Development of Advanced Photodynamic Molecular Beacons with Multiple Controls for Targeted Photodynamic Therapy

Project: Research

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Photodynamic therapy (PDT) is an established treatment modality for various superficialand localized cancers. It utilizes the combined action of a photosensitizer, light ofappropriate wavelength, and oxygen to generate reactive oxygen species (ROS) toeradicate cancer cells. Owing to the very short lifetime (< 40 ns) and diffusion range (ca.20 nm) of ROS, their action is almost confined to the site where ROS are produced.Therefore, preferential localization of the photosensitizer in tumor and preciseapplication of the light are extremely crucial that can greatly improve the therapeuticoutcome. Considerable efforts have therefore been put to enhance the tumor-targetingproperty and pharmacokinetic profiles of photosensitizers, and to advance the fiberoptics and endoscopy technologies. Apart from directing the photosensitizers to thetumor through conjugation with tumor-targeting ligands or encapsulation intomultifunctional nanocarriers, controlling their photoactivity in a specific manner isanother promising approach. These so-called photodynamic molecular beacons (PMBs)are either self-quenched or deactivated by the quenching component in the native form,but upon interactions with cancer-related stimuli, the photosensitizing units areactivated through disaggregation or separation from the quenchers, resulting inrestoration of their fluorescence and ROS generation. This approach can minimize thephotodamage of normal tissues in PDT. To further improve the tumor specificity andtherapeutic efficacy, it is desirable that the PMBs can only be activated by thecoexistence of more than one stimulus or conjugate to a tumor-targeting ligand. These“smart” PMBs with additional controls or functions, however, remain very rare whichprovides an impetus for further development. This project aims to develop advancedPMBs with multiple controls for targeted PDT. We plan to connect two 2,4-dinitrobenzenesulfonate (DNBS)-substituted phthalocyanine units with a cathepsin Bsubstrate. They are expected to be severely deactivated by self-quenching andphotoinduced electron transfer to the DNBS groups. Only in the presence of bothintracellular glutathione and lysosomal cathepsin B, which can remove the DNBS groupsand cleave the peptide linker, respectively, these PMBs are activated. To enable specificdelivery to the tumor, these PMBs will be further conjugated with a folate-modified pH-responsivecell-penetrating peptide (CPP). While the folate group can bind to theupregulated folate receptors on cancer cells, the CPP can facilitate the internalizationafter being protonated in the mild acidic tumor microenvironment. It is believed thatthese PMBs with multiple targeting-activation properties can exhibit superiorphotodynamic activities, which will be validated both in vitro and in vivo.


Project number9042546
Grant typeGRF
Effective start/end date1/01/18 → …