ABSTRACT
Non-AIE-type molecular photosensitizers (PSs) suffer from the aggregation-caused-quenching (ACQ) effect in an aqueous medium due to the strong hydrophobic and π-π interactions of their conjugated planes, which significantly hinders the enhancement of tumor photodynamic therapy (PDT). So far, some ionic PSs have been reported with good water-solubility, though the ACQ effect can still be induced in a biological environment rich in ions, leading to unsatisfactory in vivo delivery and fluorescence imaging performance. Hence, designing molecular PSs with outstanding anti-ACQ properties in water is highly desirable, but it remains a tough challenge for non-AIE-type fluorophores. Herein, we demonstrated a strategy for the design of porphyrin-type molecular PSs with remarkable solubility and anti-ACQ properties in an aqueous medium, which was assisted by quantum chemical simulations. It was found that cationic branched side chains can induce serious plane distortion in diphenyl porphyrin (DPP), which was not observed for tetraphenyl porphyrin (TPP) with the same side chains. Moreover, the hydrophilicity of the chain spacer is also crucial to the plane distortion for attaining the desired anti-ACQ properties. Compared to ACQ porphyrin, anti-ACQ porphyrin displayed type-I ROS generation in hypoxia and much higher tumor accumulation efficacy by blood circulation, leading to highly efficient in vivo PDT for hypoxic tumors. This study demonstrates the power of sidechain chemistry in tuning the configuration and aggregation behaviors of porphyrins in water, offering a new path to boost the performance of PSs to fulfill the increasing clinical demands on cancer theranostics.
ABSTRACT
Water is ubiquitous in natural systems where it builds an essential environment supporting biological supramolecular polymers to function, transport, and exchange. However, this extreme polar environment becomes a hindrance for the superhydrophobic functional π-conjugated molecules, causing significant negative impacts on regulating their aggregation pathways, structures, and properties of the subsequently assembled nanomaterials. It especially makes the self-assembly of ultrathin two-dimensional (2D) functional nanomaterials by π-conjugated molecules a grand challenge in water, although ultrathin 2D functional nanomaterials have exhibited unique and superior properties. Herein, we demonstrate the organic solvent-free self-assembly of one-molecule-thick 2D nanosheets based on exploring how side chain modifications rule the aggregation behaviors of π-conjugated macrocycles in water. Through an in-depth understanding of the roles of linking groups for side chains on affecting the aggregation behaviors of porphyrins in water, the regulation of molecular arrangement in the aggregated state (H- or J-type aggregation) was attained. Moreover, by arranging ionic porphyrins into 2D single layers through J-aggregation, the ultrathin nanosheets (thickness ≈ 2 nm) with excellent solubility and stability were self-assembled in pure water, which demonstrated both outstanding 1O2 generation and photothermal capability. The ultrathin nanosheets were further investigated as metal- and carrier-free nanodrugs for synergetic phototherapies of cancers both in vitro and in vivo, which are highly desirable by combining the advantages and avoiding the disadvantages of the single use of PDT or PTT.
Subject(s)
Neoplasms , Photochemotherapy , Porphyrins , Humans , Water , Phototherapy/methods , Neoplasms/drug therapyABSTRACT
Due to their excellent electronic and optical properties, porphyrins are extensively studied conjugated macrocycles in supramolecular chemistry for assembling functional nanomaterials. Although the aggregation of monomers plays a significant role in driving the self-assembly process into ordered nanostructures, it remains a challenge for tuning the self-assembling behavior of porphyrins through molecular structure modifications, especially in aqueous solutions. In the present work, two novel water-soluble porphyrin derivatives were synthesized by introducing cationic linear side chains into the π-conjugated core for phosphate-templated assembly through electrostatic interactions. It was found that the stacking patterns (H- or J-type aggregation) of porphyrins could be tuned by varying the number of side chains, which are associated with dramatic morphological change. The cytotoxicity and photodynamic properties of the J-aggregation-driven nano-assemblies were also investigated for the purpose of anti-cancer treatment. This study demonstrates a facile and effective strategy to regulate the aqueous self-assembling behavior of porphyrins that can impact the structure and properties of assembly, which will be of great benefit to the design and synthesis of functional nanomaterials for specific applications.
