Ligeng Yin

Synthesis and characterization of reactive PEO – PMCL polymersomes

Targeted drug delivery offers the possibility to greatly improve treatment outcomes for diseases such as cancer by enhancing specificity, thus minimizing detrimental side effects from off target delivery. Polymer vesicles, or polymersomes, have been shown to be a promising delivery vehicle capable of encapsulating a variety of hydrophilic and hydrophobic drugs in a nanoscale, long-circulating carrier. We have synthesized and thoroughly characterized the end-functionalized and amphiphilic diblock polymer poly(ethylene oxide)-block-poly(γ-methyl-e-caprolactone). This block copolymer self-assembles in water to form polymersomes containing the vinyl sulfone electrophile at the poly(ethylene oxide) corona terminus. Following polymersome self-assembly, this functional group underwent efficient, site-selective attachment to a thiol-containing targeting peptide by a conjugate addition reaction under mild conditions and did not react with targeting peptides lacking a thiol. The vesicle morphology was unaltered following peptide addition. This work develops a versatile platform for the targeted delivery of therapeutics.

Preparation and performance of hydroxypropyl methylcellulose esters of substituted succinates for in vitro supersaturation of a crystalline hydrophobic drug.

We prepared hydroxypropyl methylcellulose (HPMC) esters of substituted succinates and examined their performance for improving the aqueous solubility of crystalline hydrophobic drugs in spray-dried dispersions (SDDs). From one HPMC, we synthesized five HPMC esters using various monosubstituted succinic anhydrides. These HPMC esters along with a commercial HPMC acetate succinate (HPMCAS) were spray-dried from solutions with phenytoin. The SDDs with different matrices at 10 wt % loading had very similar bulk properties with a minimal amount of detectable crystalline phenytoin as revealed by scanning electron microscopy (SEM), powder X-ray diffraction (powder XRD), and differential scanning calorimetry (DSC). In solution, while the SDD with HPMCAS was very effective at achieving high levels of phenytoin supersaturation initially, it was not competent at maintaining such supersaturation due to the rapid crystallization of the dissolved phenytoin. Alternatively, SDDs with several synthesized HPMC esters of substituted succinates not only achieved rather high initial supersaturation but also maintained high concentrations for extended time (i.e., 1.5 h and longer). Such maintenance was largely ascribed to the inhibition of phenytoin nucleation. Structure-property relationships were established, and the most successful systems contained a high degree of substitution and a combination of a thioether with neighboring weak electron-withdrawing groups in the substituted succinic anhydrides. The effective maintenance of supersaturated solutions was only found in SDDs with rather low drug loadings, which indicates the significance of sufficiently high concentrations of polymer additives in the dissolution media.

Multicompartment Micelles by Aqueous Self-Assembly of μ-A(BC)n Miktobrush Terpolymers

The aqueous self-assembly of μ-A(BC)nmiktobrush terpolymers has been studied using dynamic light scattering and cryogenic transmission electron microscopy. In this system, the A block is hydrophilic poly(ethylene oxide), “O”, the B block is hydrophobic poly(methylcaprolactone), “C”, and the C block is hydrophobic and oleophobic poly(perfluoropropylene oxide), “F”. Two terpolymers were examined: one with an average of about two C blocks and two F blocks and another with an average of about three C blocks and two F blocks. In both cases, the total molar mass is near 40 kg mol–1, and the volume fraction of the single O block is greater than 50% of the whole. Both samples form multicompartment micelle structures with subdivided solvophobic cores of C and F domains. The morphologies observed are generally analogous to those previously observed for the self-assembly of μ-ABC miktoarm star terpolymers, namely, “raspberry” and “hamburger” micelles; however, an intriguing multicompartment polymersome morphology with compartmentalized solvophobic bilayers is also observed. These results are interpreted in terms of the relative strengths of the competing interactions among the three blocks and the solvent and in terms of the constraints imposed by the miktobrush architecture.

Trehalose-functionalized block copolymers form serum-stable micelles

Well-defined amphiphilic diblock terpolymers of poly(ethylene-alt-propylene)–poly[(N,N′-dimethylacrylamide)-grad-poly(6-deoxy-6-methacrylamido trehalose)] (denoted as PEP–poly(DMA-grad-MAT, or PT) have been synthesized using a PEP macromolecular chain transfer agent by reversible addition–fragmentation chain transfer (RAFT) polymerization. The content of MAT was varied from 5 to 14 mole percent in the hydrophilic block of the amphiphilic polymers yielding a family of diblock terpolymers. The reactivity ratios of DMA and trimethyl silyl protected MAT were determined to be r1 = 0.09 ± 0.01 and r2 = 1.6 ± 0.1 and thus, the hydrophilic block was a gradient copolymer consisting of a higher DMA ratio (closer to the PEP) that was terminated with a higher MAT ratio. The silyl groups were subsequently deprotected and micellar dispersions were prepared by two different techniques: nanoprecipitation (NP) and direct dissolution (DD). Micelles formed by the two methods were characterized by dynamic light scattering (DLS) and cryo-transmission electron microscopy (cryo-TEM). These PT diblock terpolymers self-assembled into spherical nanostructures in aqueous media with hydrodynamic radii of ca. 16 nm in the dispersions formed by nanoprecipitation. Micellar dispersions with greater MAT content (11 mole percent in the hydrophilic block) exhibited sufficient contrast in cryoTEM images and the corona were clearly seen as gray halos around the micellar cores. The stability of each micellar dispersion in different biological media was examined over a period of 14 h using DLS. These results indicated that micellar dispersions are stable in 100 percent fetal bovine serum (FBS), which offer promise for in vivo actives delivery applications.