Synthesis Of Novel Amino-acid Based Polycarboxylate Biomaterials And Its Self-assembly Nanodelivery Systems For Cancer Therapy

Due to unique characteristics,nanoparticle has demonstrated great advantages and potential application in chemotherapy.For encapsulated hydrophobic drugs,they could increase drug solubility,improve colloidal stability and achieved sustained-release.Different from normal tissue,solid tumor commonly have disorganized vascularization,defective vascular architecture and lack of effective lymphatic drainage,which resulted in the enhanced permeability and retention(EPR)effect.After administration,nanovehicles could be selectively trapped inside tumor tissue,known as passive targeting.Therefore,nanoparticles could improve local drug accumulation,enhance therapeutic efficiency and reduce drug-related side-effect.EPR related accumulation is time and dose-dependent.In order to extend the particles' circulation time,its surface physiochemical property need to modified to reduce macrophagocytosis.These targeting modules allow nanocarriers to be incorporated directly inside of cells.Polymeric nanodelivery systems are commonly generated by self-assembly of hydrophobic or amphiphilic polymers via single non-convalent interaction like hydrophobic,electrostatic or hydrogen-bonding forces.Hydrophobic drug are commonly trapped inside the hydrophobic core of nanoparticle.But these strategy have low drug loading and limited controllability for preparation process and physiochemical characteristics of nanoparticles.To circumvent this issue,we designed an novel self-assembly pattern,that multiple non-convalent interactions between polymer and drug was used to enhance the encapsulation of drug into nanoparticles.In this study,we synthesized the novel amino acid based polycarboxylate,which has multiple carboxyl group in side chain and varied hydrophobic alkyl chain.As the model drug,doxorubicin hydrochloride has cationic primary amine and hydrophobic anthracyclinone.During the self-assembly process,there were multiple electrostatic and hydrophobic inter-interaction between polymer and doxorubicin.Due to ingenious design and optimization of polymer structure,polymer-based self-assembly nanorod was generated.In order to understand the detailed self-assembly mechanism and evaluate its antitumor efficiency with the heterotypic nanostructure,the following researches were carried out in this thesis:1)Novel polycarboxylate was synthesized via one step polycondensation between amino acid and active ester with different alkyl chain.The productivity yield was more than 85%.After screening the structure component and molar ratio to optimize the coordination of multiple inter-non-covalent interaction,polymer and doxorubicin were rationally fabricated into Rod-like nanostructure.In this system,drug loading and encapsulation efficiency were dramatically high,respectively 130%and 98%.According to high solution TEM imaging,this nanostructure was solid and has great symmetrical characteristics.2)Similar with polyelectrolyte complex,our nanosystem was unstable in buffer solution.Inspired by liposome structure,we combined four different lipid components(cationic 14-TAP,amphiphilic 18-PC,anionic DSPE-PEG-3000 and neutral cholesterol)and forced them to form the layer-assembly on the surface of our nanostructures,which greatly improved nanoparticles' stability and doxorubicin sustained-release.In vitro study exhibited NPs-Rod had similar cytotoxicity and tissue penetration ability to free doxorubicin.Due to specific morphology and lipid layer,NPs-Rod could be transported into cytosol even faster than free doxorubicin.After systemic administration,heterotypic formulation demonstrated great anticancer effect and therapeutic safety on H460-xenograft mice model.3)In order to understand self-assembly mechanism and rationally control nanoparticles' morphology,we compared the structure changes while adjusting the following conditions:varied alkyl chain inside the polymer;different molar ratio;temperature;stirring speed.The multiple interaction between the two components had varied effect on nanoparticle assembly with time.After standing from 1st to 4th day,The "Rod to Sphere" shape-change was observed from polycarboxylate and doxorubicin complex solution.1H-NMR and spectrometry were utilized to measure and analyze the detailed multiple non-covalent interaction for conducting nanostructure assembly.4)According to literatures and previous results,pharmacokinetics performance was critical for nanoparticle accumulation and therapeutic efficacy in vivo.In this section,we tried to alter the lipid layer formulation for optimizing nanoparticles'surface characteristics and in vivo performance.And the effect of shape and geometry was investigated on cellular internalization,cytotoxicity,tissue penetration,biodistribution and antitumor treatment,in order to inspiring innovation and improvement of nanomedicine in cancer theranostics.