ABSTRACT
Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.
ABSTRACT
We already reported that genetically engineered resveratrol-enriched rice (RR) showed to down-regulate skin melanogenesis. To be developed to increase the bioactivity of RR using calli from plants, RR was adopted for mass production using plant tissue culture technologies. In addition, high-pressure homogenization (HPH) was used to increase the biocompatibility and penetration of the calli from RR into the skin. We aimed to develop anti-melanogenic agents incorporating calli of RR (cRR) and nanoparticles by high-pressure homogenization, examining the synergistic effects on the inhibition of UVB-induced hyperpigmentation. Depigmentation was observed following topical application of micro-cRR, nano-calli of normal rice (cNR), and nano-cRR to ultraviolet B (UVB)-stimulated hyperpigmented guinea pig dorsal skin. Colorimetric analysis, tyrosinase immunostaining, and Fontana-Masson staining for UVB-promoted melanin were performed. Nano-cRR inhibited changes in the melanin color index caused by UVB-promoted hyperpigmentation, and demonstrated stronger anti-melanogenic potential than micro-cRR. In epidermal skin, nano-cRR repressed UVB-promoted melanin granules, thereby suppressing hyperpigmentation. The UVB-enhanced, highly expressed tyrosinase in the basal layer of the epidermis was inhibited by nano-cRR more prominently than by micro-cRR and nano-cNR. The anti-melanogenic potency of nano-cRR also depended on pH and particle size. Nano-cRR shows promising potential to regulate skin pigmentation following UVB exposure.