations and produce synergistic actions, well-organized multidrug release systems, which can provide combination therapies by controlling the release behavior of each drug individually, need to be invented. Mesoporous silica nanoparticles (MSNs) have attracted widespread interest in the past decade for use in integrated functional systems. They have large surface exteriors and porous interiors that can be harnessed as reservoirs for smallmolecule-drug storage. These MSNs are nontoxic to cells and can undergo cellular uptake into acidic lysosomes by endocytosis when they are 100–200 nm in diameter, thus making them a popular candidate for drug delivery systems. In particular, MSNs can be functionalized with molecular, as well as supramolecular, switches in order to control the release of drug molecules in response to external stimuli. Oncommand release systems, which respond to a range of stimuli, including pH changes, light initiation, competitive binding, redox activation, biological triggers, and temperature changes, have been reported by us and others. To the best of our knowledge, however, all the on-command release systems reported to date cannot release multiple drugs in a step-by-step fashion. Cyclodextrins (CDs), because of their abilities to form inclusion complexes with guest molecules, have been the focus of much research. b-Cyclodextrin (b-CD), which comprises seven a-1,4-linked d-glucopyranosyl units with top and bottom cavities of 6.0 and 6.5 , respectively, has been employed as a gatekeeper in drug delivery systems. [*] Dr. C. Wang, D. Cao, Dr. Y.-L. Zhao, J. W. Gaines, Dr. O. A. Bozdemir, M. W. Ambrogio, Dr. M. Frasconi, Dr. Y. Y. Botros, Prof. J. F. Stoddart Center for the Chemistry of Integrated Systems Department of Chemistry and Department of Material Sciences Northwestern University 2145 Sheridan Road, Evanston, IL 60208 (USA) E-mail: stoddart@northwestern.edu Z. Li, Prof. J. I. Zink Department of Chemistry and Biochemistry and California NanoSystems Institute, University of California Los Angeles, 405 Hilgard Avenue, Los Angeles, CA 90095 (USA) E-mail: zink@chem.ucla.edu

Snap-Top Nanocarriers

An approach to the design and fabrication of mechanized mesoporous silica nanoparticles is demonstrated at the proof of principle level. It relies on the reductive cleavage of disulfide bonds within an integrated nanosystem, wherein surface-bound rotaxanes incorporate disulfide bonds in their stalks, which are encircled by cucurbit[6]uril or alpha-cyclodextrin rings, until reductive chemistry is performed, resulting in the snapping of the stalks of the rotaxanes, leading to cargo release from the inside of the nanoparticles.

Photoexpulsion of surface-grafted ruthenium complexes and subsequent release of cytotoxic cargos to cancer cells from mesoporous silica nanoparticles

Ruthenium(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium(II) complex is observed. We have delivered, in combination, the ruthenium(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions.

A reversible light-operated nanovalve on mesoporous silica nanoparticles

Two azobenzene α-cyclodextrin based nanovalves are designed, synthesized and assembled on mesoporous silica nanoparticles. Under aqueous conditions, the cyclodextrin cap is tightly bound to the azobenzene moiety and capable of holding back loaded cargo molecules. Upon irradiation with a near-UV light laser, trans to cis-photoisomerization of azobenzene initiates a dethreading process, which causes the cyclodextrin cap to unbind followed by the release of cargo. The addition of a bulky stopper to the end of the stalk allows this design to be reversible; complete dethreading of cyclodextrin as a result of unbinding with azobenzene is prevented as a consequence of steric interference. As a result, thermal relaxation of cis- to trans-azobenzene allows for the rebinding of cyclodextrin and resealing of the nanopores, a process which entraps the remaining cargo. Two stalks were designed with different lengths and tested with alizarin red S and propidium iodide. No cargo release was observed prior to light irradiation, and the system was capable of multiuse. On/off control was also demonstrated by monitoring the release of cargo when the light stimulus was applied and removed, respectively.

New Methods for Improved Characterization of Silica Nanoparticle-Based Drug Delivery Systems

The incorporation of silica nanoparticles into drug delivery vehicles, and other nanotech platforms, has experienced rapid and significant growth over the past decade. However, as these nanoparticle-based systems become more and more complex, the methods used to analyze these systems have evolved at a comparatively much slower pace, resulting in the need for researchers to expand their toolbox and devise new strategies to characterize these materials. This article describes how X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were recently employed in the analysis of two separate drug delivery systems which contain organic compounds covalently attached to the surfaces of silica nanoparticles. These techniques provided a deluge of qualitative and quantitative information about these drug delivery systems, and have several clear advantages over more common characterization procedures such as Fourier transform infrared spectroscopy (FT-IR) and solid state nuclear magnetic resonance (SSNMR). Thus, XPS and ToF-SIMS should be an integral component of the standard characterization protocol for any nanoparticle-based assemblies-particularly silica-based drug delivery systems-as this field of research continues to develop.

Synthesis of Monolayer Molybdenum Disulfide and ToF-SIMS Characterization

Two dimensional (2D) materials have attracted much attention in the past decade. This family of materials includes metallic graphene and semiconducting transition metal dichalcogenides such as MoS2. Due to the excellent mechanical flexibility, electron transportation property, and transparency, 2D materials have great potential applications in electronics, sensor, and supercapacitor. Mechanical exfoliation and chemical vapor deposition (CVD) are two common methods to prepare the monolayer and a few atomic layer films. Because of the high yield and good quality of the monolayer film, the CVD method becomes the main stream to prepare 2D materials.