Zwitterionic Polymer-Drug Conjugates For Inhibiting A? Aggregation And Overcoming Multidrug Resistance Of Tumor Cells

Zwitterionic materials have an increasingly numerous applying foreground and potential in the field of nanobiomedicin,due to excellent nonfouling property and biocmompatibility.In this dissertation,we investigated their potential applications in the field of Alzheimer's disease and reversal multidrug resistance.Alzheimer's disease(AD)is a progressive neurodegenerative disorder.Pathologically.Research suggests that the deposition of amyloid ?-protein(A?)aggregates in brain tissues is one of the causative factors of AD.Thus,inhibition of A? aggregation is considered as an important strategy for the precaution and treatment of AD.In this paper,we investigatd the properties of zwitterionic polymer as an inhibitor carrier of A?aggregation.Multidrug resistance(MDR)is the most common and intractable problem in the process of chemotherapy.stimuli-responsive nanomedicine has the potential to enhance targeting of drugs and reverse MDR of malignant tumor.we prepared zwitterionic materials-based nanomedicine to co-deliver anticancer drug and MDR inhibitor to achieve a synergistic effect and to overcome MDR.In the study of a A? aggregation inhibitor carrier,Curcumin(Cur)has been recognized as an effective inhibitor of A? fibrillogenesis,but its potential application is limited by its poor bioavailability.We proposed to conjugate Cur to a zwitterionic polymer,poly(carboxybetaine methacrylate)(p CB),forming Cur@p CB conjugates,which could self-assembled into nanosized hydrogels.Cur@p CB conjugates drastically improved the solubility of Cur.The results indicated that the Cur@p CB conjugates were much more efficient than molecular curcumin on inhibiting A?fibrillation.5 ?M Cur@p CB functioned similarly with 25 ?M free curcumin.Spectroscopic study and mechanism analysis demonstrate that the dense hydration layer on the conjugates strongly stabilized the bound A? on curcumin anchored on the polymer,suppressing the conformational transition of the protein to ?-sheet-rich structures.Thus,the inhibition efficiency on A? aggregation is significantly improved.Based on previous study about LK7,a new zwitterionic polymer,poly(isobutylene-alt-maleic anhydride)-N,N-dimethylethylenediamine(p ID),was introduced as carriers to conquer the self-aggregation and poor solubility of LK7.The results indicate that the solubility of LK7 was drastically improved,and the hydration layer on the p ID strongly suppressed the conformational transition of LK7 to?-sheet-rich structures.The LK7@p ID conjugates can significantly promote the nucleation of A? thereby greatly shortening the lag phase.Meanwhile,LK7@p ID could remarkably enhance the length and mount of fibres,but LK7@p ID significantly inhibit neurotoxicity induced by A? aggregates.A novel redox-sensitive co-delivery system of doxorubicin(Dox)and a chemosensitizer(Cur)based on p CB was proposed,forming Cur-p CB-Dox conjugates,and study the antitumor effect and reversal of multidrug resistance(MDR).Single drug conjugates(p CB-Dox and p CB-Cur)were prepared for comparisons.The cytotoxicity results indicated that the Cur-p CB-Dox conjugates has stronger anticancer property.Confocal laser scanning microscopy and flow cytometry revealed the greatly enhanced cell uptake of the Cur-p CB-Dox conjugate and the reduced cell efflux in comparison with p CB-Dox and p CB-Cur.This is because the co-delivered Dox and Cur on one carrier specifically transported into the same cells,which inhibited the over-expression of P-gp by Cur,reduced the efflux of Dox,and led to higher intracellular Dox concentration.Thus,the co-delivery system developed in this paper has potential application in overcoming multidrug resistance of tumor cells.