Yaming Jiang

Tuning Cationic Block Copolymer Micelle Size by pH and Ionic Strength

The formation, morphology, and pH and ionic strength responses of cationic block copolymer micelles in aqueous solutions have been examined in detail to provide insight into the future development of cationic micelles for complexation with polyanions such as DNA. Diblock polymers composed of a hydrophilic/cationic block of N,N-dimethylaminoethyl methacrylate (DMAEMA) and a hydrophobic/nonionic block of n-butyl methacrylate (BMA) were synthesized [denoted as DMAEMA-b-BMA (X-Y), where X = DMAEMA molecular weight and Y = molecular weight of BMA in kDa]. Four variants were created with block molecular weights of 14-13, 14-23, 27-14, 27-29 kDa and low dispersities less than 1.10. The amphiphilic polymers self-assembled in aqueous conditions into core-shell micelles that ranged in size from 25-80 nm. These cationic micelles were extensively characterized in terms of size and net charge in different buffers over a wide range of ionic strength (0.02-1 M) and pH (5-10) conditions. The micelle core is kinetically trapped, and the corona contracts with increasing pH and ionic strength, consistent with previous work on micelles with glassy polystyrene cores, indicating that the corona properties are independent of the dynamics of the micelle core. The contraction and extension of the corona scales with solution ionic strength and charge fraction of the amine groups. The aggregation numbers of the micelles were obtained by static light scattering, and the Rg/Rh ratios are close to that of a hard sphere. The zeta potentials of the micelles were positive up to two pH units above the corona pKa, suggesting that applications relying on micelle charge for stability should be viable over a wide range of solution conditions.

Interpolyelectrolyte Complexes of Polycationic Micelles and Linear Polyanions: Structural Stability and Temporal Evolution.

The complexation of poly(dimethylaminoethyl methacrylate)-block-poly(styrene) micelles with poly(styrenesulfonate) homopolymers was investigated in aqueous buffer at pH 4.5 as a function of ionic strength. The complexation process was monitored by turbidimetric titration, and the structure and stability of the complexes were assessed by dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryoTEM), and small-angle X-ray scattering. When complexes were formed by slow titration of one polyelectrolyte solution into the other, soluble complexes could be formed with either polyelectrolyte in excess as long as the mixture did not pass through the charge-neutral point. The initial complexes exhibited bimodal size distributions by DLS, with one population similar in size to or slightly smaller than the bare micelles, and the other significantly larger. The former correspond to individual micelles with complexed polyelectrolytes leading to a contracted corona; the latter reflect multimicelle aggregates that were directly observed by cryoTEM. At low ionic strength (e.g., 10 mM), these aggregates were stable on weeks-to-months time scales, but at high ionic strength (e.g., 500 mM), the aggregates rapidly annealed toward structures whose size and solubility depended on which polyelectrolyte was present in excess. These results are discussed in terms of the kinetics and thermodynamics of the polyelectrolyte complexation process and allow a detailed description of the interplay between kinetic and thermodynamic factors in this system. This work will inform design of polyelectrolyte complexes with tunable structure and stability for future applications.

Equilibration of Micelle–Polyelectrolyte Complexes: Mechanistic Differences between Static and Annealed Charge Distributions

The role of charge density and charge annealing in polyelectrolyte complexation was investigated through systematic comparison of two micelle-polyelectrolyte systems. First, poly(dimethylaminoethyl methacrylate)-block-poly(styrene) (PDMAEMA-b-PS) micelles were complexed with poly(styrenesulfonate) (PSS) at pH values above and below the pKa of PDMAEMA to investigate the role of charge annealing in the complexation process. Second, complexes of poly(DMAEMA-stat-oligo(ethylene glycol) methyl ether methacrylate)-block-poly(styrene) (P(DMAEMA-stat-OEGMA)-b-PS) micelles with the same PSS at low pH were used to investigate how the complexation process differs when the charged sites are in fixed positions along the polymer chains. Characterization by turbidimetric titration, dynamic light scattering, and cryogenic transmission electron microscopy reveals that whether or not the charge distribution can rearrange during the complexation process significantly affects the structure and stability of the complexes. In complexes of PDMAEMA-b-PS micelles at elevated pH, in which the charge distributions can anneal, the charge sites redistribute along the corona chains upon complexation to favor more fully ion-paired configurations. This promotes rapid rearrangement to single-micelle species when the micelles are in excess but traps complexes formed with PSS in excess. In complexes with static charge distributions introduced by copolymerization of DMAEMA with neutral OEGMA monomers, on the other hand, the opposite is true: in this case, reducing the charge density promotes rearrangement to single-micelle complexes only when the polyanion is in excess. Molecular dynamics simulations show that disruption of the charge density in the corona brush reduces the barrier to rearrangement of individual ion pairs, suggesting that the inability of the brush to rearrange to form fully ion-paired complexes fundamentally alters the kinetics of complex formation and equilibration.

One-pot synthesis of reactive oxygen species (ROS)-self-immolative polyoxalate prodrug nanoparticles for hormone dependent cancer therapy with minimized side effects

A new reactive oxygen species (ROS)-sensitive, self-immolative biodegradable polyoxalate prodrug based on the anticancer chemotherapeutic hormone analog diethylstilbestrol was synthesized via one-pot step-growth polymerization. The nanoparticles prepared from this prodrug undergo self-immolative degradation releasing the chemotherapeutic drug in ROS-rich environments, e.g., in cancer cells. This new ROS self-immolative polyprodrug backbone eliminates the need for a linker between polymer chain and drug, resulting in a more specific drug release and minimized toxic side effects to non-ROS-producing cells as proven by in vitro experiments. The strategy enables re-utilization of a successful chemotherapeutic agent that has been clinically under-utilized due to dose-related side effects.

Complexation of Linear DNA and Poly(styrenesulfonate) with Cationic Copolymer Micelles: Effect of Polyanion Flexibility

The complexation of linear double stranded DNA and poly(styrenesulfonate) (PSS) with cationic poly(dimethylamino ethyl methacrylate)-block-poly(n-butyl methacrylate) micelles was compared in aqueous solutions at various pH values and ionic strengths. The complexation process was monitored by turbidimetric titration, as a function of the ratio (N/P) of amine groups in the micelle corona to the number of phosphates (or sulfonates) in the polyanion. The size, structure and stability of the resulting micelleplexes were studied by dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM). In the short chain regime, where the contour lengths of the polyanions are shorter than or comparable to the micelle corona thickness, micelleplexes with DNA oligomers show very similar behavior to complexes with short PSS chains, in terms of titration curves and structural evolution of the complexes as a function of charge ratio. However, in the long chain regime, where the contour length of the polyanion far exceeds the micelle radius, micelleplexes of linear DNA show titration curves shifted toward lower N/P ratios, reduced stability at N/P < 1, and a higher percentage of small complexes at N/P > 1 compared to complexes with long chain PSS. Furthermore, at 1 M ionic strength, the cationic micelles could still complex with long chain PSS, but not with DNA of the same total charge. These differences are attributed to the flexibility difference between the polyanion chains, and possible mechanisms are proposed. This work highlights the importance of chain flexibility in complexation of dissimilar polyelectrolyte pairs, a factor that could therefore help guide the future design of micelleplexes for various applications.