Photochemical Synthesis of Nonplanar Small Molecules with Ultrafast Nonradiative Decay for Highly Efficient Phototheranostics.

There has been much recent progress in the development of photothermal agents (PTAs) for biomedical and energy applications. Synthesis of organic PTAs typically involves noble metal catalysts and high temperatures. On the other hand, photochemical synthesis, as an alternative and green chemical technology, has obvious merits such as low cost, energy efficiency, and high yields. However, photochemical reactions have rarely been employed for the synthesis of PTAs. Herein, a facile and high-yield photochemical reaction is exploited for synthesizing nonplanar small molecules (NSMs) containing strong Michler's base donors and a tricyanoquinodimethane acceptor as high-performance PTAs. The synthesized NSMs show interesting photophysical properties including good absorption for photons of over 1000 nm wavelength, high near-infrared extinction coefficients, and excellent photothermal performance. Upon assembling the NSMs into nanoparticles (NSMN), they exhibit good biocompatibility, high photostability, and excellent photothermal conversion efficiency of 75%. Excited-state dynamic studies reveal that the NSMN has ultrafast nonradiative decay after photoexcitation. With these unique properties, the NSMN achieves efficient in vivo photoacoustic imaging and photothermal tumor ablation. This work demonstrates the superior potential of photochemical reactions for the synthesis of high-performance molecular PTAs.

Stable Organic Photosensitizer Nanoparticles with Absorption Peak beyond 800 Nanometers and High Reactive Oxygen Species Yield for Multimodality Phototheranostics.

Effective multimodality phototheranostics under deep-penetration laser excitation is highly desired for tumor medicine, which is still at a deadlock due to lack of versatile photosensitizers with absorption located in the long-wavelength region. Herein, we demonstrate a stable organic photosensitizer nanoparticle based on molecular engineering of benzo[c]thiophene (BT)-based photoactivated molecules with strong wavelength-tunable absorption in the near-infrared region. Via molecular design, the absorption and singlet oxygen generation of BT molecules would be reliably tuned. Importantly, the nanoparticles with a red-shifted absorption peak of 843 nm not only show over 10-fold reactive oxygen species yield compared with indocyanine green but also demonstrate a notable photothermal effect and photoacoustic signal upon 808 nm excitation. The in vitro and in vivo experiments substantiate good multimodal anticancer efficacy and imaging performance of BT theranostics. This work provides an organic photosensitizer nanoparticle with long-wavelength excitation and high photoenergy conversion efficiency for multimodality phototherapy.

Magnetic nanoparticles coated with polyphenols for spatio-temporally controlled cancer photothermal/immunotherapy.

As the combination of photothermal therapy (PTT) with immunotherapy provides an effective strategy in cancer treatment, a magnetic nanoparticle delivery system was constructed to load indocyanine green (ICG) and immunostimulator R837 hydrochloride (R837) for spatio-temporally PTT/immunotherapy synergism in cancer. This delivery system is composed of Fe3O4 magnetic nanoparticles (MPs) as the core to load ICG and polyethylene glycol polyphenols (DPA-PEG) as the coating layer to load R837, which formed R837 loaded polyphenols coating ICG loaded magnetic nanoparticles (MIRDs). After intravenous injection, the formed MIRDs resulted in long circulation, magnetic resonance imaging (MRI) guides, and magnetic targeting. Once targeting to the tumor, the MIRDs with the near-infrared (NIR) irradiation caused tumor ablation and resulted in tumor-associated antigens releasing to induce the body's immunological response, which was markedly improved it to attack the tumors with the R837 releasing from the outer DPA-PEG. In this case, the synergism of the PTT and immunotherapy inhibited tumor growth, metastasis and recurrence, which resulted in potent anticancer therapeutic effects with few side effect.

Two-step tumor-targeting therapy via integrating metabolic lipid-engineering with in situ click chemistry.

Highly efficient tumor-targeted therapy remains a great challenge due to the complexity and heterogeneity of tumor tissues. Herein, we developed an in vivo two-step tumor-targeting strategy by combining metabolic lipid-engineering with a stain-promoted azide-alkyne 1,3-dipolar cycloaddition (SPAAC) reaction, independent of the tumor microenvironment and cell phenotype. Firstly, exogenously-supplied azidoethyl-cholines (AECho) were metabolically incorporated into the cell membranes in tumor tissues through the intrinsic biosynthesis of phosphatidylcholine. The pre-inserted and accumulated azido groups (N3) could subsequently serve as 'artificial chemical receptors' for the specific anchoring of dibenzocyclooctyne (DBCO) modified biomimetic nanoparticles (DBCO-RBCG@ICG) via in situ click chemistry, resulting in significantly enhanced tumor-targeting and then an improved photothermal therapy effect. Such a two-step targeting strategy based on these cutting-edge techniques provided new insights into the universal and precise functionalization of living tissues for site-specific drug delivery in the diagnosis and treatment of various diseases.

Cell Membrane Camouflaged Hydrophobic Drug Nanoflake Sandwiched with Photosensitizer for Orchestration of Chemo-Photothermal Combination Therapy.

Many candidate anticancer drugs have suffered from their intrinsic hydrophobicity, which poses several obstacles for clinical application. To overcome this challenge and further improve the performance, herein a nanocrystal-based biomimetic formulation with a sandwich structure is developed. As the core, flake shaped nanocrystals (NCs) with high loading of the hydrophobic drug hydroxycamptothecin (HCPT) are synthesized via a mild nanoprecipitation process by exploring the template effect of serum albumin. Meanwhile, the camouflaged cancer cell membrane (CM) composed of plentiful membrane proteins endows the NCs with homotypic targeting capacity at tumor sites. In addition, the photosensitizer indocyanine green sandwiched between NCs and CM not only converts near infrared light to heat for photothermal treatment but also improves the dissolution of HCPT NCs for chemotherapy. These features corporately achieve the orchestration of chemo-photothermal combination therapy and completely inhibit tumor growth with few adverse effects, showing promise as a new modality for the utilization of hydrophobic drugs to treat cancer.