Drug Carriers Based On Complex Micelles Self-Assembled From Block Copolymers

Polymeric micelles self-assembled from block copolymers have receivedenormous interest due to their capability to increase the solubility of insoluble drugsas well as their specific core-shell structure and good stability under physiologicalconditions. Micelles with core-shell-corona three-layered structure have beendemonstrated superior functions compared to their simple core-shell counterparts. Akey advantage of core-shell-corona micelles is that channels can be created in theshell, which could be applied in controlled drug release and other aspects. Moreover,the collapsed shell could not only restrain burst drug release but also controldegradation of the micelle core. Release behavior of ionic drugs from simplemicelles is obviously pH-sensitive. Polymeric complex micelles with chargedchannels on the surface provided us with an effective way to reduce the difference inthe drug release rate upon change of pH value. In addition, complex micelles withglucose-responsive shell were prepared. Repeated self-regulation of GCM releasefrom the micelles was achieved based on reversible collapse and stretch of the shellresponding to external glucose concentration.The block copolymer PCL-b-PAsp was synthesized by sequential ROP ofε-caprolactone and Asp (OBzl)-NCA. The block copolymer PCL-b-PNIPAM wassynthesized by ROP and ATRP. At room temperature, diblock copolymers ofPCL-b-PNIPAM and PCL-b-PAsp self-assembled into complex micelles with a PCLcore and a mixed PAsp/PNIPAM shell. By increasing the temperature, these complexmicelles could be converted into a core-shell-corona structure composed of a PCLcore, a collapsed PNIPAM shell and a soluble PAsp corona, and the PAsp chainsstretched from the inner core to outside, leading to the formation of charged PAspchannels. PAsp could ionize and its ionization degree and conformation could varywith pH values in aqueous solution. pH dependent release behavior of ionic drugswas effectively reduced through the interaction between charges and the variation ofconfiguration of PAsp chains. The PAsp segments of PCL-b-PAsp was modified by3-aminophenylboronic acid(APBA) to obtain the polymer PCL-b-P(Asp-co-AspPBA). PCL-b-PEG wassynthesized by ring opening polymerization (ROP) of ε-caprolactone using PEG-OHas the initiator. In alkaline water, PCL-b-PEG and PCL-b-P(Asp-co-AspPBA)self-assembled into complex micelles with a PCL core and a mixed PEG/P(Asp-co-AspPBA) shell. After dialysis against acidic water, these complex micellescould be converted into a core-shell-corona structure composed of a PCL core, acollapsed P(Asp-co-AspPBA) shell and a soluble PEG corona, and the PEG chainsstretched from the inner core to outside, leading to the formation of PEG channels.Under high glucose concentration at pH7.4, the hydrophobic P(Asp-co-AspPBA)chains would become hydrophilic gradually, leading to disaggregation of thecollapsed shell and rapid drug release rate. When glucose concentration decreased tovery low level, the P(Asp-co-AspPBA) chains would reversibly collapse onto thePCL core. The formation of collapsed shell could effectively decrease the drugrelease rate. Based on reversible collapse and stretch of P(Asp-co-AspPBA) chainsresponding to external glucose concentration, repeated self-regulation of GCMrelease from the micelles was achieved.