| Polysaccharides are a class of polymeric carbohydrate molecules consisting of a number of monosaccharides joined together by glycosidic bonds.They have been widely used in the fields of biomedicine,such as drug delivey and biological probe due to their excellent biocompatibility,biodegradability,and protein targeting and cell recognition properties.In this work,we fabricated a series of polysaccharide-based nanocarriers via hydrophobic-and hydrogen-bonding driven graft copolymerization induced self-assembly strategy(GISA strategy).Afterwards,as-prepared polysaccharide-based nanocarriers were functionalized via various approaches.On this basis,the applications of functional polysaccharide-based nanocarriers as drug delivery carriers,bio-imaging agents,and nanoreactors for in-situ synthesis of noble metal nanoparticles were systematically studied.First of all,a series of polysaccharide-based nanocarriers with various compositions and functions were fabricated via hydrophobic force,or hydrogen bonding driven GISA strategy starting from water-soluble polysaccharides and being initiated by free radical initiators in aqueous solution.For example,various functional polysaccharide-based nanocarriers were fabricated via hydrophobic force driven GISA strategy,using various polysaccharides(dextran and hydroxypropyl cellulose),hydrophobic monomers(hydroxyethyl acrylate,methyl acrylate,ethyl acrylate,n-butyl acrylate,and glycidyl methacrylate)and different functional crosslinkers(N,N'-Methylene-bis-acrylamide and diallyl disulfide).On the other hand,various polysaccharide-based nanocarriers were fabricated via hydrogen-bond driven GISA strategy,using the monomers bearing carboxyl groups(acrylic acid and methacrylic acid).We demonstrate that this approach is applicable to a broad range of polysaccharides and acrylates.The reaction mechanism was proposed and the relationship between the structures and properties of the nanocarriers was discussed.Notably,by choosing a reducing sensitive crosslinker(diallyl disulfide),the products are rendered cleavable in the reductive environments.We also demonstrate the kilogram-scale preparation of dextran-diallyl disulfide poly(methyl acrylate)(Dex-SS-PMA)nanocarriers with reducing sensitiveness,which are chosen as the representative,at mass of up to 3.14kg and at a high efficiency of 618 g·h-1 via the GISA strategy.The above results confirm that GISA strategy is an effective,universal method and is applicable to kilogram-scale preparation of nanocarriers.On the basis of abovementioned results,by choosing the two reducing environment sensitive nanocarriers,dextran-diallyl disulfide poly(methyl acrylate)(Dex-SS-PMA)and dextran-diallyl disulfide poly(acrylic acid)(Dex-SS-PAA),as representatives,we fabricated p H/redox-dual sensitive Dex-SS-PAA-DOX and Dex-SS-PMA-DOX drug loaded carriers that carried antitumor drug doxorubicina(DOX)through the acid-labile hydrazone bond.The in vitro drug release behavior,cytotoxicity,in vivo anti-cancer effects and biosafety of these drug loaded nanocarriers were systematically investigated.The results revealed that the Dex-SS-PAA-DOX and Dex-SS-PMA-DOX exhibited a strong ability to inhibit the growth of MDA-MB-231 tumor cells,while greatly reduced the toxicity of free DOX.Dex-SS-PAA-DOX drug loaded carrier was furtherly complexed with gadolinium-based small molecular nuclear magnetic resonance contrast agent,i.e.,Gd-DTPA to fabricate Dex-SS-PAA-DOX-Gd nanocarriers with diagnostic and therapeutic multi-functions.A series of in vitro and in vivo biological tests were investigated.The results demonstrated that the longitudinal relaxivity of Dex-SS-PAA-DOX-Gd was 79.7 m M-1·s-1,which is between 16-and 25-fold that of commercial Magnevist.Furthermore,Dex-SS-PAA-DOX-Gd exhibited good biocompatibility and strong ability to inhibit the growth of tumor that could be diagnosed and monitored by nuclear magnetic resonance imaging(MRI).Moreover,the method that utilized physical interaction between Gd and nanocarriers to prepare macromolecular nano-sized contrast agents to enhanced relaxivity is applicable to a broad range of polysaccharide-based nanocarriers.For example,dextran-poly(glycidyl methacrylate)(Dex-SS-PGMA)nanocarriers could be used to load Gd-DTPA by non-covalent bond as well and the longitudinal relaxivity of the resultant Dex-SS-PGMA-Gd was 44.4 m M-1·s-1,which is between 9-and 14-fold that of commercial Magnevist.Furthermore,Dex-SS-PGMA-Gd macromolecular nano-sized contrast agent has the ability to specific receptor mediated targeted imaging lymph nodes.Nobel metal nanocrystals,including gold,silver and palladium,have a wide range of applications in photothermal imaging,photothermal therapy,anti-bacterial,catalysis,etc.In order to endow metal nanocrystals with excellent biocompatibility and biofunctionality,it is an effective approach to prepare functional metal nanocrystals in the biomolecule-based nanocarriers via in-situ synthesis method.Based on this idea,the dextran-based Dex-SS-PMA nanocarriers that prepared by GISA strategy were modified by hydrazine hydrate.Nanocarrier“reactor”with reductive hydrazine groups were therefore obtained.They were successfully applied to in-situ fabrication of gold(7.74±2.04 nm),silver(1.63±0.40 nm),platinum(2.21±0.41 nm)and palladium(2.27±0.36 nm)nanocrystals.In this process,the nanoreactor worked in three different roles synchronously,i.e.,structural template,reducing agent and stabilizer.The synthetic approach is facile,efficient,and applicable to the synthesis of various metal nanocrystals.Notably,the introduction of other impurities such as reductant was avoided in this approach.Therefore,this work provides a new method as reference for the in-situ synthesis of metal nanocrystals,and as-prepared biomacromolecule-inorganic hybrid nanoparticles have a broad application prospect in biomedical field.In conclusion,we proposed and realized a hydrophobic force/hydrogen-bonding driven graft copolymerization induced self-assembly(GISA)strategy for the high efficiency synthesis of various polysaccharid-based nanocarriers.The nanocarriers with environmental sensitivity were fabricated by choosing a crosslinker bearing a disulfide bond.The applications of functional polysaccharide-based nanocarriers in loading drugs and of MRI contrasts were systematically studied by in vitro and in vivo biological tests.Furthermore,the application of polysaccharide-based nanocarriers in in-situ synthesis of noble metal nanoparticle was studied.The main novelty of this thesis lies in the realization,generalization of GISA strategy,expandation of the GISA strategy from hydrophilic acrylic acid monomers to hydrophobic acrylate monomers,and the development of the GISA strategy in large-scale production of the polysaccharide nanocarriers.Moreover,the applications of polysaccharide-based nanocarriers in loading drugs and of MRI contrasts,in-situ synthesis of inorganic noble metal nanocrystals were demonstrated,which laid a foundation for further biomedical applications of resultant polysaccharide-inorganic hybrid nanoparticles. |
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