Design And Preparation Of A Reduction-responsive Core Cross-linked Micelles Based On Disulfide Bonds For Drug Delivery System

In recent years,nanomicelles systems based on stimulus-response release function have received widespread attention because they can effectively avoid the problem of early release of drugs during blood circulation,and has many other advantages such as stronger drug stability,longer drug release,and reduced metabolic toxicity.Due to the inherent properties of ordinary micelles,after administered intravenously,the dilution of the blood circulation will cause the dissociation of the micellar structure,which will cause the exposure of the loaded drug and cause unnecessary side effects.Studies have found that the introduction of the cross-linked structure of polymer micelles can significantly enhance the structural stability of micelles,and can greatly avoid many problems caused by the instability of the carrier structure.We envision introducing a responsive core cross-linking structure into polymer micelles to achieve stable loading of drugs.Based on this,we first synthesized an amphiphilic comb polymer with dithiopyridine side groups(m PEG-b-P(LA-SS-Py))in Chapter 2.The polymer uses polyethylene glycol as the hydrophilic segment and functionalized polylactide as the hydrophobic segment.The dithiopyridine side groups provide core cross-linking sites for the formed micelles under the action of reducing agent.The experimental results show that the introduction of the core cross-linked structure effectively improves the stability of the micelles,and at the same time effectively avoids the premature release of doxorubicin loaded in the hydrophobic core.Then in order to minimize the premature release of the drug in the polymer micelles,in Chapter 3,we designed a method to synthesize core cross-linked prodrug micelles by a one-pot method,but taking into account the influence of the number of dithiopyridine(PDS)groups on the cross-linking effect,we first synthesized a new amphiphilic comb polymer to increase the number of PDS groups on the side chain.Subsequently,the sulfhydryl functionalized doxorubicin(HS-Hy-DOX)is immobilized on the micelle core through the reaction of the sulfhydryl group and the PDS group.The remaining PDS groups in the polymer side chain are used for core cross-linking under the action of reducing agent.The experimental results show that the prodrug core cross-linked micelles synthesized by the one-pot method can increase the drug loading while ensuring the stability of the micelles.It is worth noting that the prodrug cross-linked micelles basically do not have the problem of early drug release under neutral conditions,and the drug can respond to rapid release under acidic and reducing conditions.Considering the toxic side effects and weakening of curative effect that may be caused by single chemical drug treatment.In Chapter 4,we envisaged using the prodrug cross-linked micelles in Chapter 3 to re-encapsulate a hydrophobic drug to co-deliver dual drugs and realize combined chemotherapy.Therefore,we prepared dual-drug cross-linked micelles with DOX-prodrug polymer encapsulated CUR,and then evaluated the stability and drug release behavior of the dual-drug micelles.We found that the cross-linked structure in the hydrophobic core of micelles can still improve the stability of the micelles and effectively reduce the premature release of CUR.It also shows that the cross-linked structure based on disulfide bonds can effectively solve the stability of polymer micelles and the issue of early release of the drug.