Investigation Of Nano-sized Pseudo Blockpolymer Drug Delivery System Based On Host-guest Inclusion Complexation

Recently,nanomedicine has been widely used in tumor treatment.Due to the EPR effect of tumors,nano drug carriers can actively or passively accumulate in tumors,increase the tumor drug concentration and reduce the severe side effects of anticancer drug.Compared to conventional strategy,supramolecular interactions,such as hydrophobic interaction,?-? interaction,electrostatic interaction,and host-guest inclusion interaction,brings a lot of convenience and functionality in constructing novel nano vehicles.By using the host-guest inclusion complexation,we prepared pseudo block copolymer-based multi-functional nano-sized drug delivery system,prolonged the drug circulation time in blood,improved the drug accumulation in tumor site,enhanced the antitumor efficacy.The main research contents are as following:(1)?-cyclodextrin modified poly(N-vinyl pyrrolidone)(?-CD-PVP)was synthesized through RAFT polymerization,and adamantyl end-capped poly(aspartic acid)was synthesized through ring opening polymerization.Based on the host-guest interaction between ?-cyclodextrin and adamantane,and coordination interaction between anticancer drug CDDP and the carboxylic acid groups of poly(aspartic acid)(AD-PASP),CDDP-loaded non-covalently crosslinked nanoparticles were obtained.The size and morphology of the CDDP-loaded nanoparticles were characterized by DLS and TEM.Also,we investigated the stability,drug release profile,cytotoxicity,cell uptake,biodistribution and anticancer efficacy of the CDDP-loaded nanoparticles,revealing that the CDDP-loaded poly(N-vinyl pyrrolidone)-poly(aspartic acid)nanoparticles had narrowly distributed size and high stability,and could release drug in a sustained manner in the presence of chloride ion.The cell experiments also demonstrated that these drug-loaded nanoparticles had desirable cytotoxicity and cell uptake efficiency.Compared to free CDDP,these nanoparticles had excellent antitumor efficacy in vivo.The TGI of these nanoparticles was about 88%,in contrast,that of free CDDP was about 63%.(2)Through RAFT post-function method,the xanthate group of poly(N-vinyl pyrrolidone)was converted to azide group.Via the click reaction between the alkyne-modified carbamoylmannose and the azide-functioned polymer,we obtained the carbamoylmannose-modified poly(N-vinyl pyrrolidone).Based on the host-guest interaction between(3-cyclodextrin and adamantane,and coordination interaction between anticancer drug CDDP and the carboxylic acid groups of poly(aspartic acid),active tumor-targeting CDDP-loaded nanoparticles were prepared.Several cancer cell lines and normal cell line were selected to study the cell uptake mechanism of the active tumor-targeting CDDP-loaded nanoparticles.By using subcutaneous murine hepatic H22 tumor model,we investigated the biodistribution and anticancer efficacy of the active tumor-targeting CDDP-loaded nanoparticles.It was found that the carbamoylmannose-modified CDDP-loaded nanoparticles had uniform spherical morphology.The particle size was about 66 nm,and these nanoparticles could be readily redispersed in deionied water.For the test cancer cells,the carbamoylmannose moiety could significantly enhance the cell uptake efficiency of these nanoparticles via receptor-mediated pathway.By contrast,for normal cell,these nanoparticles could hardly be internalized.In the mean time,the carbamoylmannose-modified CDDP-loaded nanoparticles had the superior tumor accumulation,penetration and antitumor efficacy.Compared with non-or mannose-modified nanoparticles,the carbamoylmannose-modified CDDP-loaded nanoparticles had more desirable cytotoxicity,cell uptake efficiency,tumor-targeting ability and antitumor efficacy.(3)We synthesized 7 arm star polymer with(3-cyclodextrin as the core and poly(N-vinyl pyrrolidone)chain as the arm.Through the mild Aminolysis/Micheal addition reaction and click reaction,the trivalent carbamoylmannose was conjugated to each arm of the polymer.And through ring opening polymerization and aminolysis reaction,adamantyl end-capped poly(Asp-C6)was prepared.By using host-guest interaction between ?-cyclodextrin and adamantane,and hydrophobic interaction of adamantyl end-capped poly(Asp-C6),trivalent tumor-targeting seven poly(N-vinyl pyrrolidone)chains-modified non-covalently linked nanoparticles were prepared accordingly.Also,monovalent tumor-targeting one PVP chain-modified nanoparticles and monovalent turmor-targeting seven PVP chains-modified nanoparticles were prepared as control groups.Several cancer cell lines were selected to investigate the cell uptake behavior of these nanoparticles.