Preparation of Redox and pH Sensitive Shell Crosslinked Nanomicelles for Controlled Release ofChemotherapeutic Drugs

Recently, shell cross-linked (SCL) polymeric micelles have attracted tremendous interest asdrug carriers due to their remarkable benefits. Compare to traditional micelles, SCL micellesare more stable with respect to infinite dilution, which is helpful for maintaining high structuralstability in blood. The tightly cross-linked shells of micelles may hinder the rapid diffusion ofan entrapped drug and avoid the burst release in the initial stages. Here, we report on thefabrication of shell cross-linked (SCL) micelles of amphiphilic brush-like copolymersfunctionalized with aldehyde moieties by utilizing difunctional crosslinkers cleavable inresponse to pH and thiols. Well-defined amphiphilic brush-like copolymer was synthesizedvia free radical copolymerization of the PLGAMA, PEGMA macromers and croton aldehydemonomers. In aqueous solution, amphiphilic brush-like copolymer self-assembles intonanomicelles consisting of hydrophobic PLGA cores and hydrophilic PEG coronascovalently anchored with aldehyde groups. Nuclear magnetic resonance (NMR), FourierTransfer infrared (FTIR), dynamic light scattering (DLS), and scanning electron microscopy(SEM) were applied to investigate the compositions and the morphologies of the resultantnanomicelles. The obtained SCL micelles can be de-crosslinked via two biologically relevantmodes, namely, acidic pH-triggered cleavage of imine bonds into aldehyde and amine andthiol-triggered cleavage of disulfide linkages, which have been utilized for triggered releaseof physically encapsulated chemotherapeutic drugs. In addition, Doxorubicin (DOX), ananticancer drug loaded SCL micelles were used to investigate thiol and pH-modulated DOXrelease profiles. The reported shell cross-linking strategy can exert intricate controlconcerning the micellar stability and the release profile of encapsulated drugs in response tobiological microenvironments, which augurs well for their potential use as novel smartnanocarriers for drug delivery in cancer chemotherapy.

Keywords:

Cancer , Amphiphilic Brush-like Copolymer , Shell Cross-linked , Nanomicelles , Dox