| As one of the world's most difficult to cure non communicable diseases,cancer has attracted much attention.In the main to chemotherapy for cancer treatment research,polymeric micelles,especially p H-responsive polymer micelles,because of the unique core-shell structure,easy to adjust the nano scale and dimension and p H response,the effective realization of the drug physical load,the concentration of the cancer tissue and the release of p H regulation,has become a research hotspot in small molecule hydrophobic anticancer drug carrier.But these p H-responsive polymer micelles in the delivery process in vivo,inevitably were affected by the dilution of body fluids,leading to the dissociation of polymer micelle structure,advance and ineffective release of drugs,which caused the reduction of drug efficacy and the side effects of drugs.In order to solve the problem of structural dissociation,a large number of studies have been carried out to fix the micellar microstructure of p H-responsive polymer micelles by chemical immobilization strategy.These kinds of research were mainly based on the unique chemical reaction and clever molecular design,which successfully realized the preparation of all kinds of p H-responsive cross linked polymer micelles,however,there were few studies on the controlled release of anti-cancer drugs as anticancer drug carriers,especially the regulation of microstructure of p H-responsive shell cross-linked polymer micelles,such as the chemical composition and cross-linking degree of cross-linked shell,on the drug loading and controlled release effects still need to be further studied.In order to explore the influence of microstructure of p H-responsive shell cross-linked polymer micelles on drug loading and controlled release,well-defined poly[(ethylene glycol)-block-2-(dimethylamino)ethyl methacrylate-block-2-(diethylamino)methacrylate](PEG113-b-DMA50-b-DEA40)triblock copolymer was synthesized via atom transfer radical polymerization(ATRP)by successively polymerization of DMA and DEA monomers using a PEG-based macroinitiator,and obtained copolymer was then converted to be PEG113-b-P(DMA20-co-QDMA30)-b-PDEA40 copolymer with “clickable” moieties in the middle block by the quaternization with propargyl bromide.Through small molecule modification,the two types of the small molecule cross-linker: 1,6-bisazidehexane and bis-(azidoethyl)disulfide,which have azide groups at both ends,respectively,and have covalent bonds or reducing fractured disulfide bonds intermediate,were successfully prepared.The structure and chemical composition of the cross-linker and polymer were characterized by GPC and 1H NMR.The above two cross linker were utilized to prepare shell cross-linked(SCL)micelles with different cross-linking degree,different cross-linked shells and p H-responsive core by cross-linking the self-assembly of PEG-b-P(DMA-co-QDMA)-b-PDEA copolymer via click chemistry at basic aqueous media.Doxorubicin(DOX)was selected as a model drug,and the aggregation of the polymeric micelles were used to realize the load of DOX by the method of physical encapsulation,and further through the cumulative release of drug,and DOX in DMSO solvent characteristic absorption peak of UV and the corresponding standard curve method,the effect of tunable cross-linked layer microstructure of p H-responsive shell cross-linked(SCL)micelles for controlled release behavior of Doxorubicin was studied in detail in the physiological environment(p H 7.4)and at mimicking tumor microenvironment(p H 5.5).Dynamic light scattering(DLS)and UV-vis characterization results are shown: the cross-linked shell significantly block the release of the drug;p H-responsive PDEA resulted in drug slow release of drug in the p H 7.4 phosphate buffer solution(PBS)and the rapid release of the drug in the p H 5.5 PBS;the cross-linking of polymeric micelles and the drug loading of the order have little effect on the drug loading and release.For the SCL micelles(SCL micelles 1)prepared from 1,6-bisazidehexane which is hydrophobic and never broken,the drug release content is inversely proportional to the cross-linking degree of SCL micelles 1.Then for SCL micelles(SCL micelles 2)prepared from bis-(azidoethyl)disulfide which is hydrophilic and broken,the drug release content is independent on their cross-linking degree,and these cross-linked layer can be reduced broken by dithiothreitol(DTT),the drug release content was similar to non cross-linked polymeric micelles.This kind of research reveals the influence of the microstructure of the shell cross linked(SCL)micelles on the loading and release for hydrophobic anticancer drugs,achieves the stability of the drug in the transmission process,the concentration of anticancer drugs in cancer tissues and the controlled release of the drug in cancer cells,which provides a theoretical basis for the design and construction of ideal drug carriers. |
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