| Photodynamic therapy（PDT）has been recognized as a minimally invasive and effective method for tumor treatment.PDT mainly produces reactive oxygen species（ROS）through photochemical reactions to cause cell damage so as to achieve cancer treatment.However,its acceptance for cancer therapy is limited by severely hypoxic situation and low efficiency of ROS accumulation at the tumor site.The development of nanotechnology provides more opportunities for precise drug delivery,synergistic therapy of nano-delivery system and PDT improves the stability and permeability of traditional photosensitizer,thus remarkably improve PDT efficiency.In this study,we here provided two novel PDT collaborative multifunctional nano-delivery platforms to improve the anti-tumor efficacy of photosensitizers indocyanine green（ICG）and Chlorin e6（Ce6）in breast cancer（BC）from different perspectives.（1）While mitochondria targeted therapy by metformin has been considered as a promising strategy for reducing oxygen consumption in tumor cells,its low treatment sensitivity,short half-life and narrow gastrointestinal absorption window in vivo remain the intractable challenges.In this report,5’-guanosine monophosphate（5’GMP）,indocyanine green（ICG）,Hemin and metformin,which were extensively used as pharmaceutical products and possessed ideal biocompatibility,were combined to construct a smart injectable G quadruplex（G4）hydrogel named HMI@GEL for BC treatment.Benefiting from the photothermal（PTT）effect of ICG under irradiation,HMI@GEL exhibited excellent characteristics of NIR-light-triggered and persistent drug delivery so as to improve the short half-life of metformin.Furthermore,the amount of metformin hydrochloride loaded reached an amazing 300 mg m L-1 in a gel-like state.To the best of our knowledge,it might be the highest loading efficiency in the reported literatures.With the combination of catalase-mimicking Hemin@mil88,metformin could inhibit mitochondrial respiratory chain significantly,which sequentially permitted in situ efficient oxygen supplied to sensitize hypoxia-limited PDT treatment.Remarkable tumor apoptosis and necrosis was achieved by the combination of PTT and dual enhanced PDT as well as the activated tumor immunotherapy.Collectively,the HMI@GEL hydrogel in-situ injectable platform showed a promising strategy for enhanced PDT by metformin,and opened new perspectives for treating BC versatilely.（2）In addition to enhancing ROS accumulation by alleviating tumor hypoxia.The combination therapy reducing DNA repair function of tumor cells also maintains the damage of PDT efficiency.Here,we constructed synthesize nanomaterials Ce6@MSN-ZOP-HA that can actively target to tumor site and prevented DNA repair process.Surface modification hyaluronic acid（HA）can bind to CD44,which is highly expressed on the surface of breast cancer cells,enabling the nanomaterial to targeted to the tumor site accurately.Due to the active targeting function of Ce6@MSN-ZOP-HA,the concentration of photosensitizer in tumor site increased.MSN released Ce6 after ZIF-8 degraded in the acidic environment,which significantly enhanced intracellular ROS fluorescence intensity under 650 nm irradiation.The combined application of p38inhibitor and PARP inhibitor reduced the resistance of cells to PDT treatment.At the same time,the active targeting reduced the accumulation of drugs in liver and spleen.The as-prepared active targeting and p H responsive nanoparticle Ce6@MSN-ZOP-HA provided a new thought for the development of PDT synergistic nanodrugs with low biotoxicity and high anti-tumor efficiency. |
