Near-Infrared Light Triggered Photodynamic Therapy With An Oxygen-Shuttle Endoperoxide Of Anthracene Against Tumor Hypoxia

Photodynamic therapy(PDT)is an emerging therapeutic means against various tumors with minimal invasiveness,high spatiotemporal selectivity,low toxicity to normal tissues and promoting anti-tumor immune response during the procedure.Essentially,it employs the administration of a photosensitizer(PS)followed by local irradiation of the tumor with a suitable light.The PS harvests light and transfers the energy to the tumor-dissolved oxygen(O2)to produce highly cytotoxic reactive oxygen species(ROS)such as singlet oxygen(1O2)to kill tumor cells.However,clinical application of PDT is limited to superficial lesion.The main reason is that the therapeutic effects of PDT with an oxygen-dependent nature are limited by an inadequate oxygen supply in tumors,which is recognized as a characteristic feature of most solid tumors.Furthermore,the consumption of oxygen during PDT process further aggravate the extreme tumor hypoxia events,resulting in hypoxia-associated PDT resistance.To date,oxygen-generating materials have been proposed which can produce oxygen by self-carrying or chemical reaction in the presence of peroxides and thus can oxygenate the tumor microenvironment to achieve better PDT and chemotherapeutic outcomes.The anthracene can react reversibly with 1O2 to form an endoperoxide,which has been considered as a reliable chemical source of 1O2 and in some circumstance undergo clean(no side reactions)cycloreversion reactions to release 1O2 with considerable chemical yields.One of the most important substrates in this field is 9,10-diphenylanthracene(DPA)which can be functionalized for incorporation into various materials.However,the endoperoxide of DPA is quite stable with half-lives in years at room temperature and no obvious 1O2 release are observed even at 60 0C,which greatly hampers its application in biomedical field.We here develop novel 1O2self-carrying nanomicelles for NIR-triggered and controlled release of 1O2 to achieve self-sufficiency of oxygen source in the PDT process.A photosensitizer(tetraphenyl porphyrin,TPP)and ortho-substituted 9-10-diphenylanthracene are introduced into the amphiphilic block copolymer.The methyl and methoxyl groups are introduced in ortho positions of DPA to improve the 1O2 release,and low ratio of TPP are utilized to improve the photooxidation efficiency.After a photooxidation procedure,the novel nanoparticle constructs are fabricated by a self-assembly process.IR780 iodide,a near-infrared dye which can be applied for cancer imaging,photodynamic therapy(PDT)and photothermal therapy(PTT),is encapsulated into the core of nanoparticles by hydrophobic interactions.Taken together,the formed nanoparticles under the 808 nm NIR laser irradiation could produce heat and induce ROS release to completely destroy hypoxia tumors.This innovative nanoparticle has exhibited excellent antitumor efficiency,verified vividly by in vitro and in vivo assay,and may serve as a versatile theranostic platform for clinical tumor therapy.