Investigation On Precise Delivery System Of Anti-tumor Drug With Physical-regulation Feature

A tumor-targeted drug delivery system is the material basis of tumor precise therapy,which can maximize the tumor killing effect while minimize the damage to non-targeted organs,as a precisely guided "smart bomb".The development of nanotechnology provides new research opportunities for anti-tumor drugs precise delivery.At the same time,new therapeutic models,such as photothermal therapy,photodynamic therapy,magnetotherapy and acoustical therapy,based on those nanomaterials also provide new strategies for tumor comprehensive treatment.In this paper,near-infrared light-responsive multi-walled carbon nanotubes-titania nanocomposites?TiO₂@MWCNTs?,alternating magnetic field-responsive mesoporous Fe₃O₄ nanoparticles?mFe₃O₄?,ultrasonic-responsive invisible nanoparticles?RBC-HPBs?were prepared.Then three kinds of anti-tumor drugs precise delivery systems were designed based on these physics-responsive nanomaterials described above and used for drug targeted delivery,intelligent controlled release and tumor multi-mechanism treatment.The main contents are as follows:1.Near-Infrared-Triggered In-situ Hybrid Hydrogel System for Synergistic Cancer TherapyAs one of the most frequently-used chemotherapeutic drugs,doxorubicin?DOX?is accompanied by low accumulation in tumor and severe dose-limiting side effects with systemic administration,which limits its therapeutic index.In this work,a novel and injectable in situ photo-sensitive inorganic/organic hybrid hydrogel as a localized drug-delivery system was examined.It explored poly?ethylene glycol?double acrylates?PEGDA?as polymeric matrix,DOX as a model drug,TiO₂@MWCNTs nanocomposite as photoinitiator and photosensitizer– photothermal agent for tumor therapy with multi-mechanism by a single NIR laser.Briefly,a PEGDA solution containing DOX and TiO₂@MWCNTs was injected into tumor and rapidly gelled in vivo via photo-crosslinking action triggered by NIR laser.DOX was released from DOX/TiO₂@MWCNTs/PEGDA hydrogel sustained and long-lasting over 10 days,indicating that the PEGDA gel acted as a drug depot.Simultaneously,a NIR laser light was adopted which can be absorbed and converted into reactive oxygen species?ROS?or local hyperthermia by TiO₂@MWCNTs,leading to tumor cell death.This DOX/TiO₂@MWCNTs/PEGDA hydrogel exhibited remarkable anti-proliferative activities against MCF-7 cancer cells in vitro.Experiments in vivo showed that a single intratumoral injection of this hydrogel with 808 nm laser irradiation was the most effective among all DOX formulations in the tumor-bearing mice models.There was relatively small DOX distribution in normal tissues and much lower systemic toxicity than control group?DOX-only?.In general,it is believed that the novel photo-sensitive hybrid hydrogel system prepared in this study can afford high drug-loading,sustained and stable drug release,as well as repeatedly phototherapy of tumor with a single dose administration.2.An Intelligent and Tumor-responsive Fe²⁺ Donor and Fe²⁺-dependent Drugs Cotransport SystemFe²⁺ plays an essential role for artemisinin?ART?-based drugs in anti-cancer therapy.So it's important to realize these two agents' cotransport for improving anti-tumor efficacy.We utilized a kind of alternating magnetic field?AMF?and tumor responsive material-mesoporous Fe3O4?mFe₃O₄?to encapsulate ART.After that,the outer surface of mFe₃O₄ was capped with multifunctional hyaluronic acid?HA?which was used not only as smart gatekeeper but also as tumor targeting moiety.In vitro and in vivo studies proved that ART can be encapsulated in HA-mFe₃O₄ and protected by HA coating which could effectively avoid premature release during in vivo circulation.HA-mFe₃O₄/ART could be taken up by MCF-7 tumor cells via CD44 receptor-mediated endocytosis and locate at acidic lysosome.Subsequently,“HA gate” could be degraded by acidity and hyaluronidase.Then this system synchronously released Fe²⁺ and ART at the same site.Fe²⁺ can non-enzymatically convert ART to ROS for killing cancer cells.Under AMF irradiation,HA-mFe₃O₄ could not only effectively convert electromagnetic wave into heat for tumor thermal therapy,but also generate high levels of reactive oxygen species?ROS?for tumor dynamic therapy.These results demonstrated that the anti-tumor efficacy of HA-mFe₃O₄/ART in vivo significantly enhanced 3.7 times compared with free ART.Combining with AMF,it further improved 3.9 times?V/V0 of 0.11?,suggesting the successful combined application of HA-mFe₃O₄/ART and AMF for tumor treatment.It is believed that HA-mFe₃O₄/ART is a promising system for Fe²⁺-dependent drugs to improve their therapeutic effect.3.Study on the Ultrasonic Responsive Drug Delivery System for Tumor Precise Delivery and O₂ Self-supplied SDTHollow mesoporous materials have a huge advantage in the drug delivery field because of their high specific surface area and pore volume.In this study,hollow mesoporous Prussian blue nanoparticles?HPBs?were prepared as drug carriers.Then hematoporphyrin monomethyl ether?HMME,sonosensitizer?and perfluorohexane?PFH,oxygen-carrying and ultrasound phase change material?were loaded into HPBs.After that,the surface of HPBs was wrapped with red blood cell membrane?RBC?to prepare RBC-HPBs/HMME/PFH system,for tumor ultrasound imaging and O₂ self-supplied sound dynamic therapy?SDT?.The results showed that HPBs could effectively load HMME.The drug loading rate and entrapment efficiency were 63.9% and 88.7%,respectively.After being wrapped with RBC,the cumulative release percentage decreased to 16.0% at 24 h,effectively reducing HMME leakage during in vivo circulation.With ultrasound stimulation,PFH changed from droplets to microbubbles and then RBC ruptured to open the gated switch with cumulative release percentage of 88.9% at 24 h.The 4T1 cell line was chosen as tumor model.Results demonstrated RBC wrapping could promote the phagocytosis of HPBs/HMME/PFH by 4T1 cells.HMME and O₂ could simultaneously release under ultrasound irradiation,resulting in a large number of ROS production.These ROS triggered intracellular redox system imbalance,DNA fragmentation,mitochondrial membrane permeability change and pro-apoptotic protein release,which induced 4T1 cell apoptosis and tumor proliferation inhibition.The results of in vivo imaging and frozen sections showed that RBC-HPBs/HMME/PFH significantly increased drug distribution in the tumor site and reduced its distribution in non-target organs.Pharmacokinetic results showed RBC-HPBs/HMME/PFH could significantly reduce clearance rate of HMME in vivo and achieve long circulation.Ultrasound imaging results demonstrated that RBC-HPBs/HMME/PFH could be used as ultrasound contrast agents for in vivo track of drug delivery system and tumor diagnosis.Pharmacodynamics experiments showed that this O₂ self-supplied system alleviated the hypoxic environment within tumor and down-regulated the expression of HIF-1? and VEGF,which would inhibit tumor angiogenesis.Moreover,ultrasound-induced PFH phase transition?gaseous?could be used as a nano-bomb for mechanical destruction of existing tumor blood vessels.These effects led to the decreasement of tumor internal vascular density in RBC-HPBs/HMME/PFH group.In addition,in vivo ROS detection results showed that RBC-HPBs/HMME/PFH could greatly improve ROS yield in tumor sites for SDT treatment and significantly enhance the direct killing effect of HMME on tumor cells.