Simple and Multifunctional Natural Self-Assembled Sterols with Anticancer Activity-Mediated Supramolecular Photosensitizers for Enhanced Antitumor Photodynamic Therapy

Abstract

Supramolecular photosensitizers based on nanosized drug delivery or combination therapy have been proposed as a promising strategy for cancer treatment. Herein, we screen and develop a series of multifunctional single-component, carrier-based, natural small-molecule sterols (ergosterol, β-sitosterol, and stigmasterol) that simultaneously possess self-assembly ability, anticancer activity, and better biocompatibility and biodegradability to deliver photosensitizer chlorin e6 (Ce6) for significantly combined and safe antitumor photodynamic therapy. The resultant ergosterol–Ce6 nanodrugs (Ergo-Ce6 NPs) have enhanced reactive oxygen species (ROS) generation by promoting type I photoreactions, while Ce6 mainly exists in the monomer state in assembled Ergo-Ce6 NPs via intermolecular π–π stacking and hydrophobic interactions. In addition, with the improved water solubility and stability and higher intercellular ROS generation, Ergo-Ce6 NPs show remarkably in vitro phototoxicity with approximately 73% and 92% cell inhibition ratios to 4T1 and MCF-7 cancer cells at a rather low dosage of Ce6 (1 μg/mL), respectively. Moreover, the excellent tumor targeting ability of Ergo NPs and prolonged blood circulation ensure a quick tumor accumulation of Ergo-Ce6 NPs, resulting in a significantly enhanced in vivo anticancer efficiency of 86.4%, higher than that of the anticancer ability of Ergo NPs (51.0%) or Ce6 PDT alone (59.5%). Furthermore, the resulting nanodrugs have better biocompatibility and biodegradability and low in vivo toxicity, and all of which ensure a safe tumor therapy. This study provides a promising perspective to develop more natural self-assembled biological small-molecule nanomaterials for the fabrication of novel medicinal photosensitizers for clinical application in the future.

Supramolecular agents for combination of photodynamic therapy and other treatments

“…14). 119 A UV-Vis spectrum analysis of the Ergo-Ce6 NPs conrmed the presence of p-p stacking and hydrophobic interactions and showed that the Ce6 molecules existed mainly as monomers between stacked ergosterol molecules. In water, the Ergo-Ce6 NPs showed a uorescence quenching efficiency of about 93.7% compared to the monomer Ce6, but the heat generation process was not promoted.…”

Structure and Biological Activity of Ergostane-Type Steroids from Fungi

“…The study of cellular uptake and in vitro cytotoxicity of cyclic arginine-glycine-aspartic and octa-arginine peptide-modified ergosterol-combined cisplatin liposomes showed their stability in serum and the strongest anti-lung cancer effect [ 39 ]. The encapsulation of chlorin e6 in self-assembled ergosterol nanoparticles resulted in a novel supramolecularly assembled photosensitizer [ 64 ]. When applied to cancer cells 4T1 and MCF-7, it showed remarkable in vitro phototoxicity with cell inhibition of about 73% and 92%, respectively.…”

Assembled small organic molecules for photodynamic therapy and photothermal therapy

“…For the in vivo experiments, the anticancer efficiency of ergosterol/Ce6 nanoparticles can be as high as 86.4%, which is much higher than that of ergosterol nanoparticles (51.0%) or Ce6 PDT alone (59.5%). 59 Combined chemotherapy with PDT shows great potential for clinical application. While supramolecular assembly offers more possibilities for performing combined therapy.…”

“…A) The co-assembled ergosterol/Ce6 nanoparticles can be used for combined antitumor therapy, depending on the anticancer activity of ergosterol, as well as the PDT from Ce6;59 (this figure has been reproduced from ref. 59 with permission from American Chemical Society).…”