| The targeted nanoparticles showed significant advantages in increasing the solubility of hydrophobic drugs,improving the selectivity of tumor tissue and cells,reducing the systemic toxicity and overcoming drug resistance.However,the targeted drug carriers also face severe challenges,like increased side effects and fast clearance induced by the nonspecific binding with normal cells or proteins in the circulatory system.Hence smart target-function-modulatable drug carriers that can regulate the targeting function and drug release responding to the internal(e.g.,pH,enzyme,reductive environment and temperature)or external(e.g.,light and magnetic field)stimuli are urged to address the drawbacks.On the other hand,the smart targeted nanoparticles can also evade the recognition of P-glycoprotein(P-gp)via receptor-mediated uptake and endosome transport,and efficiently improve the enrichment of the chemotherapeutics and further overcome multidrug resistance.In this work,our study focuses on the design and construction of stimuli responsive targeting nanocarriers for drug delivery and overcoming drug resistance.In chapter 1,the construction and latest trends of stimuli responsive drug delivery system and the mechanisms of multidrug resistance were briefly reviewed,and then we emphatically introduces the application of programmed specific targeting strategies and multidrug resistance reversing mechanism.In chapter 2,the photosensitive intelligent targeting nanoparticles,Biotin-F68-Biotin/Ad-lys(F68)-PS/CD,was prepared via the host-guest interaction between ?-Cyclodextrin(?-CD)and Biotin.The coated P-CD could efficiently inhibit the targeting function of Biotin.When the nanoparticles was under irradiation of UV light,?-CDs capped on biotin ligands could be grabbed by adamantane(Ad)groups that were located in the interior of nanoassemblies before light irradiation,due to the cleavage of photo-sensitive groups and the higher binding constant between Ad and P-CD than that of biotin and ?-CD,resulting in the recovery of targeting capacity of biotin ligands on the nanocarriers.By means of photoregulation,the nanocarrier exhibited less target recognition before irradiation and superior tumor cell targeting after irradiation,which was proved by HABA/Avidin assay,flow cytometry,laser confocal microscopy and cytotoxicity assay.In chapter 3,a fructose coated targeting mixed micelles,Fructose/PBA-PEG-C18/P123,was constructed based on the selective binding of phenylboronic acid.The phenylborate formed by PBA and fructose under normal condition make the nanoparticles "invisible" to the normal tissue and cells,while accumulated into the tumor tissue,the stability of borate was dramatically decreased and the PBA can be captured by SA that were over expressed on the tumor cell membranes,which was proved by the results of fluorescence spectra,confocal laser scanning microscopy(CLSM)and flow cytometry.The in vitro cytotoxicity results indicated that the drug loaded mixed micelles could selectively increase the cytotoxicity of HepG2 cells but not injure the normal cells by this strategy.In chapter 4,by utilized of the host-guest interaction between ?-cyclodextrin(P-CD)and adamantane(Ad)as well as the borate formation between phenylboronic acid(PBA)and cis-diols,a smart pH-responsible targeting drug delivery nanoparticle,PBA-PEG-CD/Ad-lys(Diol)-PCL,was prepared via a one-step self-assembly.Under physiological conditions,the targeted function was restrained by the binding of PBA with diol-components located on the interface of self-assemblies and the shielding of hydrophilic PEG segments simultaneously.As a response to the stimuli of tumor acidic environment,the PBA groups could be unbound and exposed on the surface of self-assemblies,leading to the recovery of its targeted function,which was proved by the results of fluorescence spectroscopy,in vitro cell toxicity and uptake.Under acidic condition,PBA-PEG-CD/Ad-lys(Diol)-PCL/DOX showed significantly increased uptake and toxicity to HepG2 cells in comparison with the non-targeted particles and the smart vehicles also showed a greater toxicity to MCF-7/ADR cells.These results suggested that it may be a facile strategy to construct an efficient targeting vehicle by rational utilization of non-covalent interactions and this smart targeting particle has a great potential in inhibiting tumor growth and overcoming drug resistance.In chapter 5,an amphiphilic block copolymer PEG-P(AMPC-g-PTA)was firstly synthesized by a ring-opening polymerization(ROP),and then via the DTT catalyzed disulfide exchange reaction between PBA-PEG-CD/Ad-lys(Diol)-PCL-TA and PEG-P(AMPC-g-PTA),dual bio-responsive and core-crosslinked mixed targeted micelles responding to tumor acidic and cytoplasmic reductive environment were prepared and used for co-delivery of DOX and TQR(a P-gp inhibitor).They showed excellent stability in normal physiological environment and could efficiently prevent the leakage of drug before achieving tumor site.After these mixed micelles was accumulated into tumor site by the enhanced permeability and retention(EPR)effect,the target ligands were exposed onto the surface of the micelles under the stimulation of tumor acidic environment,and recovered the ligand-receptor mediated drug delivery.Finally,when the drug loaded micelles were transported into cytoplasm by endosome,DOX and TQR were released quickly,exhibiting an excellent effect of overcoming drug resistance. |
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