(483c) Dendron-Based Micelles: A Potential Nanocarrier Platform

Dendron-based amphiphilic copolymers possess unique features such as well-defined structure, self-assembling capability, and precise controllability over functionalities and high hydrophilicity.  To assess the ability of dendron-based copolymers for use in drug delivery, we have synthesized novel, highly PEGylated dendron copolymers (PDC) with controlled hydrophilic-lipophilic ratios (HLs) ranging from 52:48 to 91:9.  We then systematically compared their self-assembly properties with those of linear-block copolymer (LBC) counterparts at similar HLs.  PDCs were synthesized via a multistep synthetic procedure.  A hydroxyl-terminated generation 3 (G3) polyester dendron bearing a focal acetylene moiety was conjugated with poly(e-caprolactone) (PCL) by ‘click’ chemistry followed by PEGylation of the dendron surface with multiple methoxy poly(ethylene glycol) (mPEG) moieties.  Four types of both PCL-G3-mPEG PDCs and PCL-mPEG LBCs with different block lengths were prepared and their structures were confirmed using ¹H NMR, FT-IR, and GPC.  The critical micelle concentration (CMC) of PDCs was measured as low as 1.17 X 10^-8.  The CMC values of the LBCs were up to 2 orders of magnitude higher than those of the PDCs at the same HLs, demonstrating superior thermodynamic stability of the PDC micelles.  TEM images revealed that the PDCs formed spherical micelles (20-30 nm in diameter) with narrow size distributions, which was further supported by dynamic light scattering measurements.  To understand in molecular detail the differences in self-assembly between PDCs and LBCs we utilized atomistic molecular dynamics (MD) simulations.  Individual PDC copolymers were observed to adopt a stable conical shape in water, which is ideal for precise packing into spherical structures.  Interestingly, the core was more completely covered by PEG in PDC micelles.  The higher PEG surface coverage of PDC micelles may result in longer circulation half-lives due to decreased opsonization and enhanced accumulation at the therapeutic target site.  Each micelle formulation was found to exhibit controlled release properties over 3 days using indomethacin as a model drug.  PDCs exhibited no apparent toxicity up to concentrations as high as 100 mM evaluated by MTS assay.  The low CMC at high HLs, controlled micelle morphologies, controlled release properties, and high PEG surface coverage all indicates the promising potential of the PDCs as a nanocarrier platform.