Two-Photon Near-Infrared AIE Luminogens as Multifunctional Gene Carriers for Cancer Theranostics

Abstract

Construction of multifunctional nonviral gene vectors to execute defined tasks holds great potential for the precise and effective treatment of gene-associated diseases. Herein, we have developed four large π-conjugation triphenylamine derivatives bearing two polar [12]­aneN3 heads and a lipophilic tail for applications in gene delivery, one/two-photon-triggered near-infrared (NIR) fluorescence bioimaging, and combined photodynamic therapy (PDT) and gene therapy of cancer. These compounds possess typical NIR aggregation-induced emission characteristics, mega Stokes shifts, strong two-photon excitation fluorescence, and excellent DNA condensation abilities. Among them, vector 4 with a tail of n-hexadecane realized a transfection efficiency as high as 6.7 times that of the commercial transfection agent Lipofectamine 2000 in HEK293T cell lines. Using vector 4 as an example, transfection process tracking and ex vivo/in vivo tumoral imaging and retention with high resolution, high brightness, deep tissue penetration, and good biosafety were demonstrated. In addition, efficient singlet oxygen (1O2) generation by the DNA complex formed by vector 4 (4/DNA) resulted in effective PDT. Combined with anticancer gene therapy, collaborative cancer treatment with a dramatically enhanced cancer cell-killing effect was achieved. The development of this “three birds, one stone” approach suggests a new and promising strategy for better cancer treatment and real-time tracking of gene delivery.

The fast-growing field of photo-driven theranostics based on aggregation-induced emission

“…215 Motivated by the favorable merits that two-photon excitation showed in highresolution imaging and deep-seated PDT, many two-photon excitation activatable AIEgens have been exploited for twophoton fluorescence imaging (TPFL) and TPFL-guided PDT by adjusting the conjugation length, coplanarity degree and polarizability extent. [216][217][218][219][220][221][222][223][224][225][226][227][228][229] Particularly, AIEgens are also demonstrated to show excellent aggregation-enhanced nonlinear optical effects as the two-photon absorption cross-section of AIE NPs can be increased by simply enhancing the loading amount of AIEgens inside the NPs. 230 In 2020, Zheng and coworkers prepared lipid-encapsulating AIE NPs by loading an ingeniously designed two-photon excitation-active AIEgen (TPE-PTB) (Fig.…”

Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical

“…Moreover, TTC-L-M-4/DOPE/p53 was injected into HeLa orthotopic tumor-bearing mice subcutaneously, and irradiated for 30 min, 24 h after injection, showing more effective tumor inhibition ability than other groups. Based on the same design principle, Tang et al proposed a promising strategy for gene delivery in HEK293T cell lines [ 124 ]. Finally, combined with PDT therapy to achieve synergistic therapy, the killing effect on cancer cells was significantly enhanced.…”

The locations of triphenylamine and tetraphenylethene on a cyclohexyl ring define a luminogen as an AIEgen or a DSEgen

“…In general, luminophores with charge-transfer (CT) characteristics are susceptible to solvent polarity, which in turn brings about obvious PL color changes in solvents with varying polarities, a phenomenon referred to as solvatochromism. 38,39 Thus, it is reasoned that TPAcTPE could exhibit a solvatochromic effect, while TPEcTPE and TPEcTPA should not have this property. To verify this speculation, the solvent effects on both the UV-vis and PL spectra were then examined in solvents with varying polarities.…”