Article pubs.acs.org/JACS Photoswitchable Nanoparticles for Triggered Tissue Penetration and Drug Delivery Rong Tong,†,‡ Houman D. Hemmati,‡ Robert Langer,† and Daniel S. Kohane*,‡ †Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ‡Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, United States *S Supporting Information ABSTRACT: We report a novel nanoparticulate drug delivery system that undergoes reversible volume change from 150 to 40 nm upon phototriggering with UV light. The volume change of these monodisperse nanoparticles comprising spiropyran, which undergoes reversible photoisomerization, and PEGylated lipid enables repetitive dosing from a single administration and enhances tissue penetration. The photo- switching allows particles to fluoresce and release drugs inside cells when illuminated with UV light. The mechanism of the light-induced size switching and triggered-release is studied. These particles provide spatiotemporal control of drug release and enhanced tissue penetration, useful properties in many disease states including cancer. ■ INTRODUCTION Controlled release technology is expected to have a profound impact in many medical fields including oncology.1 The incorporation of chemotherapeutic agents in nanoparticle (NP) delivery vehicles has improved drug solubility, reduced clearance, reduced drug resistance, and enhanced therapeutic effectiveness.2 With controlled release NP systems, a single dose can sustain drug levels within the desired therapeutic range for long periods in various diseases (e.g., diabetes3 or cancer4). Several nanoparticulate therapeutics, for example, Doxil (∼100 nm PEGylated liposome loaded with doxorubicin) and Abraxane (∼130 nm albumin-bound paclitaxel nano- particles), have been approved by the FDA, and have shown improved pharmacokinetics and reduced adverse effects compared to their parent drugs.5 However, currently approved nanomedicines provide modest survival benefits for patients,5,6 perhaps in part because of poor tumor penetration. Nanoparticle size is one crucial determinant of accumulation and penetration into tumor tissue.7 Nanoparticles with sub-100 nm sizes are optimal for the enhanced permeation and retention (EPR) effect for passive tumor targeting.8 However, physiological barriers, such as the dense interstitial matrixa complex assembly of collagen, glycosaminoglycans, and proteoglycanshinder the delivery of drugs throughout the entire tumor.9 For example, Doxil (∼100 nm) is found trapped near the tumor vasculature.10 Although the small size (molecular weight = 544 Da) of doxorubicin released from Doxil allows rapid diffusion, doxorubicin cannot migrate far from the particles due to rapid uptake of doxorubicin by perivascular cells, which results in heterogeneous therapeutic effects.11 Deep penetration of nanoparticles in tumors is necessary to enhance their therapeutic effect.12 Another significant drawback of commercially available drug delivery NPs is that drugs are released at a predetermined rate irrespective of patient needs or changing physiological circumstances. A triggerable drug delivery system would allow repeated on-demand dosing that would be adaptable to the patients’ regimen and allow multiple dosages from a single administration.13 It might also help address the potential importance of timing on therapeutic effect (“chrono-admin- istration”) in the treatment of cancer,14 a concept that is receiving burgeoning recognition, for example, the periodicity of VEGF expression in breast cancer regulates tumor cancer vascular permeability.15 Another clinical example of the importance of timing is that periodic infusion of angiotensin II via the tail vein can enhance macromolecular delivery into tumors by overcoming the barrier of elevated interstitial fluid pressure within tumors; no such increase of macromolecular uptake occurs either by an acute or chronic increase in blood pressure induced by angiotensin II.16 Furthermore, the permeability of many tumor models varies with time and in response to treatment, so that vascular pore sizes vary greatly, resulting in heterogeneous NP extravasation and drug delivery efficacy.5,17 On-demand drug release from NPs accumulated in tumors could allow in situ chrono-administration, potentially increasing drug retention in cancers, maximizing tumor killing and minimizing metastatic spread. Received: December 20, 2011 Published: March 5, 2012 © 2012 American Chemical Society 8848 dx.doi.org/10.1021/ja211888a | J. Am. Chem. Soc. 2012, 134, 8848−8855