Folate Receptor-Targeted and Cathepsin B-Activatable Nanoprobe for In Situ Therapeutic Monitoring of Photosensitive Cell Death

Abstract

The integration of diagnostic and therapeutic functions in a single system holds great promise to enhance the theranostic efficacy and prevent the under- or overtreatment. Herein, a folate receptor-targeted and cathepsin B-activatable nanoprobe is designed for background-free cancer imaging and selective therapy. The nanoprobe is prepared by noncovalently assembling phospholipid-poly(ethylene oxide) modified folate and photosensitizer-labeled peptide on the surface of graphene oxide. After selective uptake of the nanoprobe into lysosome of cancer cells via folate receptor-mediated endocytosis, the peptide can be cleaved to release the photosensitizer in the presence of cancer-associated cathepsin B, which leads to 18-fold fluorescence enhancement for cancer discrimination and specific detection of intracellular cathepsin B. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen for triggering photosensitive lysosomal cell death. After lysosomal destruction, the lighted photosensitizer diffuses from lysosome into cytoplasm, which provides a visible method for in situ monitoring of therapeutic efficacy. The nanoprobe exhibits negligible dark toxicity and high phototoxicity with the cell mortality rate of 0.06% and 72.1%, respectively, and the latter is specific to folate receptor-positive cancer cells. Therefore, this work provides a simple but powerful protocol with great potential in precise cancer imaging, therapy, and therapeutic monitoring.

Dynamic interactions and intracellular fate of label-free, thin graphene oxide sheets within mammalian cells: role of lateral sheet size

“…Lysosomes-GFP. This result is in agreement with the literature suggesting that internalised GO ends up in the lysosomes 9,32 . Some studies show that surface charge of GO can be modified using different chemical moieties in order to influence the intracellular fate of GO 16,18,80 From Video S1-S6, we could also see a consistent exchange of both materials between the lysosomal vesicles, and with no obvious disruption to the lysosome membrane up to 48 h of treatment.…”

“…This favours cellular attachment and proliferation, but also provides good dispersibility in aqueous environment [4][5][6] . Some of the most promising applications of GO include the development of biosensors, drug delivery platforms, bio-imaging agents and photodynamic/photothermic therapeutic agents [6][7][8][9][10][11] .…”

The application of titanium dioxide, zinc oxide, fullerene, and graphene nanoparticles in photodynamic therapy

“…Tian et al ( 2015 ) synthesized GO coupled to FA, a PS, and to an enzyme-responsive substrate (peptide) to control the selective release of PS at specific sites. The folate-based conjugate and the PS-labeled peptide substrate consist of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N -[folate(poly ethylene glycol)-2000] (DSPE-PEG2000-FA) and Ce6-GRRGKGGFFFF (Ce6-Pep), respectively, and were loaded onto GO by π – π and hydrophobic interactions.…”

Endogenous Stimuli-responsive Nanocarriers for Drug Delivery

“…52 Thus, it offers an attractive choice for triggering selective cancer therapy. Tian et al 53 designed a CaB-activatable theranostic nanosystem for background-free cancer imaging and selective therapy. The nanocarrier used a chlorine e6 (Ce6)-labeled peptide substrate to perform a cancer-specific stimulus via CaB activation, which led to the release of Ce6 from the graphene oxide sheet into the lysosomes of cancer cells.…”