How can micelle stability be improved?
Micelles can have limited in vitro and in vivo stability due to their dynamic nature of self-assembly into drug delivery systems. This instability can lead to premature drug release. There are two main approaches to improve micelle stability. Firstly, the selection of block copolymers could improve micelle stability by using nucleating hydrophobic blocks. Secondly, micelle cross-linking strategies can also be used to improve stability. Since drug loading in micelles occurs during self-assembly, the cross-linking strategy occurs after micelle formation and drug loading. Micelles can be permanently cross-linked by amide bond formation, thiol-ene, click chemistry, etc. Recently, reversible micelle cross-linking techniques have also been explored to improve stability and create responsive drug carriers that can release the payload at the site of action. For example, pH-sensitive or redox-sensitive micelles have been used to deliver drug responsiveness to tumor sites. Reactive cross-linked micelles can be generated by core cross-linked, shell cross-linked, or interlayer cross-linked micelles with reversible linkages such as pH-sensitive, ketal, acral, imine, or redox-unstable linkages such as disulfide bonds. In addition, cross-linking using enzyme-sensitive peptides has been explored. For all types of cross-linking, the polymers that make up the micelle require chemical functional groups that favor cross-linking, such as terminal or side chain functional group polymers. Ideally, the chosen cross-linking strategy should have mild and biocompatible reaction conditions that do not require catalysts in order to avoid additional purification steps.