Visualization of drug delivery processes using AIEgens

Abstract

Drug delivery systems (DDSs) have been extensively studied as carriers to deliver small molecule chemo-drugs to tumors for cancer therapy. The therapeutic efficiency of chemo-drugs is crucially dependent on the effective drug concentrations in tumors and cancer cells. Novel DDSs that can simultaneously unveil drug distribution, drug release/activation behaviors and offer early evaluation of their therapeutic responses are highly desirable. Traditional fluorescent dye-labeled DDSs may suffer from notorious aggregation-caused quenching (ACQ) with limited sensitivity for bioimaging; in addition, the intrinsic fluorescence of these dyes requires careful selection of energy acceptor or quencher moieties for a light-up probe design, which complicates the development of self-reporting DDSs, especially the ones for reporting multiple processes. The recently emerged fluorogens with aggregation-induced emission characteristics (AIEgens) offer a straightforward solution to tackle this challenge. Thanks to the unique properties of AIEgens, new theranostic DDSs have been developed for simultaneous drug delivery and bioimaging with high signal to background ratio and multiple signal reporting capabilities. In this mini-review, we summarize the recent development of theranostic DDSs based on AIEgens for monitoring the drug distribution, drug activation and prediction of the therapeutic responses. Through illustration of their design principles and application examples, we hope to stimulate the interest in the design of more advanced theranostic DDSs for biomedical research.

Fig. 1. Fluorescence photographs of solutions or aggregates of tetraphenylethene (TPE) in THF/water mixtures with different amounts of water (vol%), showing a typical AIE phenomenon.

Fig. 2. Schematic representation of the DDSs based on AIEgens used for monitoring the drug distribution, drug activation, and in situ prediction of therapeutic responses.

Fig. 3. Schematic illustration of drug-loaded micelles with AIE properties as novel theranostic platforms for intracellular imaging and cancer treatment. Reprinted with permission from ref. 24, 26 and 27. Copyright 2014 American Chemical Society. Copyright 2015 Royal Society of Chemistry.

Fig. 4. (A) Schematic illustration showing the formation of TPE–DOX NPs, the intracellular drug releasing site, and real time sub-cellular imaging of TPE NPs and DOX by emission color transitions. (B) Spatial distributions of TPE NPs, DOX and TPE–DOX NPs in MCF-7s cells. CLSM images of TPE NPs, DOX and TPE–DOX NPs distribution; lysosomes were stained by Lysotracker Green. (C) Detailed TPE–DOX NPs spatiotemporal distribution in MCF-7s cells. Reprinted with permission from ref. 29. Copyright 2014 Wiley-VCH.

Fig. 5. (A) Chemical structure of a reactive oxygen species (ROS) responsive polymer. (B) The mechanism of ROS responsive nanoparticles (S-NPs) complexed with DNA (S-NPs/DNA) to the transgene expression. (C) CLSM images of HeLa cells incubated with YOYO-1 labeled S-NPs/DNA complexes (C1) in the dark, and with light irradiation for (C2) 2 min and (C3) 5 min. Green: YOYO-1 fluorescence (E _x: 488 nm; E _m: 505–525 nm); red: S-NPs fluorescence (E _x: 405 nm; E _m: > 560 nm). Yellow: co-localization of red and green pixels. (C4) CLSM image illustrating the localization of YOYO-1–DNA after light irradiation with a further 4 h incubation. Green: YOYO-1 fluorescence; red: living nuclei stained with DRAQ5 (E _x: 633 nm; E _m: > 650 nm); yellow: co-localization of red and green pixels. Reprinted with permission from ref. 30. Copyright 2015 Wiley-VCH.

Fig. 6. Intracellular trajectory of nanoscaled drug delivery systems of the TPE–Hyd–DOX nano-prodrug in cells. Reprinted with permission from ref. 33. Copyright 2015 American Chemical Society.

Fig. 7. (A) Schematic illustration of the TPE-based prodrug design strategy and (B) the fluorescence turn-on monitoring of drug activation with different incubation times. Reprinted with permission from ref. 35. Copyright 2014 Royal Society of Chemistry.

Fig. 8. (A) Chemical structure of TPP–TPE–NQO1. (B) Representative images of mice bearing HCT116 cells, pretreated with control plasmid (left) and NQO1 expression plasmid (right) under white light (top) and the representative in vivo fluorescence images of TPP–TPE–NQO1 accumulation in xenograft tumors (bottom; E _x: 430–480 nm, E _m: 490–550 nm). (C) Dissected organs and tumors (top) and their fluorescence images (bottom) of TPP–TPE–NQO1-injected mice (E _x: 430–480 nm, E _m: 490–550 nm). Reprinted with permission from ref. 39. Copyright 2016 Royal Society of Chemistry.

Fig. 9. (A) Chemical structure of a red emissive AIE probe for targeted bioimaging and photodynamic therapy of cancer cells. (B) CLSM images of HeLa cells after incubation with the probe (10 μM) in an acidic (pH 5.5) environment. The probe was excited with a 488 nm laser, and the emission was collected with a 580–680 nm filter. (C) Comparison of cell viability for HeLa cells, U2OS cells, and HEK293 cells under different conditions. Reprinted with permission from ref. 48. Copyright 2014 American Chemical Society.

Fig. 10. (A) Structure of theranostic probe TPETP–AA–Rho–cRGD and schematic representation of the proposed singlet oxygen self-reporting mechanism. (B and C) CLSM images of the probe (10 μM), incubated MDA-MB-231 cells, with light irradiation at a power density of 0.10 W cm^–2 for (B1 and C1) 0 min, (B2 and C2) 2 min, (B3 and C3) 4 min and (B4 and C4) 4 min in the presence of Asc (100 μM). (B1–B4) Red fluorescence (TPETP, E _x: 405 nm; E _m: > 650 nm); (C1–C4) green fluorescence (Rho, E _x: 488 nm, E _m: 505–525 nm). Reprinted with permission from ref. 51. Copyright 2015 Royal Society of Chemistry.

Fig. 11. (A) The molecular structure of the targeted theranostic platinum(iv) prodrug TPS–DEVD–Pt–cRGD. (B) Schematic illustration of the targeted theranostic platinum(iv) prodrug TPS–DEVD–Pt–cRGD with a built-in AIE light-up apoptosis sensor for non-invasive in situ early evaluation of its therapeutic responses. (C) Real-time CLSM images displaying the apoptotic progress of TPS–DEVD–Pt–cRGD (5 μM) stained U87-MG cells. The green fluorescence is from TPS (E _x: 488 nm, E _m: 505–525 nm). Reprinted with permission from ref. 54. Copyright 2014 American Chemical Society.

Fig. 12. (A) Chemical structure of theranostic DDS TPETP–SS–DEVD–TPS–cRGD. (B) Schematic illustration of the dual-targeted probe for real-time and in situ monitoring of PS activation and therapeutic responses. (C) Confocal images of MDA-MB-231 cells after incubation with the probe for different times. The blue fluorescence is from the cell nuclei stained with Hoechst (E _x: 405 nm; E _m: 430–470 nm); the red fluorescence is from the AIE residue (E _x: 405 nm; E _m: > 560 nm). (D) Confocal images of MDA-MB-231 cells upon incubation with the probe for 4 h with light irradiation for different times. The blue fluorescence is from the nuclei of the cells stained with Hoechst; the green fluorescence is from the TPS residue (E _x: 405 nm; E _m: 505–525 nm). Reprinted with permission from ref. 55. Copyright 2015 Wiley-VCH.

Fig. 13. (A) Chemical structure of theranostic DDS PLL-g-PEG/DPA/TPS/PheA. (B and C) Schematic illustration of PLL-g-PEG/DPA/TPS/PheA used for self-tracking, cancer cell imaging, phototoxicity restoration (PS activation) in the acidic lysosome, and in situ monitoring of lysosomal membrane disruption as an indicator of therapeutic responses and cell death prediction. Reprinted with permission from ref. 56. Copyright 2015 Wiley-VCH.