| The diagnosis and treatment of malignant tumors is a worldwide problem.The development of nanomedicine has currently combined the multi-disciplines of chemistry,biology,medicine,material science and others,and exhibiting tremendous outcomes to solve the tumor problem.However,the intrinsic hypoxia property in tumor microenvironment is uncovered,which initiates the terrible resistance of radiotherapy,chemotherapy,photodynamic therapy,immunotherapy etc.Therefore,it is of great necessity to develop a highly effective and safe tumor oxygenation strategy,to regulate the tumor microenvironment and achieve enhanced tumor therapeutic effect.In this thesis,two kinds of artificial oxygen carriers have been developed based on polymerlipid nanoparticles and hybrid protein nanoparticles.With integration of diagnostic and therapeutic agents,the artificial oxygen carriers serve as theranostic nanoplatform.By self-supplying oxygen,the tumor hypoxia is altered,and oxygen-boosted photodynamic or chemo-photodynamic therapy is realized,which paves a new way for improving the efficacy of cancer treatments.1.Self-monitoring artificial red cells(I-ARCs)as oxygen nanocarries for oxygen-boosted tumor photodynamic therapyIn this work,through electrostatic and hydrophobic interactions,hemoglobin and indocyanine green formed complex(ICG-Hb),and was encapsulated in a polymer core,which was further coated with lipid layer(simulating the red cell membrane),forming the I-ARCs.The I-ARCs had excellent size stability,and maintained oxygen carrying ability even under pH 6.8 and 60 °C condition.The I-ARCs offered sufficient oxygen source for photodynamic therapy,with a 9.5-fold enhancement in generation of cytotoxic reactive oxygen species(ROS),and the ROS furtherly oxidized ferrous-Hb to ferryl-Hb(63.8% convertion rate),which proloned and enhanced the cytotoxicity.By fluorescent/photoacoustic imaging,I-ARCs were able to be self-monitored for indicating the real-time amount of photosensitizer/oxygen in the tumor region.The result demonstrated that I-ARCs significantly improve the tumoral oxygen status for at least 6 hours.The in vitro and in vivo treatment with I-ARCs were performed,and we realize the enhanced photodynamic therapy by effectively inhibited the tumor growth without reccurence.Related results were publicated in Scientific Reports(2016,6,23393),Journal of Controlled Release(2017,259,e191-e192),and applied for 3 national patents.2.Hybrid protein oxygen carriers(HPOCs)for oxygen-enhanced chemophotodynamic combination therapy with a single doseHybrid protein oxygen carriers(HPOCs)were fabricated through through a disulfide-bond reconfiguration strategy to hybridize hemoglobin and human serem albumin.Oxygen,doxorubicin(DOX)and chlorin e6(Ce6)were co-loaded to form the ODC-HPOCs,which incorporated advantages of two natural proteins,the oxygencarrying hemoglobin and the tumor-targeting human serum albumin.The ODCHPOCs presented an outstanding performance in tumor targeting,for optimized tumor oxygenation and drug accumulation,which was real-timely monitored by in vivo photoacoustic/fluorescent imaging.On one hand,the released oxygen inhibited DOX efflux by downregulating the HIF-1?,MDR1 and consequently,the P-gp expression,with 48% declination,resulting in reduced DOX efflux and effective chemotherapy.On the other hand,the targeted delivered oxygen successfully enhanced PDT with massive generation of reactive oxygen species.The monitoring of photoacoustic imaging indicated that ODC-HPOCs improved 25% of tumor oxygen within 6 hours,and the oxygen was diffused into the hypoxic region which was far from the tumor vessels.A single dosed treatment of ODC-HPOCs without laser exhibited potent efficacy with 89.5% inhibition rate of tumor growth.The combinatio of oxygen-enhanced chemotherapy and photodynami therapy completely inhibited tumor growth without reccrence.Related results were publicated in ACS Nano(2016,10,10049-10057),Advanced Functional Materials(2017,27,1703197),and applied for 3 national patents. |
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