Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light

Abstract

Nanotechnology has begun to play a remarkable role in various fields of science and technology. In biomedical applications, nanoparticles have opened new horizons, especially for biosensing, targeted delivery of therapeutics, and so forth. Among drug delivery systems (DDSs), smart nanocarriers that respond to specific stimuli in their environment represent a growing field. Nanoplatforms that can be activated by an external application of light can be used for a wide variety of photoactivated therapies, especially light-triggered DDSs, relying on photoisomerization, photo-cross-linking/un-cross-linking, photoreduction, and so forth. In addition, light activation has potential in photodynamic therapy, photothermal therapy, radiotherapy, protected delivery of bioactive moieties, anticancer drug delivery systems, and theranostics (i.e., real-time monitoring and tracking combined with a therapeutic action to different diseases sites and organs). Combinations of these approaches can lead to enhanced and synergistic therapies, employing light as a trigger or for activation. Nonlinear light absorption mechanisms such as two-photon absorption and photon upconversion have been employed in the design of light-responsive DDSs. The integration of a light stimulus into dual/multiresponsive nanocarriers can provide spatiotemporal controlled delivery and release of therapeutic agents, targeted and controlled nanosystems, combined delivery of two or more agents, their on-demand release under specific conditions, and so forth. Overall, light-activated nanomedicines and DDSs are expected to provide more effective therapies against serious diseases such as cancers, inflammation, infections, and cardiovascular disease with reduced side effects and will open new doors toward the treatment of patients worldwide.

Figure 1

Light-activated mechanisms used for DDSs, including photoshrinking, photoisomerization, photobond cleavage, photothermal, photoreduction, as well as electrostatic assembly/disassembly.

Figure 2

(a) Photocleavable DDSs: (i) encapsulation of the cargo, photocleavage reaction, and subsequent cargo release; (ii) light-triggered release of proteins (bovine serum albumin) from nanocages. Reprinted with permission from ref ; copyright 2016, American Chemical Society. (b) Schematic indicating synthesis of a nanocarrier comprised of HMS@C18@HAMAFA-b-[7-(didodecylamino)coumarin-4-yl] methyl methacrylate and its application for delivery and controlled release of cargos using degradation upon NIR light exposure. Reprinted from ref ; copyright 2013, The Royal Society of Chemistry.

Figure 3

(a) The principle of uncaging photolabile protecting groups through exposure to light, followed by release of the caged and protected compound. Reprinted from ref (open access). (b) Intracellular uncaging and deprotecting of an NDBF-caged thiol group-incorporated peptide due to UV irradiaton followed by migration of the liberated peptide from the Golgi/cytosol to the cellular plamsa membrane as a result of enzymatic palmitoylation. Reprinted with permission from 35; copyright 2016, American Chemical Society. (c) Mechanism of the photodynamic effect: a photosensitizing dye or molecule in ground-state absorbs a photon and then excites to a singlet state, and fluorescence emission occurs due to an energy loss; intersystem crossing can then lead to a long-lived triplet state that can induce photochemical reactions or lose energy via phosphorescence. This photochemistry can trigger local generation of ROS (e.g., singlet oxygen, superoxide radicals, or hydroxyl radicals). Reprinted with permission from ref ; copyright 2011, John Wiley and Sons. (d) Synthesis of diselenide-cross-linked nanogels and their biodegradable behavior as well as NIR-induced ROS-triggered nanogel degradation and controlled release of the cargos. Reprinted with permission from ref ; copyright 2015, John Wiley and Sons.

Figure 4

(a) Fabrication process of cross-linked nanovehicles from cargo molecule-loaded Au nanovehicles for light-sensitive cargo release, including AuNP surface modification with semifluorinated ligands, then forming self-assembled and cross-linked nanovehicles. Reprinted with permission from ref ; copyright 2013, American Chemical Society. (b) Red-light-triggered DDS using mAzo/β–CD supramolecular valve-modified MSNs. Reprinted with permission from ref ; copyright 2016, American Chemical Society. (c) Effect of 254 nm irradiation on gel-to-sol transition of Polyamide 6 bearing pendant cinnamoyl moieties in hexafluoroisopropanol milieu. Reprinted with permission from ref ; copyright 2014, American Chemical Society. (d) Photo-cross-linking of cinnamate moieties under 280 nm UV irradiation leading to a size decrease in the NP. Reprinted with permission from ref ; copyright 2009, American Chemical Society.

Figure 5

(a) Photoinduced thermosensitive Cu 1.75 S@p(N-isopropylacrylamide (NIPAAm)) methylacrylic acid nanocomposites. Reprinted with permission from ref ; copyright 2015, Springer. (b) Chemical structure of light-responsive Pt(IV) prodrugs C1–C4 (top), fabrication and self-assembly of micellar NPs NC1–NC4, and their UVA irradiation-triggered cargo (Pt(II)) release (bottom). Reprinted with permission from ref ; copyright 2014, Elsevier.

Figure 6

(a) Light-triggered autonomous self-assembly/disassembly (i), and mechanism of spiropyran-functionalized Janus motors using UV and green light irradiation (ii). (b) Time lapse images of the dynamic self-assembly (i) and disassembly (ii). Reprinted with permission from ref ; copyright 2015, American Chemical Society. (c) Schematic of cargo release profile from the colloidosomes induced by 365 nm laser irradiation with a 5 min on/off cycle. (d) Schematic of formation of the stable colloidosome vehicles via self-assembly of oppositely charged NPs (NBSN-1 and NBSN-2) in an oil/water emulsion and their disassembly by light irradiation (365 nm laser for 10 min). Reprinted with permission from ref ; copyright 2015, John Wiley and Sons. (e) Light-induced self-assembly of nonphotoresponsive NPs functionalized with COOH-terminated ligands within a protonated merocyanine (MCH⁺)-containing photoswitchable medium. (f) Transmission electron microscopy images showing reversible dispersion/disassembly (left) and aggregation/assembly (right) of Au NPs. Reprinted with permission from ref ; copyright 2015, Nature Publishing Group.

Figure 7

(a) MSNs incorporating azobenzene moieties “A” and two photon fluorophores “F”, forming so-called MAF nanoimpellers, and a 760 nm two-photon irradiation-triggered drug molecule release from them via FRET and photoisomerization of azobenzenes. Reprinted with permission from ref ; copyright 2013, John Wiley and Sons. (b) Two-photon excited photocleavage and uncaging of photolabile protecting groups: (i) two-photon excitation, (ii) dye donates an electron to the release unit, (iii) this unit undergoes a photochemical reaction ending in cargo release. Reprinted from ref ; copyright 2015, permission from The Royal Society of Chemistry.

Figure 8

(a) Photoreactions of photolabile compounds triggered by conversion of NIR to UV/vis via UCNPs, (b) synthesis of NIR-responsive multifunctional core–shell–shell UCNPs for theranostics of cancers. Copyright 2015, permission from The Royal Society of Chemistry. (b) (i) UCNP core, (ii) core–shell structure of UCNP@SiO₂ methylene blue, (iii) core–shell–shell structure of UCNP@SiO₂ (methylene blue)@mSiO₂ NP, (iv) surface modification of the cargo-loaded NPs with linker β-CD, (v) NIR-triggered release of cargos (i.e., rhodamine B), cell imaging, and PDT in which ¹O₂ generation is induced and causes cleavage of ¹O₂-sensitive linkers followed by dissociation of β-CD gatekeepers. Reprinted with permission from ref ; copyright 2016, American Chemical Society. (c) (i) Fabrication process of mesoporous silica-coated UCNPs and (ii) NIR-activated release of DOX employing UCNPs and trans–cis photoisomerization of azobenzene moieties incorporated in the pores of the mesoporous silica layer. Reprinted with permission from ref ; copyright 2013, John Wiley and Sons.

Figure 9

(a) Scheme of the preparation and (b) release profile of coumarin 102. Under UV irradiation, dissociation of the self-assembled micelles occurred, and an acidic milieu induced swelling of the micelles with both conditions leading to drug release. The combination of pH and light stimuli gave a substantial boost to the release rate compared to that of a single pH or light trigger. In alkaline milieu or above the lower critical solution temperature (LCST), NPs shrunk with insignificant release. Reproduced from ref ; copyright 2015, permission from The Royal Society of Chemistry.

Figure 10

Schematic illustrating the anticancer activity of DOX and irinotecan coloaded GO under NIR laser irradiation. Reprinted with permission from ref ; copyright 2015, American Chemical Society.

Figure 11

(a) Nanocarrier comprised of DNA and PpIX-trapped pH-responsive chimeric peptide: (i) PpIX and DNA encapsulation, (ii) matrix metalloproteinase-2 enzyme-induced detachment of PEG, (iii) nanocarrier endocytosis facilitated by electrostatic interaction, (iv) endosome formation together with acidification, (v) “proton sponge” effect and photochemical internalization (PCI) effect-induced endosomal escape, (vi) cytoplasmic diffusion;, (vii) translocation into nucleus followed by gene expression, and (viii) long-term photoirradiation-triggered phototoxicity. Reprinted with permission from ref ; copyright 2015, John Wiley and Sons. (b) Antitumor activity (i.e., tumor volume versus time curve) in a Panc-1 xenograft animal model under 665 nm light irradiation. Au nanorods/DOX/siRNA with NIR irradiation indicates the strongest inhibition. Reproduced from ref (open access). (c) Schematic of NIR-activated single-stranded DNA (ssDNA)-caged aptamer-conjugated nanocarrier. Reprinted with permission from ref ; copyright 2015, Springer.

Figure 12

(a) Radiosensitization by a UCNP core/porous silica shell nanoplatform with CDDP as a radio-sensitizer. Reprinted with permission from ref ; copyright 2013, American Chemical Society. (b) Red-light triggered disassembly of the mAzo/β-CD complexes due to cis–trans isomerization, and their blue light/photothermal-triggered reassembly (left), followed by (c) red-light-induced protein release (right). Reprinted from ref ; copyright 2015, permission from The Royal Society of Chemistry.

Figure 13

(a) (i) Dgel, (ii) Dox (red dots)- and AuNP (yellow balls)-incorporated Dgel, (iii) photothermal heating (AuNPs become heated (red balls)), and (iv) heat-triggered denaturation of AuNP-Dgel inducing release of DOX. AuNP assembly and disassembly represented as a shift in absorption peak in the curve. Reproduced from ref ; copyright 2015, permission from The Royal Society of Chemistry. (b) (i) Light-responsive AuNC copolymer and (ii, iii) its logic-gate function through NIR irradiation encoding. Reprinted with permission from ref ; copyright 2014, John Wiley and Sons.