Guest Commentary pubs.acs.org/JPCL
Development of Pharmaceutically Adapted Mesoporous Silica Nanoparticles Platform
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processes, a number of biologically optimized MSNP delivery systems have emerged from our studies. One example is overcoming multidrug resistance by designing MSNP surfaces that allows for the codelivery of anticancer drug and siRNA into drug-resistant cancer cells.7 The functionalization of the particle surface with phosphonate groups allows electrostatic binding of the chemotherapeutic agent doxorubicin to the porous interior. Phosphonate modification allows exterior coating with the cationic polymer, polyethyleneimine (PEI), which endows the MSNP with the ability to bind and deliver P-glycoprotein (Pgp) siRNA that silences the expression of the efflux protein. In one study, we showed that functionalized MSNP can effectively deliver doxorubicin plus Pgp siRNA simultaneously to a drug-resistant cancer cell line.7 This resulted in enhanced cell killing by synergistic action of this dual delivery system in restoring drug sensitivity. Another example is the introduction of nanovalves that mechanize the pore opening of MSNP to achieve an on-demand release, either autonomously or remotely controlled.15 This strategy minimizes the premature release of cargo, which increases the delivery efficacy at the site of interest. We have demonstrated a variety of examples where different stimuli, such as pH, light, enzyme, and an external magnetic field, are utilized to control the delivery event.15 Shape control is a new design feature that plays a key role in the optimization of MSNP. We have recently demonstrated that the aspect ratio of rod-shaped MSNPs determines the rate and abundance of MSNP uptake in cancer cells.16 Through the use of a shape design feature, a more efficient drug delivery could be achieved by MSNPs, exhibiting aspect ratios of 2.1−2.5.16 In summary, in order to develop a pharmaceutically adapted and optimized MSNP platform, use of the knowledge generated by innovative discovery at the cellular nano/bio interface has been shown to elucidate and tune the properties (e.g., size, interior/exterior particle surface, shape, nanovalve, embedded metal/metal oxide, etc.) that maximize MSNP therapeutic efficacy in vivo. In addition to effectiveness, a comprehensive safety assessment analysis of MSNP should be integral to the design and in vivo implementation of this delivery system. Our collective efforts to date demonstrate that mesoporous silica nanoparticle is devoid of the surface characteristics that may render silica polymorphs made under temperature conditions hazardous in vitro and in vivo. Moreover, all of the Si present in intravenously injected MSNP is recovered in the urine and feces of experimental animals within a matter of days, showing biodegradability of this material.21−23 Thus, the ability to stably endow the multifunctional MSNP platform with design features to optimize in vivo drug delivery and to do so safely presents us
he nascence of nano- and submicrometer-sized mesoporous silica nanoparticles (MSNPs) can trace back to 1997, when Kaiser et al. used a cohydrolysis method in the synthesis of Mobile crystalline material-41 (MCM-41).1,2 In recent years, MSNPs have been successfully developed as a multifunctional platform to deliver therapeutic/diagnostic agents (e.g., drug, siRNA, imaging probe, etc.) in studies involving a variety of cell types and animal models.3−11 In order to effectively package and precisely deliver cargo molecules for a controlled and on-demand release, with the potential capability of imaging the targeted delivery site, multiple research groups have developed a list of design features that can advance the utility of the MSNP platform for therapeutic purposes. This includes particle size control,12,13 surface ligand modification,14 charge variation,9 pore mechanizing,15 shape tuning,16 and so forth. Among these design features, the size and dispersal control are important topics because they have direct bearing on the in vivo outcomes, including pharmacokinetic profiles, biodistribution, and delivery capability of MSNPs. One example is the ability to improve the efficiency of passive tumor delivery via an enhanced permeability and retention (EPR) effect, the basis of which are the abnormally large fenestrations and leakiness of solid tumor. It is generally agreed that particles with diameters less than 200 nm (but occasionally bigger) are less avidly removed by the reticuloendothelial system (RES) but, on a size exclusion basis, are favored by the tumor EPR effect.17−19 Nanoparticles may also be decorated with polymer chains (e.g., polyethylene glycol, PEG) to provide steric hindrance to prevent opsonization and phagocytic removal by the RES, thereby prolonging the circulation time and enhancing the EPR effect.20 We also want to point out that besides the use of dialysis to obtain nonaggregated particles, credit should also be awarded to approaches using chemical modification or polymer coating to achieve good dispersion. For instance, MSNPs can be stabilized via electrostatic repulsion by introducing additional surface charge, such as phosphanate grafting and polyethyleneimine-PEG (PEI−PEG) copolymer coating; both surface modifications lead to successful enhancement of the EPR effect. 12,21 Moreover, the complexity involved in achieving good dispersion in vivo requires even more comprehensive design and assessment of MSNP properties to stabilize the nano carrier for optimal passive delivery. For instance, particle size, surface properties, tumor type and differentiation, tumor size, heterogeneity, and vascularity all influence the delivery efficacy in tumor xenografts. Our mutidisplinary research team at UCLA utilizes deliberate design and optimization of our multifunctional MSNP-based delivery system based on cellular high-content screening and discovery at the nano/bio interface to achieve optimal outcomes in disease models. Through the introduction of a series of design features and implementation of iterative design © 2012 American Chemical Society
Received: January 6, 2012 Accepted: January 12, 2012 Published: February 2, 2012 358
dx.doi.org/10.1021/jz300021x | J. Phys. Chem.Lett. 2012, 3, 358−359
The Journal of Physical Chemistry Letters
Guest Commentary
Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model. ACS Nano 2011, 5, 4131−4144. (13) Febvay, S.; Marini, D. M.; Belcher, A. M.; Clapham, D. E. Targeted Cytosolic Delivery of Cell-Impermeable Compounds by Nanoparticle-Mediated, Light-Triggered Endosome Disruption. Nano Lett. 2010, 10, 2211−2219. (14) Ferris, D. P.; Lu, J.; Gothard, C.; Yanes, R.; Thomas, C. R.; Olsen, J.-C.; Stoddart, J. F.; Tamanoi, F.; Zink, J. I. Synthesis of Biomolecule-Modified Mesoporous Silica Nanoparticles for Targeted Hydrophobic Drug Delivery to Cancer Cells. Small 2011, 7, 1816− 1826. (15) Ambrogio, M. W.; Thomas, C. R.; Zhao, Y.-L.; Zink, J. I.; Stoddart, J. F. Mechanized Silica Nanoparticles: A New Frontier in Theranostic Nanomedicine. Acc. Chem. Res. 2011, 44, 903−913. (16) Meng, H.; Yang, S.; Li, Z.; Xia, T.; Chen, J.; Ji, Z.; Zhang, H.; Wang, X.; Lin, S.; Huang, C.; Zhou, Z. H.; Zink, J. I.; Nel, A. E. Aspect Ratio Determines the Quantity of Mesoporous Silica Nanoparticle Uptake by a Small GTPase-Dependent Macropinocytosis Mechanism. ACS Nano 2011, 5, 4434−4447. (17) Lee, H.; Fonge, H.; Hoang, B.; Reilly, R. M.; Allen, C. The Effects of Particle Size and Molecular Targeting on the Intratumoral and Subcellular Distribution of Polymeric Nanoparticles. Mol. Pharm. 2010, 7, 1195−1208. (18) Perrault, S. D.; Walkey, C.; Jennings, T.; Fischer, H. C.; Chan, W. C. W. Mediating Tumor Targeting Efficiency of Nanoparticles Through Design. Nano Lett. 2009, 9, 1909−1915. (19) Cho, K.; Wang, X.; Nie, S.; Chen, Z.; Shin, D. M. Therapeutic Nanoparticles for Drug Delivery in Cancer. Clin. Caner Res. 2008, 14, 1310−1316. (20) Nel, A. E.; Madler, L.; Velegol, D.; Xia, T.; Hoek, E. M. V.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Understanding Biophysicochemical Interactions at the Nano−Bio Interface. Nat. Mater. 2009, 8, 543−557. (21) Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F. Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small 2010, 6, 1794−1805. (22) Souris, J. S.; Lee, C.-H.; Cheng, S.-H.; Chen, C.-T.; Yang, C.-S.; Ho, J.-A. A.; Mou, C.-Y.; Lo, L.-W. Surface Charge-mediated Rapid Hepatobiliary Excretion of Mesoporous Silica Nanoparticles. Biomaterials 2010, 31, 5564−5574. (23) Cauda, V.; Schlossbauer, A.; Bein, T. Bio-degradation Study of Colloidal Mesoporous Silica Nanoparticles: Effect of Surface Functionalization with Organo-Silanes and Poly(ethylene glycol). Microporous Mesoporous Mater. 2010, 132, 60−71.
with a unique nano carrier system for drug delivery and theranostics.
Huan Meng,†,# Min Xue,‡,# Jeffrey I. Zink,*,‡,§ Andre E. Nel,*,†,§ †
Division of NanoMedicine, Department of Medicine, Department of Chemistry & Biochemistry, and § California NanoSystems Institute, University of California, Los Angeles, United States ‡
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (A.E.N.);
[email protected]. edu (J.I.Z.). Author Contributions #
Equal contribution.
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REFERENCES
(1) Kaiser, C.; Buchel, G.; Ludtke, S.; Lauer, I.; Unger, K. K. Processing of Microporous/Mesoporous Submicron-Size Silica Spheres by Means of a Template-Supported Synthesis. Characterization of Porous Solids IV; Enaney, B., Mays, T. J., Rouquerol, J., Rodriguez-Reinoso, F., Sing, K. S. W., Unger, K. K., Eds.; Royal Society of Chemistry: Cambridge, U.K., 1997; pp 406−412. (2) Buchel, G.; Grun, M.; Unger, K. K. Tailored Syntheses of Nanostructured Silicas: Control of Particle Morphology, Particle Size and Pore Size. Supramol. Sci. 1998, 5, 253−259. (3) Lu, J.; Liong, M.; Zink, J.; Tamanoi, F. Mesoporous Silica Nanoparticles as a Delivery System for Hydrophobic Anticancer Drugs. Small 2007, 3, 1341−1346. (4) He, Q.; Zhang, Z.; Gao, F.; Li, Y.; Shi, J. In Vivo Biodistribution and Urinary Excretion of Mesoporous Silica Nanoparticles: Effects of Particle Size and PEGylation. Small 2011, 7, 271− 280. (5) Lee, C.-H.; Cheng, S.-H.; Wang, Y.-J.; Chen, Y.-C.; Chen, N.-T.; Souris, J.; Chen, C.-T.; Mou, C.-Y.; Yang, C.-S.; Lo, L.-W. NearInfrared Mesoporous Silica Nanoparticles for Optical Imaging: Characterization and In Vivo Biodistribution. Adv. Funct. Mater. 2009, 19, 215−222. (6) Liong, M.; Lu, J.; Kovochich, M.; Xia, T.; Ruehm, S. G.; Nel, A. E.; Tamanoi, F.; Zink, J. I. Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery. ACS Nano 2008, 2, 889−896. (7) Meng, H.; Liong, M.; Xia, T.; Li, Z.; Ji, Z.; Zink, J. I.; Nel, A. E. Engineered Design of Mesoporous Silica Nanoparticles to Deliver Doxorubicin and P-Glycoprotein siRNA to Overcome Drug Resistance in a Cancer Cell Line. ACS Nano 2010, 4, 4539−4550. (8) Meng, H.; Xue, M.; Xia, T.; Zhao, Y.-L.; Tamanoi, F.; Stoddart, J. F.; Zink, J,I.; Nel, A. E. Autonomous In Vitro Anticancer Drug Release from Mesoporous Silica Nanoparticles by pH-Sensitive Nanovalves. J. Am. Chem. Soc. 2010, 132, 12690−12697. (9) Xia, T.; Kovochich, M.; Liong, M.; Meng, H.; Kabehie, S.; George, S.; Zink, J. I.; Nel, A. E. Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs. ACS Nano 2009, 3, 3273−3286. (10) Radu, D. R.; Lai, C.-Y.; Jeftinija, K.; Rowe, E. W.; Jeftinija, S.; Lin, V. S. Y. A Polyamidoamine Dendrimer-Capped Mesoporous Silica Nanosphere-Based Gene Transfection Reagent. J. Am. Chem. Soc. 2004, 126, 13216−13217. (11) Slowing, I. I.; Trewyn, B. G.; Lin, V. S. Y. Mesoporous Silica Nanoparticles for Intracellular Delivery of Membrane-Impermeable Proteins. J. Am. Chem. Soc. 2007, 129, 8845−8849. (12) Meng, H.; Xue, M.; Xia, T.; Ji, Z.; Tarn, D. Y.; Zink, J. I.; Nel, A. E. Use of Size and a Copolymer Design Feature to Improve the 359
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