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To study the effects of X-shaped amphiphilic block copolymers on delivery of docetaxel (DTX) and the reduction-sensitive property on drug release, a novel reduction-sensitive amphiphilic copolymer, (PLGA) 2 -SS-4-arm-PEG 2000 with a Gemini-like X-shape, was successfully synthesized. The formation of nanomicelles was proved with respect to the blue shift of the emission fluorescence as well as the fluorescent intensity increase of coumarin 6-loaded particles. The X-shaped polymers exhibited a smaller critical micelle concentration value and possessed higher micellar stability in comparison with those of linear ones. The size of X-shaped (PLGA) 2 -SS-4-arm-PEG 2000 polymer nanomicelles (XNMs) was much smaller than that of nanomicelles prepared with linear polymers. The reduction sensitivity of polymers was confirmed by the increase of micellar sizes as well as the in vitro drug release profile of DTX-loaded XNMs (DTX/XNMs). Cytotoxicity assays in vitro revealed that the blank XNMs were nontoxic against A2780 cells up to a concentration of 50 µg/mL, displaying good biocompatibility. DTX/XNMs were more toxic against A2780 cells than other formulations in both dose- and time-dependent manners. Cellular uptake assay displayed a higher intracellular drug delivery efficiency of XNMs than that of nanomicelles prepared with linear polymers. Besides, the promotion of tubulin polymerization induced by DTX was visualized by immunofluorescence analysis, and the acceleration of apoptotic process against A2780 cells was also imaged using a fluorescent staining method. Therefore, this X-shaped reduction-sensitive (PLGA) 2 -SS-4-arm-PEG 2000 copolymer could effectively improve the micellar stability and significantly enhance the therapeutic efficacy of DTX by increasing the cellular uptake and selectively accelerating the drug release inside cancer cells.

Due to the shortcomings of nanocarriers, the development of carrier-free nanodelivery systems has attracted more and more attention in cancer treatment. However, there are few studies on carrier-free nanosystems that can simultaneously achieve monitoring functions. Here a multifunctional carrier-free nanosystem loaded with curcumin and irinotecan hydrochloride was established for the treatment and monitoring of gastric cancer. Methods: In this study, an irinotecan hydrochloride-curcumin nanosystem in the early stage (the system is named SICN) was prepared. Based on the fluorescence of curcumin, flow cytometry, laser confocal microscopy, and zebrafish fluorescence imaging were used to study the monitoring function of SICN in vivo and in vitro. In addition, HGC-27 human gastric cancer cells were used to study SICN cytotoxicity. Results: Flow cytometry and zebrafish fluorescence imaging monitoring results showed that the uptake of SICN was significantly higher than free curcumin, and the excretion rate was lower. SICN had higher accumulation and retention in cells and zebrafish. Laser confocal microscopy monitoring results showed that SICN was internalized into HGC-27 cells through multiple pathways, including macropinocytosis, caveolin, and clathrin-mediated and clathrin -independent endocytosis, and distributed intracellularly throughout the whole cytoplasm, including lysosomes and Golgi apparatus. In vitro cell experiments showed that SICN nanoparticles were more toxic than single components, and HGC-27 cells had more absorption and higher toxicity to nanoparticles under slightly acidic conditions. Conclusion: SICN is a promising carrier-free nanoparticle, and the combination of two single-component therapies can exert a synergistic antitumor effect. When exposed to a tumor acidic environment, SICN showed stronger cytotoxicity due to charge conversion. More importantly, the nanoparticles' self-monitoring function has been developed, opening up new ideas for combined tumor therapy.

Camptothecin (CPT), an alkaloid, was first discovered from plants and has potent anti-tumor activity. Since then, CPT analogs (namely Irinotecan and Topotecan) have been approved by the FDA for cancer treatments. Curcumin, on the other hand, is a widely used photosensitizer in photodynamic therapy (PDT) treatment. In our previous work, we have reported a straightforward strategy to construct a drug self-delivery system in which two-molecular species Irinotecan and Curcumin can self-assembly into a complex of ion pairs, namely ICN, through intermolecular noncovalent interactions. We found that ICN has slightly better chemotherapy efficacy than its individual components with much fewer side effects. In this paper, we aim to combine the chemotherapy and the PDT of ICN to further improve its anti-tumor performance. The efficient cellular uptake of ICNs was observed by confocal microscopy. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the generation of singlet oxygen species. We found that the cell viability was 9% with both chemotherapy and PDT, and 31% with chemotherapy alone for the case with an ICN concentration of 10 μM, which demonstrated that the anti-tumor efficacy against the HT-29 cancer cell line was enhanced substantially with the combination therapy strategy. The study with an in vivo mouse model has further verified that the chemo-PDT dual therapy can inhibit tumor growth by 84% and 18.8% comparing with the control group and the chemotherapy group, respectively. Our results demonstrated that the new strategy using selfassembly and carrier-free nanoparticles with their chemo-PDT dual therapy may provide new opportunities to develop future combinatorial therapy methods in treating cancer.