期刊
PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES
卷 7, 期 7, 页码 775-781出版社
SPRINGERNATURE
DOI: 10.1039/b800653a
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资金
- NCI NIH HHS [R21-CA 95330] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R21CA095330] Funding Source: NIH RePORTER
We report a new class of photodynamic molecular beacon (PMB) with tumor specific mRNA-triggered control of singlet oxygen (O-1(2)) production. The beacon contains a single-stranded oligonucleotide linker that forms a stem-loop structure (hairpin) in which the sequence is an antisense oligonucleotide (AS-ON) complementary to a target mRNA. The stem is formed by the annealing of two complementary arm sequences that are on either side of the loop sequence. A photosensitizer molecule (PS) is attached to the end of one arm and a quencher (Q) is similarly attached to the other end. The conformationally-restricted hairpin forces Q to efficiently silence the photoreactivity of PS. In the presence of target mRNA, the hairpin opens and the PS is no longer silenced. Upon irradiating with light, the PS then emits fluorescence and generates cytotoxic O-1(2). To show proof of concept, we have synthesized a c-raf-1 mRNA-triggered PMB using pyropheophorbide (Pyro) as PS, carotenoid as Q and c-raf-1 mRNA-targeted AS-ON as the loop sequence. We show that the O-1(2) production of Pyro is quenched in its native state by 15-fold and is restored 9-fold by the addition of the target RNA. Comparing this to our recently reported self-folding peptide linker-based PMB, the hairpin effect results in an enhanced O-1(2) quenching efficiency that decreases the residual O-1(2) production by over 3-fold, thus providing enhanced control of O-1(2) production upon target-linker interactions. When incubated with c-raf-1 expressing MDA-MB-231 cancer cells, the PMB displayed efficient cellular uptake and subsequently effective PDT activation in targeted cells.
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