Rosmarinic Acid‐Crosslinked Supramolecular Nanoassembly with Self‐Regulated Photodynamic and Anti‐Metastasis Properties for Synergistic Photoimmunotherapy

Abstract

for overcoming the limitation facing traditional nanocarrier, but three stand out. Cyclodextrins come as a particular boon to hydrophobic chemodrugs, whose solubility can be notably improved by hostguest interaction. Another benefit arises from facile modification of such functional groups as targeting ligands, therapeutic or imaging agents into the building blocks. In addition, driven by dynamic and reversible host-guest recognition, these assemblies respond to a wide range of physiologic stimulus, like pH, redox, and enzyme, to on-demand release drug. This property further endows it with excellent biodegradability and rapid excretion, subsequently avoiding long-term retention toxicity. Despite these merits, the cyclodextrin-based nanoassembly is susceptible to ionic strength and protein adsorption during circulation, which might result in micelle collapse, burst drug release, and clearance. Therefore, enhancing structural robustness during circulation as well as on-demand disassembly at targeted sites is critical for the cyclodextrin-enabled drug delivery. Stimuli-responsive crosslinked strategies, [3][4][5] including the core or shell-crosslinked, represent a feasible candidate for enhancing stability under physiological environment and controllable drug release, relative to non-crosslinked counterparts. However, the incorporation of nonfunctional crosslinkers, such as disulfide, [6][7][8] salt bridge, [9] and Schiff base bonds, [10,11] will add to the complexity of preparation. On this ground, chosen crosslinkers with some specific antitumor features are seemingly more conducive to therapeutic response. Rosmarinic acid (RA), a natural phenolic compound, has two catechol moieties that can interact with boronic acid through pH-responsive boronate ester bonds, [3,[12][13][14] resulting in the formation of intraparticle crosslinkage, while inducing tumor apoptosis and suppressing the epithelial-mesenchymal transition (EMT) process of tumor cells. [15,16] RA with catechol structure also has strong antioxidant ability. [17] Concerning these superior features, introducing RA-boronic acid crosslinkage could equip cyclodextrinbased nanoassembly with multiple functions, including better stability, redox-mediating function, and antimetastasis ability. A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self-regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6-conjugated β-cyclodextrin (CD-Ce6) acts as the main PDT agent and ferrocene (Fc)-terminated phenylboronic acid-containing conjugates entering into the cavity of CD-Ce6, as well as rosmarinic acid (RA)boronic acid crosslinked shell. Compared with ...

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple‐negative breast cancer

“…H 2 O 2 ‐responsive nanomaterials combined with photodynamic therapy (PDT) have shown great potential in TNBC treatment (Yang et al, 2020). Zhou et al, utilized chlorine e6 (Ce6)‐conjugated β‐cyclodextrin and ferrocene‐containing phenylboronic acid to construct a PDT nanoparticle bound to redox response (Zhou, Zhang, et al, 2023). Under laser irradiation, CPR produced a large amount of ROS to damage tumor cells and induced immunogenic cell death (ICD).…”

Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

“…[ 29 ] For instance, Yang Zhou et al reported a rosmarinic acid–cross‐linked supramolecular nanoassembly that can regulate the level of PDT‐induced reactive oxygen species (ROS) and inhibit epithelial–mesenchymal transition (EMT), so that the damage to normal tissue be diminished while the cytotoxicity to tumor cells is preserved. [ 30 ] Rou Xie et al have proposed an acid‐triggered self‐assembled gold nanoparticle targeted at heat shock protein 70 that is expressed on the membrane of glioma cells, thus selectively transporting doxorubicin that was encapsulated inside the nanoparticles into glioma. In vivo experiments showed that when in combination with PD‐1 checkpoint blockade, powerful synergistic effects would take place accompanied with the multiplication of mature dendritic cells (DCs), cytotoxic T‐lymphocytes (CTLs) and survival time.…”

Self-assembled nanodrug delivery systems for anti-cancer drugs from traditional Chinese medicine

“…In recent years, CFDDSs have been developed with high drug-loading capacity, low off-target toxicity, and minimal immunogenicity for cancer treatment. [12][13][14] Further, self-assembly technology holds enormous potential for the development of new drugs. 15,16 In self-assembled nanodrug delivery systems (SANDDSs), NSMs form nanocarrier complexes spontaneously through non-covalent bonds (including van der Waals forces, hydrogen bonds, π-π stacking, halogen bonds, hydrophobic interactions, cation-π bonds, ionic bonds, CH-π bonds and solvation) under equilibrium conditions and can be combined with photosensitizers or other drug molecules to form nano-sized multifunctional drug complexes targeting tumor tissues.…”