Cancer is one of the most dreaded diseases causing high mortality and deaths around the world. Tremendous efforts have been made to develop effective therapeutic methods such as chemotherapy and surgery for curing cancer. Although significant progress has been achieved, integrating high therapeutic efficiency and low side effects in one therapeutic approach is still challenging. As emerging treatment modalities, phototherapies bring new hope for cancer treatment owing to their merits of high selectivity, effective antitumor results, and lower side effects. Phototherapies mainly include photodynamic therapy (PDT) and photothermal therapy (PTT), which use light activatable agents to generate reactive oxygen species (ROS) and heat, respectively, to kill cancer cells. Regarding excitation light source, near-infrared light (NIR) is preferred in tumor eradication due to its deep tissue penetration and low phototoxicity to the body. Among all phototherapy agents, organic nanoparticles (NPs) show great potential as they have ideal biocompatibility, good metabolism properties, superior therapeutic and diagnosis effects. This thesis mainly focuses on NIR light-activatable organic NPs in cancer diagnosis and therapies, including PDT and PTT.

Chapter 1 introduces the general background of phototherapies and bioimaging modalities, including their fundamental principles, therapeutic agents, and current limitations. Besides, the nanoparticles in cancer theranostics are summarized from the perspectives of general NPs’ characteristics and recent advances in phototheranostics nanoparticles design.

Chapter 2 reports a biocompatible free radical nanogenerator for high-performance sequential hypoxic tumor therapy. A safe carrier bovine serum albumin (BSA) is used to load U.S. Food and Drug Administration-approved photothermal molecule indocyanine green (ICG) and radical initiator AIPH to form BIA NPs. Under 808 nm irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, the aggregation-quenched fluorescence of ICG molecules in the NPs can be gradually recovered upon irradiation enabling real-time drug release monitoring. More attractively, these BIA NPs exhibit remarkable antitumor effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate.

Although a NIR-excited radical nanogenerator is developed in Chapter 2, it encounters the problem of loading radical initiator leakage during delivery. Thus, developing a single molecule with good radical generation capability for NIR phototherapy is highly desired. Chapter 3 reports a stable organic photosensitizer for NIR light-activated phototheranostics, which addresses the problems in the previous research. Herein, A donor (D)-π-acceptor (A)-configured polar molecule (BT3) with an absorption peak beyond 800 nm is employed for combined PDT and PTT. After assembled with polyethylene glycol (PEG), the formed nanoparticles show over 10-fold ROS yield compared with commercially used ICG and demonstrate a notable photothermal effect and photoacoustic signal upon 808 nm excitation. In vitro and in vivo results substantiate high multimodal anticancer efficacy and good imaging performance of developed organic theranostics.

As a further extension of the study in Chapter 3, Chapter describes NIR-II emissive aggregation-induced emission (AIE) NPs for imaging-guided photothermal therapy. This study solves the problem of lacking NIR-II fluorescence imaging guidance in the last project. After inserting a phenyl ring and methyl group into the BT3 molecule in chapter 3, the formed D-π-A type BT5 molecule shows apparent AIE effects in contrast to the aggregation-caused quenching (ACQ) effects observed in BT3. This intriguing change of optical properties is because the added methyl group improves the backbone distortion in BT5, which finally induces the desired AIE effects. The BT5 NPs show good absorption in 808 nm and apparent NIR-II fluorescence in 900-1200 nm. Compared with NIR imaging dye ICG, the developed NPs show better stability even under laser irradiation of high power densities. Under 808 nm laser irradiation, the NPs show remarkable photothermal performance and cancer cell killing effect. This study demonstrates superior AIE NPs for NIR-II imaging-guided PTT of cancer.

The thesis is summarized with a conclusion of all the studies mentioned above in Chapter 5 and a discussion on the future development of near-infrared light activatable nanoparticles in phototheranostics.