| Currently,the main focus of researcher's attention on cancer problems of diagnosis and treatment,which is based on high prevalence and mortality.With the in-depth physiological intercellular study for tumors and normal cells,investigator found that have some high otherness,such as pH difference,GSH levels and enzyme overexpress.Moreover,chemotherapy remains is general trend of the times in cancer treatment.However,traditional chemotherapy created some side effects,such as resulting in incalculable shoulder with patients,including systemic toxicity of body and high economic loss.Thus,preparation of multifunctional drug delivery systems?DDSs?plays an important role to efficient delivery antitumor drugs under blood circulation process in order to resolve self-anticancer drug drawbacks such as:lack of bio-specificity of between normal cells and cancers cells and drug dissolubleness etc.,improvement anticancer efficiency and safeness for cancer treatment.In paper,choose different martials?natural liner polysaccharide,factitial polymeric microsphere and easily obtained fluorescent carbon dots?as frameworks and fabricated several structures were prepared as DDSs with divers loaded ways?including electrostatic adherence,Schiff base bonds and hydrazine bonds,etc.?and high loaded content of anticancer drug?DOX?.Meanwhile,introducing diver fluorescent substances?rhodamine derivative and carbon dots?into DDSs were designed in diagnosis filed,which achieve real-time monitor for drug delivery process and anticancer drug release trace.Therefore,we will mainly discussed as follow sections in paper.Firstly,based on the natural liner alginate as substance,the as-prepared oxidized alginate synthesized by the periodate oxidation method to collected partial aldylation alginate cornerstone.The alginate-based multifunctional theranostic prodrug nanogels were designed by PEGylated targeted folic acid?FA?and fluorescent monomer rhodamine B?RhB?were modified oxidized alginate?OAL-g-PEGFA/RhB?with cystamine?Cys?,followed covalent conjugation of DOX via acid-labile Schiff base bond.Suitable size and distinct biodegradability nanogels were tested by the DLS and TEM technology.pH-modulated fluorescent COAL-g-PEG-FA/RhB nanogels at different pH media,the steady-state fluorescent emission spectra were recorded,and result suggested that fluorescent imaging for tumor diagnosis,with the cancer-associated,stimuli-driven and turn-on characteristics.Therefore,the intercellular responsive DOX release,biodegradable,FA targeted and pH-modulated fluorescence of prodrug nanogels was proposed,to achieving diagnosis,treatment and target in together.Followed by,the functional PGMA microspheres were prepared via a facile emulsion polymerization.After the ring-opening reaction with ethyldiamine?EDA?,the tumor microenvironment bioreducible degradation,pH-activated surface charge reversal,and pH-triggered“off-on”fluorescence and drug release of the PGMA-DMMA microspheres were then collected via amidated reaction with2,3-dimethylmaleic anhydride?DMMA?,which named as theranostic nanoplatforms for precise imaging-guided diagnosis and chemotherapy.the carboxyl groups in the final PGMA-DMMA microspheres could be used to load doxorubicin?DOX?via electrostatic interaction with DLC=18.5%for DOX.PGMA-DMMA nanospheres have good biocompatibility,low cytotoxicity and pH fluorescence guidance characteristics by drug release in vitro,MTT tested and apoptosis tested.PGMA-DMMA/DOX nanospheres have pH/GSH double stimulus-responsive drug delivery system.Therewith,considering that drug leaking from the drug delivery during blood cycles process,we used pH-responsive hydrazine bonds to graft anticancer drug DOX to PEG-PGMA-Hy polymeric microsphere,which architecture of pH-triggered“off-on”fluorescence and tumor-biodegradation of the PEG-PGMA-Hy-DOX prodrug microsphere.Under simulation cells microenvironment in vitro,the DOX released nearly was zero in pH 7.4+10?M GSH while DOX possessed sustaining release DOX and accumulation release DOX from prodrug microspheres upon 60%at 56 h,suggested that effectually avoided drug leaking during blood circulation and tumor intercellular triggered DOX release and distribution DOX into cell nucleus.MTT test,CLSM images and apoptosis results further illustrated that the PEG-PGMA-Hy-DOX prodrug microsphere possessed fluorescent diagnosis and significant chemotherapy.Owing to strong fluorescent property,facial surface decoration and simple preparation etc.,carbon dots?CDs?has been extensively explored in biomedical filed,especially as biomedical probes and drug carriers.Additionally,small size of carbon dots?<10 nm?was easily discharged from kidney organ,the clinical application of the theranostics based on single carbon dots is limited.Thus,before the as-prepared CDs-Br as macromolecule initiator,the Janus-like poly?methyl methacrylate?-b-poly?ethylene glycol?-folic acid block-copolymer-grafted fluorescent carbon dots?CDs-PMMA-PEG-FA?were synthesized by the mean of surface-initiated atom transfer radical polymerization?SI-ATRP?with methyl methacrylate?MMA?in ethanol,then,the PEGylation via click chemistry.In self-assemble process,they formed sphere pattern with hydrodynamic diameter of about 150 nm and loaded DOX capacity of 67.2%with about 270 nm.The DOX release from nanoassemblies was about?80%in pH 5.0 condition at 56 h,while that at pH 7.4 was only zero release,so,it's implied that the nanoassemblies possessed pH triggered DOX release switch.MTT and CLSM further tested that CDs-PMMA-PEG-FA nanoassemblies could theranostics application in anticancer drug delivery,owing to strong fluorescent property,FA targeted cancer cells and enhance anticancer efficiency.Finally,due to strong blue fluorescence feature and easily decorated surface function group?-OH,-COOH?,based on carbon dots could contrasted different architectures as drug carriers.Fluorescent hyper-cross-linked?-cyclodextrin-carbon quantum dot??-CD-CQD?hybrid nanosponges were prepared for tumor theranostic application by facile condensation polymerization of carbon quantum dots?CQDs?with?-cyclodextrin??-CD?at different feeding ratio.The DOX@?-CD-CQD theranostic nanomedicine loaded DOX with DOX-loading capacity of 39.5%via host-guest complexation.DOX release experiment in vitro,MTT and CLSM test showed a pH responsive controlled release and released DOX in the simulated tumor microenvironment in a sustained release mode,and internalizing into HepG2 cells and remarkable antitumor efficacy more enhanced than that of the free drug.Based on aforementioned works,it is still a challenge to develop smart Cdots-based nanotheranostics with different fluorescent properties in the normal and tumor tissues.Thus,smart Cdots-based nanotheranostics(SSCDots-Hy-DOX)with unique tumor-specific fluorescent property were designed and applied in the in-situ real-time fluorescent monitoring of therapeutic response in future tumor therapy.Simply speaking,surface-active amine groups of as-prepared amino-riched CDots were crosslinked with BACy via Michael addition reaction to produce the CDots-based nanoclusters.Then,the proposed SSCDots-Hy-DOX nanotheranostics were obtained by conjugating chemotherapeutic drug DOX via an acid-labile hydrazone bond onto the SSCDots nanoclusters after reduction with hydrazine.Owing to the pH and reduction dual-stimuli responsiveness,the proposed Cdots-based nanotheranostics possessed unique tumor-specific fluorescent property and tumor-specific controlled drug release performance,indicating their promising potential for the in-situ real-time fluorescent monitoring of therapeutic response in future tumor therapy. |
PDF Full Text Request