Finely-Tailored Conjugated Small Molecular Nanoplatforms for Near-Infrared Phototheranostics


Student thesis: Doctoral Thesis

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Award date15 Sept 2022


Near-infrared (NIR) phototheranostics that simultaneously achieve diagnosis and therapy upon NIR light excitation have received intense attention recent years. Among many phototheranostic agents, conjugated small molecular agents stand out by virtue of their precisely defined chemical structure, flexible and versatile molecular design, high reliability, and superior photophysical properties. This thesis mainly focuses on the design and development of conjugated small molecular (CSMs) nanoplatforms for biomedical applications, including imaging, therapy, and synergistic theranostics.

Firstly, we developed a biodegradable photothermal therapeutic (PTT) agent, π-conjugated oligomer nanoparticles (F8-PEG NPs), for highly efficient cancer theranostics. By exploiting an oligomer with excellent near-infrared (NIR) absorption, its nanoparticles show a high photothermal conversion efficiency (PCE) up to 82% surpassing more reported inorganic and organic PTT agents. In addition, the oligomer nanoparticles show excellent photostability and good biodegradability. The F8-PEG NPs are also demonstrated to have excellent biosafety and PTT efficacy both in vitro and in vivo. This work not only demonstrates a promising oligomer-based PTT agent, but also provides insight into developing highly efficient nanomaterials for cancer theranostics.

Secondly, a near-infrared (NIR) small molecule (ETTC) with “acceptor-donor-acceptor” structure was designed and synthesized by coupling rigidity and flexibility to simultaneously achieve fluorescence imaging in the second NIR window (NIR-II FL), photoacoustic (PA) imaging, photothermal therapy (PTT) and photodynamic therapy (PDT). Efficacy of each functionality is well balanced and optimized (NIR-II quantum yield: 3.0%; reactive oxygen species generation: 3.2 folds higher than ICG; photothermal conversion efficiency: 52.8%), which are attributed to the appropriate coupling of rigid and flexible structures in ETTC to tactically manipulate energy dissipation paths (non-radiative against radiative decay). As a proof-of-concept, under effective guidance of local-tumor imaging by PA and whole-body imaging by NIR-II FL, complete tumor eradication was achieved via PDT and PTT combinational therapy. This work provides a novel perspective into conceiving and developing small molecules for efficient versatile biomedical applications.

Thirdly, we exploit a diradicaloid molecular structure for enhancing NIR absorption to facilitate efficient photoacoustic imaging (PAI)-guided photothermal therapy (PTT). The donor (D)-acceptor (A) interaction in the diradicaloid molecule (DRM) leads to strong charge transfer leading to obvious diradical characteristics which is beneficial for NIR absorption. The DRM possesses excellent light-harvesting ability, with a mass extinction coefficient of ~220 L g-1 cm-1 which is much higher than those (~ 5 to 100 L g-1 cm-1) of typical organic molecules. After assembling into nanoparticles (DRM NPs), they show good water dispersibility, good photostability and impressive performance for PAI-guided PTT in vitro and in vivo. The impressive in vitro and in vivo performance show that developing small molecules with diradicaloid structures can be an effective approach for enhancing NIR harvesting capability for biomedical applications.

Fourth, 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 (NIR) 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 NSMNs have ultrafast nonradiative decay upon 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.