Dendron-mediated self-assembly of highly PEGylated block copolymers: a modular nanocarrier platformw

Self-assembled molecular nanoconstructs with controllable physical, chemical, and biological properties represent one of the most versatile platforms for drug delivery. Above their critical micelle concentrations (CMCs), linear, branched, and hyperbranched amphiphilic block copolymers can assemble into thermodynamically stable supramolecular structures of different sizes, morphologies, and properties. Among those copolymers, dendron-coils (DC) have attracted a great deal of scientific interest due to their unique structure and properties. A DC is comprised of a dendron, a branch of a dendrimer, and flexible hydrophilic and/or hydrophobic linear polymers, which allows us to engineer its amphiphilicity in a form suitable for self-assembly and molecular delivery. The monodisperse, highly branched molecular architecture of the dendron imparts a precise control over the peripheral functional groups and multivalency, as in dendrimers. Uniquely, DCs have been reported to self-assemble into micelles at CMCs as low as in the order of 10 8 M, which are expected to be significantly lower than CMCs of linear-block copolymers with similar hydrophilic–lipophilic balances (HLBs). The high HLB is important for a nanocarrier to achieve a large surface coverage by a hydrophilic layer, e.g., poly(ethylene glycol) (PEG), to maximize its in vivo circulation time while minimizing its non-specific interactions with biological components. Although DC-based micelles are ideally suited for nanocarriers, the role of dendrons should be explored by systematic and quantitative studies. In this study, we perform a systematic quantitative study of the dendron role during the self-assembly of supramolecular structures, by comparing the micelle morphology and CMCs when formed from DCs and linear polymers with the same HLBs. We support our experiments with detailed atomistic molecular dynamics (MD) simulations to clarify the self-assembly conditions. Our results indicate that the DC-based micelles exhibit a significantly greater thermodynamic stability and surface coverage of hydrophilic layers than the linear polymer-based micelles, demonstrating great potential as a nanocarrier platform. We have synthesized four novel PEGylated DCs (PDCs) that are designed to be suitable as drug delivery vehicles. Our biocompatible PDCs consist of three functional components: (1) poly(e-caprolactone) (PCL), used as a hydrophobic, biodegradable core-forming block; (2) biodegradable 2,2-bis(hydroxyl-methyl)propionic acid generation 3 (G3) dendron with an acetylene core, chosen to mediate the coreand shell-forming blocks through selective click chemistry and to achieve a localized high density of peripheral functional groups; and (3) biocompatible methoxy-terminated PEG (mPEG) forming the hydrophilic corona. We have also chosen two different molecular weights of PCL and mPEG (3.5 and 14 kDa for PCL; 2 and 5 kDa for mPEG) to vary the HLB values of the resulting PDCs in a wide range. The synthetic route to produce the PDCs is summarized in Fig. 1 (see details in ESIw). Similarly, the linear-block copolymer counterparts were prepared. All 8 amphiphilic copolymers (4 dendronbased and 4 linear as listed in Table 1) were successfully synthesized with low polydispersity indices (PDIs lower than 1.4), as confirmed using FT-IR, H-NMR, and GPC at each reaction step (Fig. S3–S7 and Table S1, ESIw). To directly assess the thermodynamic stability of the molecular assemblies, the CMC of each amphiphilic copolymer was measured as shown in Fig. S8 (ESIw). A low CMC is particularly important for a nanocarrier in the bloodstream, due to an immediate, large dilution factor upon injection. Table 1 summarizes the measured CMCs, HLBs, and hydrophilic–lipophilic (HL) ratios of the 8 copolymers. The CMCs of the linear-block copolymers are in good agreement with the previous reports and are comparable in magnitude to those of the PDCs, which have 2–4 fold higher HLBs. Fig. 2a shows a nearly linear correlation between CMC and HLB, observed for both linear and dendron-based copolymers. Department of Biopharmaceutical Sciences, University of Illinois at Chicago, 833 S. Wood St. Chicago, IL 60612, USA. E-mail: [email protected]; Fax: +1 312-996-0098; Tel: +1 312-413-8294 Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St. Chicago, IL 60607, USA. E-mail: [email protected]; Fax: +1 312-996-0431; Tel: +1 312-996-6319 w Electronic supplementary information (ESI) available. See DOI: 10.1039/c1cc14331j z These authors contributed equally to this work. ChemComm Dynamic Article Links