| With the development of cross-fertilization of various disciplines,nano-drug delivery technology has shown great application prospects in the field of drug delivery.The formation of nano-sized gels for drug delivery by loading drugs with various carriers can not only improve the shortage of in vivo circulation time of small molecule drugs,but also solve the application limitation of poor stability of most biological macromolecule drugs.Among them,polymer-and lipid-based nanocarriers are widely used in the construction of drug delivery systems due to their simple preparation and easy modification.Researchers have found that the physicochemical properties of nanodrug carriers,such as size,surface potential,particle shape,and surface ligands,determine the circulation and distribution of nanodrugs in living organisms.Properly designed nanodrug carrier materials can improve their bioavailability and achieve responsive release of drugs to various stimuli.However,polymeric and lipid nanodrug carriers pack or adsorb drugs mainly through intermolecular noncovalent interactions during preparation,and the stability of such drug delivery systems often fails to meet the application standards in the face of complex external and physiological environments.Therefore,how to achieve modulation of physicochemical properties of nanodrug carriers by simple methods with excellent stability in applications and stimuli-responsive release of drugs at specific sites is a major challenge in the construction of nanodrug delivery systems.In this thesis,the stability of drug carriers can be greatly enhanced by in situ radical polymerization on the surface of nano-drug carriers through different design approaches to form a polymeric shell layer with cross-linked network structure.The selection of monomers can modulate the physicochemical properties of the nano-drug carriers to improve the accumulation and uptake at specific sites;meanwhile,the selection of cross-linkers in the reaction can also achieve controlled release of drugs in response to endogenous substances and greatly improve the therapeutic effect of the drug delivery system.The specific studies are as follows:1.first,we formed micellar nanodrug carriers by introducing a free radical reaction initiation site N,N,N’,N’-tetramethylethylenediamine(TEMED)at the end of the conventional polymer Pluronic F127 and then assembled with the model drug paclitaxel.the combination of TEMED and ammonium persulfate(APS)allows in situ free radical initiation on the surface of the micelles,forming a cross-linked polymer shell layer and enhancing stability of the micelles.The physical and chemical properties of the micelle surface such as potential and particle size can be regulated by adjusting the type and addition of monomers;the choice of cross-linker can achieve controlled drug release.The modified nano drug carriers show high stability in different solute solutions,different acid-base solutions and different temperatures.To further improve the application of the nanodrug carriers,we selected pH-sensitive monomer 2(diethylamino)ethyl methacrylate(DMAEMA)and GSH-responsive cross-linker N,N’bis(propionyl)cystamine(BAC),and the modified nanodrug carriers could achieve charge reversal under low pH conditions and drug release under reducing conditions.The modified nano-drug carriers exhibited higher stability under physiological conditions after surface radical polymerization,and the physicochemical properties and therapeutic efficacy of drug delivery were successfully verified in cellular and animal experiments.2.In order to extend the application of surface free radical polymerization reactions while reducing the difficulty of synthetic preparation,we combined the drug loading diversity of liposomal drug carriers and formed liposomal nanodrug carriers co-loaded with paclitaxel and platinum drugs by inserting lipid molecules with C=C double bonds into the bilayer membrane structure of liposomes and self-assembled them.The introduction of C=C double bond can serve as a free radical polymerization active site for the formation of new polymeric shell layers through in situ free radical polymerization reactions.It was shown that free radical reactive modification of liposomal surfaces by C=C double bonding can successfully prepare nanodrug carriers that maintain high stability in complex external environments.The potential as well as the particle size of the carriers can be adjusted by monomers.Also based on the consideration of biocompatibility,surface potential and drug release,we chose the amphiphilic molecule 2-methacryloyloxyethyl phosphorylcholine(MPC)as the polymeric monomer and also added carboxymethyl chitosan monomer to improve the biocompatibility of nanoparticles as well as to achieve the modulation of surface charge.Diallyl disulfide(DADS)cross-linker was chosen to achieve controlled drug release.The modified liposomal nanodrug carriers are not only highly stable under physiological environment,but also highly biocompatible lipid molecules and monomers are more suitable for biological applications.Compared with conventional liposomes,the modified liposomal nanopharmaceutical carriers overcome the disadvantage of easy drug leakage,demonstrate better controlled release performance in toxicity tests,and show higher physicochemical performance advantages and therapeutic effects in cellular and animal experiments.3.In order to further simplify the preparation process and achieve in situ free polymerization reaction on the surface of nanodrug carriers while increasing the drug loading of the carriers,based on the high drug loading of dimeric drugs,we first used conventional polymer F127 and paclitaxel dimer for the preparation of nanodrug carriers.Since the surface of the nano-drug carriers assembled with F127 is negatively charged,we selected the cationic monomer N-(3-aminopropyl)methacrylic acid hydrochloride(APM)and used supramolecular electrostatic interaction to adsorb with the carriers to carry C=C double bonds on the surface as the active site for free radical polymerization,which successfully realized the surface in situ free radical polymerization and obtained the cross-linked polymer shell,and achieved the nanodrug carriers in a simple and efficient way.The high drug loading capacity and high stability of the nano-drug carriers were achieved in a simple and efficient way.It was demonstrated that the modified nano-drug carriers were more stable than conventional nano-drug carriers under different external environmental and physiological conditions.Meanwhile,based on the importance of charge reversal and controlled release in drug delivery,the cross-linker containing disulfide bonds was selected during the free radical reaction and 3-methylmaleic anhydride was selected for surface positive charge shielding after the reaction,and the obtained nano-drug carriers could achieve charge reversal under acidic conditions and controlled release of drugs in reducing environments.Cellular experiments and animal experiments further demonstrated the higher stability and therapeutic effects of the simply modified nanodrug carriers relative to conventional nanodrug carriers. |
