| Polymer nano-drug carriers play an indispensable role in diagnosis and treatment of disease. Compared with small molecule drugs, polymer nano-drugs have the advantages of good stability, high solubility in the physiological environment, high bioavailability, reducing drug side effects, more specific targeting to tumour tissues and so on. So polymer nano-drugs studing is one of the hot topic of drug research in recent years. Small-molecule drug camptothecin(CPT) is limited in clinical application due to its instability lactone form, insoluble nature and cell cytotoxicity. We prepared a new series of CPT micelles, and studied the structure, drug loading, sustained drug release, cytotoxcity and cellular uptake. The details are given as follows.Chapter1:IntroductionThe research of nanomedicine has attracted wide attention in recent years. And the research of polymer nano-drug provides a theoretical basis and practical guidance on the prevention and treatment of cancer. One end of hydrophilic and one end of hydrophobic polymer nano-drug micelles overcome the barrier of insoluble small molecular drugs, so it is easy to reach the tumor tissue to have the effect of sustained-release and become a hot topic widely. Using polyethylene glycol (PEG) and polyurethane as the carrier of polymer with the above advantages to become a good drug carrier. With a detailed study, the introduction of PEG segments of polymeric drugs influenced the phagocytic uptake which it is harmful for the drug achieve to the tumor cells and influenced the therapeutic effects. It is encouraging that the introduction of a disulfide in the polymer is a good solution to this bottleneck. The disulfide bonds are prone to break due to the high concentration of GSH. Because of that the concentration of GSH is higher in tumor tissue than that of normal tissue, disulfide bonds are easy to break. After taking off the PEG segments, phagocytosis is not affected and achieve the treatment effect.Chapter2:Synthesis and characteristic of polymer-CPTIn this chapter, mPEG-SS-NH-g-PSI was synthesized by pratly opened PSI with mPEG-SS-NH2Next, mPEG-SS-NH-g-PHAsp was synthesized by opening the residual pentacyclic rings in mPEG-SS-NH-g-PSI with amino acid. And then mPEG-SS-NH-g-PHAsp-CPT conjugate was prepared via esterification between20-hydroxyl groups of CPT and carboxylic groups of mPEG-SS-NH-g-PHAsp. MPEG-SS-NH-g-PHAsp-CPT was self-assembly into micelles. MPEG-SS-NH-g-PHAsp-CPT micelles improved the stability of lactone form of native CPT and increased the drug loading of CPT. The copolymers were examined by nuclear magnetic resonance (NMR) and FT-IR. The characteristic of mPEG-SS-NH-g-PHAsp-CPT micelles was confirmed by the methods of fluorescence spectrophotoscopy, UV-vis, DLS and TEM.Chapter3:Evaluation of mPEG-SS-NH-g-PHAsp-CPT micellesMPEG-SS-NH-g-PHAsp-CPT micelles showed sustained drug release behaviors over80h. Compared with free CPT, the accumulative drug release behaviors of the mPEG-SS-NH-g-PHAsp-CPT micelle in the absence of DTT showed slow gradual profiles,28%of CPT was released in80h. In contrast, minimal drug release (<30%) was observed within80h for the reduction insensitive mPEG-NH-g-PHAsp-CPT micelles under the same conditions as well as for mPEG-SS-NH-g-PHAsp-CPT micelles in the absence of DTT. MPEG-SS-NH-g-PHAsp-CPT micelles showed less toxic than that of free CPT. MPEG-NH-g-PHAsp-CPT was treated with10mM DTT prior to incubation with cells showed a profoundly increasing of fluorency intensity. As expected, we also found a significant enhancement of uptake in the case of micelles containing disulfide bonds rather than the control ones in the condition of no extra DTT addition. |
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