Nanophotosensitizers For Hypoxia Promotion And Cancer Theranostics

Photodynamic therapy(PDT)has shown great promise in modern medicine due to its safety and efficacy.Until now,most photosensitizers is still oxygen-dependent type II photosensitizers,which can achieve high efficacy at oxygen-rich tissues.However,most solid tumors owns the feature of hypoxia,which their oxygen content is significantly lower than normal tissues,making the low efficacy of PDT.Therefore,alleviating tumor hypoxia is of great significance for PDT.In addition,the PDT process may decrease the oxygen content,which further suppresses the efficacy.Promoting the tumor hypoxia may improve the effect of PDT and provides novel approach for high-performance PDT.Until now,suppressing HIF-1α and tumor oxygen consumption are two conventional methods for promoting tumor hypoxia,and have been demonstrated to have good effect.Compared with single PDT,such approach provided a synergistic therapeutic method to achieve enhanced PDT.Herein,we combine photosensitizers with hypoxia alleviation drugs to develop two nanophotosensitizers for enhanced PDT.The nanosensitizers also have good NIR fluorescence signal,which can achieve fluorescence imaging-guided enhanced PDT.The detailed research content is as follows:(1)HIF-1α inhibiting nanophotosensitizers for cancer PDTWe designed an ACF and m PPa-loaded nanoparticle Am PPa NP.ACF is a HIF-1α inhibiting drug,while m PPa is a NIR photosensitizer.Am PPa NP is prepared via encapsulating hydrophobic m PPa into amphiphilic copolymer PSMA-PEG,and then loading ACF by electrostatic interaction.Am PPa NP can accumulate into tumor site via enhanced permeation and retention(EPR)effect,and internalized by tumor cells.ACF can be released under acidic tumor microenvironment to inhibit HIF-1α and alleviate hypoxia.On the other hand,m PPa can conduct PDT under 635 nm laser irradiation,achieving a better PDT efficacy combined with ACF.Meanwhile,m PPa has good NIR-I fluorescence imaging capability,which can precisely image tumor.Thus,Am PPa NP is a good candidate for NIR fluorescence imaging-guided enhanced PDT.Both in vitro and in vivo experiments prove the good HIF-1α inhibition rate and PDT effect of Am PPa NP.(2)Nanophotosensitizers simultaneously inhibit HIF-1α and oxygen consumption for enhanced PDTOn the basis of HIF-1α inhibition,we introduce an OXPHOS inhibitor into the nanosystem to suppress the oxygen consumption of tumor,which can further alleviate the tumor hypoxia.To achieve such goal,we co-load YC-1 and metformin into NIR-II emitting nanoparticles Met/YC-1@SPN.Met/YC-1@SPN is prepared by encapsulating NIR-II emitting PCPDTBT and YC-1 by PSMA-PEG,and then loading metformin onto the surface of nanoparticles via electrostatic interaction.YC-1 is a HIF-1α inhibitor,while metformin is an OXPHOS inhibitor.PCPDTBT is a semiconducting polymer with high NIR-II fluorescence intensity and singlet oxygen quantum yield.Met/YC-1@SPN can accumulate into tumor via EPR effect.Under acidic condition,metformin will be released to inhibit OXPHOS and suppress oxygen consumption.YC-1 can be further released within cell and inhibit HIF-1α.The combination of YC-1 and metformin can greatly alleviate tumor hypoxia.under 635 nm laser irradiation,PCPDTBT can trigger the PDT process which may be enhanced by the alleviated hypoxia.In addition,the NIR-II fluorescence signal of PCPDTBT can delineate the position of tumor.Both in vitro and in vivo experiments indicate that Met/YC-1@SPN can effectively alleviate hypoxia and achieve NIR-II fluorescence imaging-guided enhanced PDT.