Multimodal therapy is attracting increasing attention to improve tumor treatment efficacy, but generally requires various complicated ingredients combined within one theranostic system to achieve multiple functions. Herein, a multifunctional theranostic nanoplatform based on a single aggregation‐induced‐emission luminogen (AIEgen), DDTB, is designed to integrate near‐infrared (NIR) fluorescence, photothermal, photodynamic, and immunological effects. Intravenously injected AIEgen‐based nanoparticles can efficiently accumulate in tumors with NIR fluorescence to provide preoperative diagnosis. Most of the tumors are excised under intraoperative fluorescence navigation, whereafter, some microscopic residual tumors are completely ablated by photodynamic and photothermal therapies for maximally killing the tumor cells and tissues. Up to 90% of the survival rate can be achieved by this synergistic image‐guided surgery and photodynamic and photothermal therapies. Importantly, the nanoparticles‐mediated photothermal/photodynamic therapy plus programmed death‐ligand 1 antibody significantly induce tumor elimination by enhancing the effect of immunotherapy. This theranostic strategy on the basis of a single AIEgen significantly improves the survival of cancer mice with maximized therapeutic outcomes, and holds great promise for clinical cancer treatment.
Red blood cell (RBC)-mimicking nanoparticles (NPs) are a promising platform for drug delivery owing to their prolonged circulation time, reduced immunogenicity, and specific targeting ability. Herein, we report the design and preparation of RBC membrane-bound NPs (M@AP), for tumoral photodynamic-immunotherapy. M@AP is formed by the self-assembly of the positively charged aggregation-induced emission luminogen (AIEgen) (named P2-PPh3) and the negatively charged polyinosinic: polycytidylic acid (Poly(I: C)), followed by RBC membrane encapsulation. P2-PPh3 is an AIE-active conjugated polyelectrolyte with the additional photosensitizing ability for photodynamic therapy (PDT), while Poly(I: C) serves as an immune-stimulant to stimulate both tumor and immune cells to activate immunity and thus reduces tumor cell viability. When applied in tumor-bearing mice, the M@AP NPs are enriched in both the tumor region owing to the enhanced permeability and retention (EPR) effect and the spleen due to the homing effect of the RBC mimicking shell. Upon light-irradiation, P2-PPh3 promotes strong ROS generation in tumor cells, inducing the release of tumor antigens (TA). The anti-tumor immunity is further enhanced by the presence of Poly(I: C) in M@AP. Thus, this strategy combines the PDT properties of the AIE-active polyelectrolyte and immunotherapy properties of Poly(I: C) to achieve synergistic activation of the immune system for anti-tumor activity, providing a novel strategy for tumor treatment.
Downregulating programmed cell death ligand 1(PD‐L1) protein levels in tumor cells is an effective way to achieve immune system activation for oncology treatment, but current strategies are inadequate. Here, we design a caged peptide‐AIEgen probe (GCP) to self‐assemble with miR‐140 forming GCP/miR‐140 nanoparticles. After entering tumor cells, GCP/miR‐140 disassembles in the presence of Cathepsin B (CB) and releases caged GO203 peptide, miR‐140 and PyTPA. Peptide decages in the highly reductive intracellular environment and binds to mucin 1 (MUC1), thereby downregulating the expression of PD‐L1. Meanwhile, miR‐140 reduces PD‐L1 expression by targeting downregulation of PD‐L1 mRNA. Under the action of PyTPA‐mediated photodynamic therapy (PDT), tumor‐associated antigens are released, triggering immune cell attack on tumor cells. This multiple mechanism‐based strategy of deeply downregulating PD‐L1 in tumor cells activates the immune system and thus achieves effective immunotherapy.
In the field of tumor imaging and therapy, the aggregation-caused quenching (ACQ) effect of fluorescent dyes at high concentration is a great challenge. In this regard, the aggregation-induced emission luminogens (AIEgens) show great potential, since AIEgens effectively overcome the ACQ effect and have better fluorescence quantum yield, photobleaching resistance, and photosensitivity. Polyethylene glycol (PEG)-polymer is the most commonly used carrier to prepare nanoparticles (NPs). The advantage of PEGylation is that it can greatly prolong the metabolic half-life and reduce immunogenicity and toxicity. Considering that the hydrophobicity of most AIEgens hinders their application in organisms, the use of PEG-polymer encapsulation is an effective strategy to overcome this obstacle. Importantly, bioactive functional groups can be modified on PEG-polymers to enhance the biological effect of NPs. The combination of powerful AIEgens and PEG-polymers provides a new strategy for tumor imaging and therapy, which is promising for clinical application.
Abstract. The present study focused on the development of a mucoadhesive patch of methotrexate (MTX) for targeted delivery in oral cancer. Initially, MTX-loaded liposomes were prepared using the thin film hydration method, and had a mean diameter of 105.7-137.4 nm and percentage entrapment efficiency of 54.6±3.5. These liposomes were cast in optimized mucoadhesive film. The film was characterized by its release pattern, thickness, weight and percentage swelling index and the sustained release profile of the optimized film was evaluated. The developed liposomes and liposomes cast in the film formulation were evaluated for cytotoxicity in HSC-3 cells using an MTT assay, and a significant decrease in the half maximal inhibitory concentration of MTX was identified with the MTX-entrapped liposomal film, M-LP-F7. The results of the mitochondria-dependent intrinsic pathway demonstrated that there was significant mitochondrial membrane potential disruption with M-LP-F7 compared with the plain drug. M-LP-F7 increased the rate of apoptosis in HSC-3 cells by almost 3-fold. Elevated levels of reactive oxygen species provided evidence that M-LP-F7 exerts a pro-oxidant effect in HSC-3 cells.
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