Figure 9. Proposed assembly states of reversible light-triggered SP NPH size switching: SP NPH converted MC NPH upon irradiation (solid arrow, i to ii); graduate transition (dash arrow, ii to iii to i) from MC NPH to SP NPH in the dark, with the conversion of zwitterionic MC-C9 to hydrophobic SP-C9 to cause the reassembly of NPH. Yellow oval, SP molecule; blue line, the alkyl chain in SP; red, lipid part; green line, PEG; and purple oval, MC molecule. PEG shell, beneath which are the hydrophobic alkyl chains of the DSPE and the SP-C9 (Figure 9i). Given the reported destabilization of monolayer surfactant films by SP,48 SP is likely to perturb the alkyl chain packing inside the SP NPH, causing the hydrophobic core to have a loose structure (Figure 9i) and increasing particle size. Upon irradiation, SP converts to zwitterionic MC, that moves outward to relatively polar microenvironments within the NPH, such as the phosphogly- cerol moiety linking DSPE and PEG.49 The polar micro- environment around MC in NPH is evidenced by the fact that the λmax of MC in NPH (551 nm) is comparable to the λmax of MC in polar solvents (Figure S11).49b (The effective dielectric constant of the microenvironment of MC in NPH is ∼18, i.e., is relatively polar; detailed discussion in Figure S11.) As MC moves toward the more hydrophilic PEG layer of the NPH, it moves away from the alkyl chains of the DSPE and lecithin, allowing them to assemble tightly inside the hydrophobic cores; in consequence, the NPH volume shrinks (Figure 9ii). The NPH size will increase again once MC reverts to SP and translocates into the hydrophobic core, perturbing the assembly of the lipids. The alkyl chains of DSPE and lecithin may impede the isomerization of MC to SP, as suggested by the fact that the isomerization in NPH (λmax = 551 nm) was 12.2-fold slower than that of free MC-C9 in acetonitrile (λmax = 560 nm, Figure S12). This slowing of the isomerization from MC to SP has also been observed in MC in polymeric films.18a ■ CONCLUSION We have described photoswitchable NPHs that allow spatiotemporal controlled release of drugs and enhanced tissue penetration upon UV illumination. This formulation was simple ■ ■ ■ Journal of the American Chemical Society Article REFERENCES (1) (a) Langer, R. Acc. Chem. Res. 1993, 26, 537. (b) Langer, R.; Folkman, J. Nature 1976, 263, 797. (2) (a) Gref, R.; Minamitake, Y.; Peracchia, M. T.; Trubetskoy, V.; Torchilin, V.; Langer, R. Science 1994, 263, 1600. (b) Langer, R. Nature 1998, 392, 5. (3) Kost, J.; Langer, R. Adv. Drug Delivery Rev. 2001, 46, 125. (4) Farokhzad, O. C.; Langer, R. ACS Nano 2009, 3, 16. (5) Jain, R. 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K.; Berk, D. A.; Papahadjopoulos, 8854 dx.doi.org/10.1021/ja211888a | J. Am. Chem. Soc. 2012, 134, 8848−8855 to produce, and tolerated lyophilization, which may facilitate potential clinical translation.28 The NPHs could achieve high loadings with various drugs (chemotherapeutic, local anes- thetics). The NPHs developed here could be adapted for a range of applications, as they could be modified with functional ligands. The phototriggering system could also be used to enhance NPH tissue penetration, which might improve antitumor efficacy, penetration into ocular tissue and across the tympanic membrane. This is quite different from conventional approaches, where external energy sources enhance penetration by disrupting tissues.50 The photoswitchability is an attractive feature in that it can allow fine spatiotemporal control of drug release: drug is released at the irradiated site, during irradiation. This approach also obviates the need for developing a specific ligand to the tissue of interest. We have previously developed an analogous approach to the same problem by decorating nanoparticles with nonspecific ligands caged with photosensitive chemical protecting groups; upon irradiation, the caging groups would come off, allowing the nanoparticles to bind.41b These two approaches and others13 could prove synergistic. ASSOCIATED CONTENT *S Supporting Information Experimental details, characterization of SP NPHs, in vitro characterization, ex vivo histology, mechanism study. This material is available free of charge via the Internet at http:// pubs.acs.org. AUTHOR INFORMATION ACKNOWLEDGMENTS Corresponding Author Daniel.Kohane@childrens.harvard.edu Notes The authors declare no competing financial interest. ■ The work was supported by a grant from Sanofi-Aventis, and NIH (R21DC009986).