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MITF-siRNA formulation is a safe and effective therapy for human melasma.

ABSTRACT: It is unclear whether siRNA-based agents can be a safe and effective therapy for diseases. In this study, we demonstrate that microphthalmia-associated transcription factor-siRNA (MITF-siR)-silenced MITF gene expression effectively induced a significant reduction in tyrosinase (TYR), tyrosinase-related protein 1, and melanocortin 1 receptor (MC1R) levels. The siRNAs caused obvious inhibition of melanin synthesis and melanoma cell apoptosis. Using a novel type of transdermal peptide, we developed the formulation of an MITF-siR cream. Results demonstrated that hyperpigmented facial lesions of siRNA-treated subjects were significantly lighter after 12 weeks of therapy than before treatment (P < 0.001); overall improvement was first noted after 4 weeks of siRNA treatment. At the end of treatment, clinical and colorimetric evaluations demonstrated a 90.4% lightening of the siRNA-treated lesions toward normal skin color. The relative melanin contents in the lesions and adjacent normal skin were decreased by 26% and 7.4%, respectively, after treatment with the MITF-siR formulation. Topical application of siRNA formulation significantly lightens brown facial hypermelanosis and lightens normal skin in Asian individuals. This treatment represents a safe and effective therapy for melasma, suggesting that siRNA-based agents could be developed for treating other diseases such as melanoma.

SUBMITTER: Yi X

PROVIDER: S-EPMC3034856 | biostudies-other | 2011 Feb

REPOSITORIES: biostudies-other

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Project description:Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes. Instead, significantly improved outcomes likely require synergistic therapies that target various cellular pathways. In this study, we target two proteins upregulated in cancers: the cannabinoid CB2 receptor (CB2R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the CB2R-targeted PS, IR700DX-mbc94, triggered necrotic cell death upon light irradiation, whereas PDT with the TSPO-targeted IR700DX-6T agent led to apoptotic cell death. Both PSs significantly inhibited tumor growth in vivo in a target-specific manner. As expected, the combined CB2R- and TSPO-PDT resulted in enhanced cell killing efficacy and tumor inhibition with lower drug dose. The median survival time of animals with multilayer PDT treatment was extended by as much as 2.8-fold over single PDT treatment. Overall, multilayer PDT provides new opportunities to treat cancers with high efficacy and low side effects.Statement of significancePhotodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.

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MITF-siRNA formulation is a safe and effective therapy for human melasma.

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