| Cancer is one of the leading causes of death and a major public health problem.Among many therapies,chemotherapy is still indispensable for cancer treatments However,most antitumor drugs,owning to its poor solubility,can be cleared rapidly in the body and are lack of selectivity in tissue distribution,thus leading to lower drug efficacy and many side effects.In recent years,with the development of nanomedicine,a wide variety of nano-materials are used for fabricating chemotherapy drug carriers,which has effectively overcome the dilemma of delievering chemotherapy drug to the tumor cells.Nanomedicines possess therapeutic advantages over free drugs,including enhanced water solubility,prolonged circulation time and accumulated tumor drug concentration.To large extent,nanomedicines reduced the overall side effects of traditional free drugs on vital organs.Liposomes are widely used as one of drug delivery carriers due to their unique structure,good biocompatibility and biodegradability.At present,some liposomal drugs have been approved to be listed on the market,showing great application prospect.However,due to the fluidity and lipophicity of liposomal membrance,liposomal carriers are susceptible to various components in the blood and quickly cleared by reticuloendothelial system in vivo,making liposomal drug a short blood circulation time and weak tumor accumulation ability.To achieve the prolonged circulation time in the body and enhance the efficacy of the drug,some protective macromolecules,like PEG,are adapted to modify the surface of the liposome.The protective modification has surely shielded the liposomal drug from removing out of the body prematurely,but it has greatly hindered the liposomal drug to be recognized and then uptaken by tumor cells,thus weakening the antitumor effect of liposomal drug eventually.In our previous work,N-oxide structure,as a highly hydrophilic neutral group,was found to have a weak interaction with protein and possess similar "shielding" function with PEG.And the N-oxide drug carriers are easily recognized and uptaken by tumor cells compared with PEGylated carriers.Therefore,we assume that liposome with N-oxide hydrophilic structure can be easily uptaken by tumor cells after well accumulated in tumor tissue through EPR effect.In this dissertation,a series of N-oxide lipids are devised and synthesized,and the properties of N-oxide liposomes are studied systematically.The first part of this dissertation is the synthesis of N-oxide lipids.We use 2,2-Bis(hydroxymethyl)propionic acid(BHP)as linker to easily synthesize expected 28 N-oxide lipids.However,some objective N-oxide structures can not be synthesized by the certain method in the oxidation step,so we just get 16 N-oxide lipids.In the second part,we first investigate the structure of lipids and the molar ratio of lipids on the stability of liposomes,and then we use N-oxide liposome to encapsulate SN38/CPT-11 NPs with the optimal lipids ratio,shielding the positive charge of SN38/CPT-11 NPs.In the end,various experiments are carried out to evaluate the biological properties of N-oxide liposomes and in vitro/vivo toxicity of liposomal NPs;By studying the plasma clearance rate and biological tissue distribution of the liposomal drug,we find that N-oxide liposome is as good as PEGylated liposome in body circulation and can effectively accumulate in tumor tissue;In real-time imaging the cellular uptake of liposomes,the N-oxide liposome is shown to enter the tumor cells faster than the PEGylated liposome;And in HepG2 tumor xenograft model,SN38/CPT-11 liposomal NPs achieve more robust therapeutic efficacy than unpacked SN38/CPT-11 NPs,especially TPGS-NO-Lipo/S4C1. |
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