期刊
PHARMACEUTICS
卷 15, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics15030919
关键词
docking; virtual screening; MD simulations; MM-GBSA; temoporfin (mTHPC); apomyoglobin; apohemoglobin; blood transport proteins; hemopexin; photodynamic therapy (PDT)
Temoporfin (mTHPC) is a promising photosensitizer used in photodynamic therapy. However, its lipophilic character limits its potential. By using reverse docking, we identified blood transport proteins that can monodisperse mTHPC. We synthesized the mTHPC@apoMb complex and demonstrated its ability to disperse mTHPC and enhance ROS production, showing its effectiveness in vitro photodynamic treatment.
Temoporfin (mTHPC) is one of the most promising photosensitizers used in photodynamic therapy (PDT). Despite its clinical use, the lipophilic character of mTHPC still hampers the full exploitation of its potential. Low solubility in water, high tendency to aggregate, and low biocompatibility are the main limitations because they cause poor stability in physiological environments, dark toxicity, and ultimately reduce the generation of reactive oxygen species (ROS). Applying a reverse docking approach, here, we identified a number of blood transport proteins able to bind and disperse monomolecularly mTHPC, namely apohemoglobin, apomyoglobin, hemopexin, and afamin. We validated the computational results synthesizing the mTHPC-apomyoglobin complex (mTHPC@apoMb) and demonstrated that the protein monodisperses mTHPC in a physiological environment. The mTHPC@apoMb complex preserves the imaging properties of the molecule and improves its ability to produce ROS via both type I and type II mechanisms. The effectiveness of photodynamic treatment using the mTHPC@apoMb complex was then demonstrated in vitro. Blood transport proteins can be used as molecular Trojan horses in cancer cells by conferring mTHPC (i) water solubility, (ii) monodispersity, and (iii) biocompatibility, ultimately bypassing the current limitations of mTHPC.
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