Structure Regulation And Biological Function Research Of Block Copolymers Based On 2-hydroxypropyl Methacrylamide

Chemotherapy is currently one of the most effective treatments for cancers.The small-molecule anti-cancer drugs used for chemotherapy have a short in vivo circulation time and serious non-speeific enrichment phenomena,and therefore require repeated administration and are often accompanied by serious toxic and side effects.Therefore,nano drug delivery systems have always been a hot issue for scientists.PHPMA is a type of water-soluble polymer commonly used in drug carriers.It has good biocompatibility,non-toxicity,and immunogenicity.This dissertation focuses on the synthesis,topology and chemical composition of 2-hydroxypropyl methacrylamide(HPMA)-based polymers,as well as the relationship between the biological properties and the structure and composition of the prepared polymers.The first part of this dissertation focused on the synthesis and biological functions research of star-shaped tri-block polymers based on HPMA.By combining anionic ring-opening polymerization(ROP)and reversible addition-fragmentation chain transfer(RAFT)polymerization techniques with pentaerythritol and tripentaerythritol as cores,a series of four-and eight-armed tri-block copolymers PEG-b-PBHMAGG(DOX)-b-PHPMA with well-defined architectures and controlled compositions were synthesized.The prepared polymer-drug conjugates self-assembled into nanomicelles in aqueous solution.DLS and TEM studies showed that star polymer micelles presented secondary aggregation in aqueous solution,and the degree of micellar aggregation was concerned with polymer topologies and chemical compositions.The interactions between star polymers and cells were studied.With the increase of polymer arm numbers,the uptake of micelles decreased,and further down-regulated the cytotoxicity,cell cycle and cell apoptosis.The phannacokinetics and biodistribution of star polymers with different topological structures were studied by animal experiments.The results showed that increasing the number of star polymer arms dramatically prolonged the blood circulation half-life of micelles and increased the accumulation of micelles in tumor tissues.In the assessment of anti-tumor behavior,the anti-tumor efficiency of the eight-armed tri-block polymer was optimal.In addition,all prepared star polymer micelles were cleared through the kidneys,ensuring biosafety at high dosage treatment.The second part of this thesis focused on the synthesis and biological behaviors study of comb-like PHPMA.Although comb polymers can greatly increase the branching degree of the polymer and thus improve the biological properties such as the blood circulation time,the synthesis and biological properties studies of comb-like PHPMA have rarely been reported.In this work,for the first time,we studied the synthesis of comb-like PHPMA by ATRP.Firstly,the feasibilities of synthesizing comb-like PHPMA by means of Me4Cyclam mediated ATRP were explored through kinetic studies.The optimal reaction conditions and post-treatment methods were determined.Secondly,a series of comb-like PHPMAs with different topologies(comb numbers,lengths,and densities),controlled compositions,and narrow molecular weight distributions were successfully synthesized.Cytological evaluations indicated that the internalization of comb-like PHPMA-DOX conjugates were low due to their large molecular weight and resulted in reduced cytotoxicity.The in vivo pharmacokinetics and biodistributions of comb-like PHPMA were dependent on polymer topologies and molecular weight compositions,and the optimal topology and chemical composition was determined to provide guidance for follow-up polymer design and synthesis.The physical and chemical properties of nanomedicines(such as particle size and surface charge)determine their biological properties.For example,the surface charge of micelles has a significant influence on the blood circulation half-life of micelles and non-specific enrichment of organs.Current research on the surface charge of micelles mainly macroscopically focused on direct relationships between different biological properties and distinct types of charge(positive,negative,and electrically neutral)nanoparticles,however,biological properties of charged micelles with same charge type but different charge sources have rarely been reported.The third part of this thesis focused on the preparation and biological behaviors of diverse cationic micelles.This work used PEG-PSN38 as a model polymer to synthesize tri-block polymer PEG-b-P(CFG)-b-PSN38 bearing a positively charged functional block,and a series of cationic micelles with same particle size but different positive charge sources were prepared.The interaction of cationic micelles with cells was investigated.The results showed that cationic micelles are helpful for cellular uptake.Cationic micelles inclined to bind to mitochondria,causing mitochondrial damage,and further synergistically promoting cell apoptosis and death with SN38.Cationic micelles presented stronger tumor penetrating abilities than non-cationic micelles,and distinct positively charged functional groups exhibited different penetrating ability.Cationic micelles were enriched in the liver,but it caused little damage to the liver due to the low release efficiency of SN38.Cationic micelles with primary amines and quaternary amines as the positively charged functional groups were highly accumulated in tumor sites.They exhibited better target abilities to tumor blood vessels and penetration into tumors.Therefore,greater anti-cancer efficiencies on solid tumors were obtained.