Environmentally Sensitive Drug Loaded Polysaccharide Nanoparticles For Cancer Chemotherapy

Currently,the main methods to treat tumors are chemotherapy,surgical excision,radiotherapy and immunotherapy.However,traditional chemotherapy drugs usually have defects of high toxicities,poor tumor targeting and drug resistance.The development of nanomedicine has provided a possibility for the targeted delivery of chemotherapy drugs to tumor tissues and improve the above defects of chemotherapy drugs.Nanomedicine has become a hotspot in the field of cancer chemotherapy in recent years.Based on the advantages of nanomedincines,some anti-tumor nanomedicine have been approved for clinical applications.For example,in 1995,PEG modified DOX-liposome Doxil?has been approved for the treatment of ovarian cancer,breast cancer,and Kaposi sarcoma.Clincial strudies showed that,Doxil?can effectively enhance cycle time in vivo,help the enrichment of DOX in tumor tissue,reduction of side effects,and improvent of survival time in patients.In 2005,paclitaxel albumin nanoparticles Abraxane?approved by FDA has beacome the first-line drugs for the treatment of metastatic breast cancer.But there is a huge gap between translation and research of nanomedicine.This is because naomedicine only can reduce the toxicity of chemotherapeutics through EPR effect by prolonging its physicochemical property.Nonetheless,based on EPR effect only can not sufficiently realize the efficacy of nanomedicine,and can not fully renduce the toxic and side effects of chemotheraputics.After nanomedicine enter the blood ciculation in vivo,it will face many barriers caused by the internal physiological environment.For example,Mononuclear Phagocyte System(MPS),high interstitial pressure,tumor cell resistance limit the therapeutic effect of nano-borne drug delivery system in the body.Therefore,our group has proposed five requirements of designing new nanomedicine.“Run fast”-the nanomedicine should be long-circulated in blood;"able to stop"-nano drug delivery system can accumulate in the tumor site,"deep penetration"-nanomedicine system can deeply penetrate in the tumor tissue;"uptake"-nanomedicine can enter tumor cells;"releaseable"-nanomedicine can release drugs inside tumor cells.However,the demands of the nanomedicine usually ask for contradictory charateristics.For example,long circulation required the surface ofnanomedicine should be hydrophilic,negative or neutral,while cell uptake required the surface of nanomedicine should be hydrophobic and positive.The small diameter of nanomedicine is beneficial for deep penetration into tumor tissue,but small is rapidly metabolized by the kidney in blood circulation,which is not conducive for long circulation.Based on these contradictions,recently,scientisits have adopted environmental responsive molecules(temperature sensitive,p H sensitive,ionic strength sensitive,enzyme sensitive,near-infrared light sensitive,redox sensitive,anoxia sensitive)in fabrication of nanomedicine,to improve long circulation,target,deep penetration in tumor tissue,cell uptake and intracellular release.In this paper,two environmental-sensitive molecules have been applied in fabrication of two novel nanomedicine.Main reaserach and results are as follow:1.By conjugating Folic acid(FA)onto Dextran(DEX),and other four polysaccharide,we have achieved five FA conjugated polymers to afford FA-polysaccharide.And then,five FA-polysaccharide were self-assembled into nanoparticles by p H-adjustment method.Then,DEX-FA was used as a typical example to domenstrate three function of FA in tumor treatment.First,FA was used as a hydrophobic group to guide the self-assemble of DEX-FA nanoparticles;second,Doxorubicin(DOX)could be encapsulated via electrostatic interactions between DOX and FA,DOX could be released by tuning p H;third,DOX@DEX-FA NPs exhibit typical FA-FRs mediated endocytosis in vitro and targeted delivery in vivo,altogether contributing to an enhanced antitumor efficacy,75.3 %,which is much higher than the free DOX,61.6 %.The FA+DOX@DEX-FA group achieved tumor inhibition rate of 21.6%.Except that,DOX@DEX-FA nanoparticles can effectively reduce the toxicity compared with the free DOX,and enhance median survival time of mice by 30%.Therefore,DOX@DEX-FA nanoparticle have been demonstrated to be a simple,safe and efficient nanoplatform,holding significant translation potential for treating FRs overexpressed cancers.This study has utilized the active targeting and p H sensibity abilities of FA to achieve “able to stop”,“uptake” and “releasable” functions of DOX@DEX-FA NPs.2.We have developed a new NIR responsive nanoparticle,ICG@HES-SS-DOX,by crosslink HES-SS-DOX through ICG.Serving as a temporal and sacrificial cross-linker,ICG plays a decisive role in ICG@HES-SS-DOX NP: first,ICG crosslink HES-SS-DOXvia electrostatic and hydrophobic interactions between ICG and DOX,facilitating the formation of a stable 125 nm ICG@HES-SS-DOX NP;upon 5 minutes near infrared(NIR)laser light exposure,ICG degrades and thus disintegrates ICG@HES-SS-DOX NP.The scattered HES-SS-DOX conjugates,which are 10 nm nanoparticles,can penetrate deep in both tumor spheroid model and tumor bearing mice.Therefore,the disintegrable ICG@HES-SS-DOX NP has better tumor penetration capacity than its counterparts,those with no NIR light responsive property.ICG,DOX and HES have been applied in clinical settings,the reported ICG@HES-SS-DOX NP might be potent in treating malignant tumors with dense extracellular matrix,including liver and pancreatic cancers.The study has utilized the degradability of ICG and reduction sensitivity of HES-SS-DOX in vivo to achieve “able to stop”,“deeply penetration” and “releasable” functions.