Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs.

A critical obstacle and challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. It is particularly important to improve the aqueous solubility of drugs, as low drug solubility in aqueous media hampers the ability of drugs to be administered through the intravenous route. Since many important anticancer agents have poor water solubility, the development of novel delivery systems for these molecules without the use of organic solvents has received significant attention. Nanoparticles offer great potential and a promising approach to deliver therapeutic agents into targeted organs or cells and they have been actively developed for application in cancer therapy. We have incorporated a representative hydrophobic anticancer drug, camptothecin (CPT), into the pores of fluorescent mesoporous silica nanoparticles (FMSNs) and delivered the drug into a variety of human cancer cells to induce cell death, a procedure suggesting that the mesoporous silica nanoparticles might be used as a vehicle to overcome the insolubility problem of many anticancer drugs. CPT and its derivatives are considered to be among the most promising anticancer drugs of the 21st century. Although studies have demonstrated their effectiveness against carcinomas of the stomach, colon, neck, and bladder, as well as breast and small-cell lung cancers, and leukemia, in vitro, clinical application of CPT in humans has not been achieved to date because the poor water solubility of the drug requires changes to the physicochemical characteristics. The need to formulate water-soluble salts of CPT (that is, alkaline solutions for intravenous injections) led to chemical modifications of the molecule with loss of antiACHTUNGTRENNUNGtumor activity and significant alterations in the toxicological profile of the drug. Although derivatives such as irinotecan have produced good clinical results, irinotecan was shown to have far lower cytotoxicity to cancer cells than CPT (10%), and CPT remains the most potent compound. Among a variety of drug-delivery systems, mesoporous silica materials have several attractive features for use in the delivery of water-insoluble drugs. These particles have large surface areas and porous interiors that can be used as reservoirs for storing hydrophobic drugs. The pore size and environment can be tailored to selectively store different molecules of interest, while the size and shape of the particles can be tuned to maximize cellular uptake. Unlike polymer-based nanoparticles, these robust inorganic materials can tolerate many organic solvents. Silica-based materials have been successfully used as drug-delivery vectors, gene transfection reagents, cell markers, and carriers of molecules. Here, we describe the preparation of fluorescent mesoporous silica nanoparticles that are highly stable in aqueous solution and their use for the delivery of the hydrophobic anticancer drug CPT. The FMSNs were prepared by using a base-catalyzed sol–gel process at high temperature with a modification of published procedures. 25,26] In a typical synthesis, fluorescein isothiocyanate (FITC) was first treated with 3-aminopropyltriethoxysilane (APTS) in ethanol. The mixture was then added, along with tetraethylorthosilicate, to cetyltriACHTUNGTRENNUNGmethylammonium bromide solution at 80 8C. The surfactants were removed from the pores by refluxing the nanoparticles in acidic methanol, the success of which was confirmed by Fourier transform infrared spectroscopy (FTIR; see Supporting Information). Electron microscopy and Xray diffraction (XRD) analysis showed that the particle shape and hexagonal arrays of the pores in the FMSNs remained intact after the surfactant-removal process (Figure 1). The nanoparticles were roughly spherical in shape and smaller than 130 nm in diameter. An average pore diameter of around 2 nm was observed by using transmission electron microscopy (TEM) and an interplanar spacing of dACHTUNGTRENNUNG(100) 4 nm was calculated from the XRD pattern. It is necessary for efficient cellular uptake of the particles that the FMSNs remain dispersed and do not aggregate in the buffer solution. The observed aggregation is caused by interparticle hydrogen-bonding interactions between the amine groups (from the unreacted APTS) and the silanols (Scheme 1A). By modifying only the surfaces of the FMSNs with trihydroxysilylpropyl methylphosphonate (THMP) after particle formation, we reduced the aggregation and increased the stability of the particles in aqueous solution (Scheme 1B, see Supporting Information). [*] Dr. J. Lu, Prof. F. Tamanoi Department of Microbiology, Immunology, and Molecular Genetics California NanoSystems Institute, JCCC University of California, Los Angeles 609 Charles E. Young Drive East, Los Angeles, CA 90095 (USA) Fax: (+1)310-206-5231 E-mail: fuyut@microbio.ucla. edu