Spatio-temporal controlled release of therapeutic agents (drug) is critical to achieve local expression of pharmacological action of drug. One strategy of controlled release that has gained recent attention is the use of light preferably NIR light.We first propose 'Click and Photo-unclick Chemistry' of aminoacrylate (�- enamino eater) which can be built readily and cleaved fast by amine-yne and dioxetane reactions after 690 diode laser irradiation.We designed and synthesized a prodrug of combretastatin A4. Combretastatin A4 was conjugated to a photosensitizer through a photo-cleavable aminoacrylate linker. PS-L-CA4, PS = photosensitizer) and L = aminoacrylate linker.Two pseudo-prodrugs (PS-NCL-CA4 and PS-L-Rh) also were prepared: PS-NCL-CA4 could not release free CA4 even after the irradiation (NCL = non-cleavable linker) and PS-L-Rh as a special fluorescence probe that emits bright rhodamine fluorescence only after cleavage of the linker to releases fluorescent rhodamine after the irradiation.In vitro study using MCF-7 cells, the prodrug conjugate PS-L-CA4 was 5 fold less toxic than parent drug CA4 without NIR laser irradiation IC50D = 164 nM ? IC50P = 28 nM which is presumably due to the release of CA4. The dark toxicity and photo toxicity of PS-NL-CA4 was quite similar IC50D: 1802 nM ? IC50P= 1063 nM (PS-NCL-CA4) since the release of CA4 is not possible. Most exciting result was that PS-L-CA4 showed better antitumor effects than PS-NCL-CA4 upon irradiation.This concept of release mediated by singlet oxygen cleavable linker provide control in term of the quantity, location and time of release of drug. The easy and high yield reaction and the photo-unclick chemistry of of aminoacrylate linker can find many applications, not limited to anticancer drugs and prodrugs, for spatio-temporally controlled release of active compounds but delivery vehicles liposomes, polymers, quantum dots, gold nanoparticle, carbon-nanotube etc.

Emerging strategy for controlling drug release using visible/near IR light

247th National Meeting (2014)

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