Design And Application Of Reactive Oxygen Sensitive Dextran Based Durg Delivery Systems

Presently although chemotherapy still is the routine method for cancer clinical treatment,the therapeutic effect of single small-molecule chemotherapy drugs is not satisfied due to the multi-drug resistance of small-molecule drugs.Meanwhile,the side effect to normal tissues is also confusing.In order to overcome these shortcomings,the dextran with excellent biocompatibility and biodegradability was chosen as the hydrophilic backbone to fabricate photodynamic-chemotherapy combined drug delivery systems by metal coordinated supramolecular interaction,in which the release of conjugated drug was triggered by reactive oxygen species.The thesis mainly consists the following two parts:(1)First,taking advantage of the reactivity of hydroxyl group,the dextran backbone were respectively modified by histidine(His)and active oxygen sensitive thioketal(TK)to prepare DHT(histidine and thioketal modified dextran).And then,DOX was conjugated on dextran to prepare polymeric conjugated drug(DHTD)through TK linker.Finally,the ROS-triggered photodynamic-chemotherapy combined drug delivery system was fabricated by the metal coordinatied supramolecular interaction between histidine and zinc porphyrin(Zn-TPP).The chemical structure of DHTD was proved by ~1H NMR and FT-IR.The behavior of supramolecular assembly were verified by UV spectra,dynamic light scattering,transmission electron microscopy and critical micelle concentration.In vitro drug release behavior indicated that the designed drug delivery system DHTD/Zn-TPP would disassemble and release the loaded Zn-TPP under the tumor internal acidic environment(pH=5.3).With an irradiation of a certain wavelength,the produced ROS would break TK linker and trigger the release of conjugated DOX to realize the photodynamic-chemotherapy combined treatment.The date from cell assay further verified that this ROS-triggered drug delivery system could effectively combine the photodynamic therapy and chemotherapy and show higher anticancer efficacy compared with single chemotherapy treatment.(2)On the basis of the previous study,during the assembly of Zn-TPP and DHTD,the other chemotherapeutic drug,paclitaxel(PTX),was simultaneously loaded to fabricate a dual drug delivery system DHTD/Zn-TPP/PTX in order to more effectively solve the multidrug resistance.Under tumor internal acidic environment(pH=5.3),PTX and Zn-TPP first released due to the disassemble of the metal coordinated supramolecular interaction.With an irradiation of a certain wavelength,the produced ROS would break TK linker and the conjugated DOX release successively and effectively combine the photodynamic therapy and dual drug chemotherapy.MTT experimental date indicated that DHTD/Zn-TPP/PTX has a better antitumor effect compared to DHTD/Zn-TPP for MCF-7 and HeLa tumor cells.Furthermore,DHTD/Zn-TPP/PTX showed more pronounced anti-tumor effects than DHTD/Zn-TPP and the small molecule chemotherapy drug DOX for DOX-resistant cells MCF-7/ADR,demonstrating that dual drug combinations can be effective inhibit multidrug resistance.Moreover,the therapeutic efficacy of DHTD/Zn-TPP/PTX with light conditions was significantly better than the control group without light,indicating that photodynamic-dual-drug combination therapy can effectively inhibit tumor cell proliferation and resolve multidrug resistance.