Kinetically Arrested Assemblies of Architecturally Distinct Block Copolymers

The rapid coassembly of linear and linear–dendritic amphiphiles from homogeneous solution and high supersaturation produces kinetically arrested nanoparticles, the morphologies of which are distinct from equilibrium structures. The binary system of poly­(d,l-lactide-<i>co</i>-glycolide)-<i>block</i>-poly­(ethylene glycol) with a linear or dendritic architecture of the hydrophilic component, forms spherical hybrid nanoparticles regardless of dendron generation or poly­(ethylene glycol) length. Controlled variation in nanoparticle size was achieved through a balance of amphiphile architecture, blend composition, and final solvent content. These results demonstrate how kinetic features of the assembly process influence the formation of hybrid copolymer nanoparticles

Macromolecular Brushes as Stabilizers of Hydrophobic Solute Nanoparticles

Macromolecular brushes bearing poly­(ethylene glycol) and poly­(d,l-lactide) side chains were used to stabilize hydrophobic solute nanoparticles formed by a rapid change in solvent quality. Unlike linear diblock copolymers with the same hydrophilic and hydrophobic block chemistries, the brush copolymer enabled the formation of ellipsoidal β-carotene nanoparticles, which in cosolvent mixtures developed into rod-like structures, resulting from a combination of Ostwald ripening and particle aggregation. The stabilizing ability of the copolymer was highly dependent on the mobility of the hydrophobic component, influenced by its molecular weight. As shown here, asymmetric amphiphilic macromolecular brushes of this type may be used as hydrophobic drug stabilizers and potentially assist the shape control of nonspherical aggregate morphologies

Organocatalytic Copolymerization of a Cyclic Carbonate Bearing Protected 2,2-bis(hydroxymethyl) Groups and d,l‑lactide. Effect of Hydrophobic Block Chemistry on Nanoparticle Properties

The organocatalytic copolymerization of a derivative of trimethylene carbonate bearing protected 1,3-diols and d,l-lactide was studied. Homopolymerization of the cyclic carbonate from a PEG macroinitiator exhibited a controlled character, obeying pseudo first-order kinetics up to a conversion of ∼60%. Longer reactions resulted in more polydisperse materials. Kinetics of copolymerization with DLLA showed a considerable accelerative effect of the ester on the polymerizability of the carbonate, attributed to relief of steric limitations that characterize the polymerization of this and other bulky cyclic carbonates. Postpolymerization hydrogenolysis, conveniently adjusted though catalyst concentration, yielded functional poly­(ester carbonate)­s (PECs) with enhanced chain mobility and hydrophilicity compared to protected analogues. PEG-<i>b</i>-PECs were further used as stabilizers for the formation of fluorophore nanoparticles via flash nanoprecipitation. Nanoparticle size and core properties were discussed in terms of hydrophobic block chemistry. The regulation offered by organocatalysts for the synthesis of diol-functionalized PECs with precise molecular characteristics provides access to biodegradable materials with readily tunable physicochemical properties through controlled installation of reactive handles. In the context of hydrophobic solute encapsulation, regulated functionalization allows fine-tuning of nanoparticle core properties, ultimately impacting solute loading, release, and stability

Phenylboronic Acid-Installed Polycarbonates for the pH-Dependent Release of Diol-Containing Molecules

Environmental responsiveness is an appealing trait of emerging polymeric materials, as shown for a variety of pH-responsive drug delivery systems. The chemical versatility of the conjugation site and conjugate lability to physiologically relevant changes in pH will largely determine their applicability. Herein, we report on the use of a drug–polymer complex based on boronic acid-functionalized polycarbonates (PPBC) as the substrate for the pH-sensitive delivery of a diol-containing drug, capecitabine (CAPE). Complexation of CAPE with a PEGylated-PPBC block copolymer, via boronic ester formation, resulted in amphiphiles capable of self-assembling into spherical nanoparticles. We examined nanoparticle stability and release kinetics in neutral and acidic media and relate differences in release profiles and particle stability with changes to polymer chemistry. Comparison of complexed nanoparticles with their noncomplex analogues revealed striking differences in release rate and particle stability. Illustrated herein for capecitabine, the pH-sensitive dissociation of boronate esters from PPBCs can be applied in a general manner to diol- or catechol-containing solutes, demonstrating the utility of these polymers for biomedical applications

Versatile Route to Colloidal Stability and Surface Functionalization of Hydrophobic Nanomaterials

We introduce a general method for the stabilization and surface functionalization of hydrophobic nanoparticles using an amphiphilic copolymer, poly­(maleic anhydride-<i>alt</i>-1-octadecene)-poly­(ethylene glycol) methacrylate (PMAO-PEGMA). Coating nanoparticles with PMAO-PEGMA results in colloidally stable nanoparticles decorated with reactive carboxylic acid and methacrylate functionalities, providing a versatile platform for chemical reactions. The versatility and ease of surface functionalization is demonstrated by varying both the core material and the chemistry used. Specifically, the carboxylic acid functionalities are used to conjugate wheat germ agglutinin to conducting polymer nanoparticles via carbodiimide-mediated coupling, and the methacrylate groups are used to link cysteamine to the surface of poly­(ε-caprolactone) nanoparticles via thiol–ene click chemistry and to link temperature-responsive polymer shells to the surface of gold nanoparticles via free radical polymerization

Nanoparticles from Amphiphilic Heterografted Macromolecular Brushes with Short Backbones

Heterografted macromolecular brushes are highly grafted macromolecules with two different side chains attached to a backbone. When endowed with an amphiphilic character, these can serve as unique stabilizers of biphasic systems and solute carriers and yield interesting self-assembled structures. Herein, we report on the solution structure of amphiphilic double-brush copolymers with short backbonesi.e., comparable to the length of the side-chainsin a selective solvent for one of the grafted blocks. As determined by small-angle neutron scattering measurements, poly­(ethylene glycol)/poly­(d,l-lactide) double brushes adopt a cylindrical structure with highly extended backbones in DMSO. In contrast, brushes undergo intermolecular self-assembly into spherical nanoparticles in water, with aggregation numbers that vary inversely with backbone degree of polymerization. While considerably less susceptible to intermolecular association than linear diblocks of similar hydrophobic and hydrophilic block lengths, the inability of the PEG component to maintain their unimolecular form results in well-defined spherical nanoparticles with very low aggregation numbers (3 < <i>N</i>_agg < 10) which could potentially lead to interesting compartmentalized nanomaterials

Nanoparticles from Amphiphilic Heterografted Macromolecular Brushes with Short Backbones

Heterografted macromolecular brushes are highly grafted macromolecules with two different side chains attached to a backbone. When endowed with an amphiphilic character, these can serve as unique stabilizers of biphasic systems and solute carriers and yield interesting self-assembled structures. Herein, we report on the solution structure of amphiphilic double-brush copolymers with short backbonesi.e., comparable to the length of the side-chainsin a selective solvent for one of the grafted blocks. As determined by small-angle neutron scattering measurements, poly­(ethylene glycol)/poly­(d,l-lactide) double brushes adopt a cylindrical structure with highly extended backbones in DMSO. In contrast, brushes undergo intermolecular self-assembly into spherical nanoparticles in water, with aggregation numbers that vary inversely with backbone degree of polymerization. While considerably less susceptible to intermolecular association than linear diblocks of similar hydrophobic and hydrophilic block lengths, the inability of the PEG component to maintain their unimolecular form results in well-defined spherical nanoparticles with very low aggregation numbers (3 < <i>N</i>_agg < 10) which could potentially lead to interesting compartmentalized nanomaterials

Synthesis of Copolymers from Phenylboronic Acid-Installed Cyclic Carbonates

Organoboron polymers play important roles in biomedical applications. An ample number of monomers bearing boronic acid derivatives have been synthesized, particularly focusing on controlled free radical polymerization methods. Organoboron polymers synthesized by ring-opening polymerization (ROP) routes are far less explored. We report on the ROP of boronic acid-installed cyclic carbonates, catalyzed by DBU from a poly­(ethylene glycol) macroinitiator. Controlled polymerization proceeded to relatively high conversions (∼70%) with low polydispersity. Deprotection of the copolymer to generate the boronic acid pendant group was readily achieved by displacement of the protecting group with free diboronic acid. The resulting amphiphilic copolymers self-assembled in water into spherical nanoparticles or vesicles, depending on hydrophilic/hydrophobic ratio. We envision these functional carbonates finding direct applications for core stabilization of biodegradable amphiphilic assemblies or in drug and protein encapsulation

Solute-Triggered Morphological Transitions of an Amphiphilic Heterografted Brush Copolymer as a Single-Molecule Drug Carrier

We describe the use of an amphiphilic macromolecular brush based on poly­(ethylene glycol) (PEG) and poly­(d,l-lactide) (PLA) as a stabilizer of hydrophobic solutes. The brush, which in solution adopted an extended backbone conformation consequent with excluded volume effects of the side chains, retained an elongated character in water following the hydrophobic collapse of PLA and the backbone triggered by a rapid change in solvent quality. However, in the presence of hydrophobic solutes at low concentrations in a homogeneous environment, the brush formed spherical unimolecular nanoparticles achieving high solute encapsulation efficiency. As solute content increased and exceeded what appears to be a limit for intramolecular solubilization, intermolecular assembly took place along with the formation of large aggregates, the properties of which were highly dependent on the solute. This first observation of the solute-triggered unimolecular collapse of an amphiphilic macromolecular brush should find important applications for the design of polymeric drug carriers whose properties can be conveniently modified at the single molecule level

Core–Shell Structure and Aggregation Number of Micelles Composed of Amphiphilic Block Copolymers and Amphiphilic Heterografted Polymer Brushes Determined by Small-Angle X‑ray Scattering

A large group of functional nanomaterials employed in biomedical applications, including targeted drug delivery, relies on amphiphilic polymers to encapsulate therapeutic payloads via self-assembly processes. Knowledge of the micelle structures will provide critical insights into design of polymeric drug delivery systems. Core–shell micelles composed of linear diblock copolymers poly­(ethylene glycol)-<i>b</i>-poly­(caprolactone) (PEG-<i>b</i>-PCL), poly­(ethylene oxide)-<i>b</i>-poly­(lactic acid) (PEG-<i>b</i>-PLA), as well as a heterografted brush consisting of a poly­(glycidyl methacrylate) backbone with PEG and PLA branches (PGMA-<i>g</i>-PEG/PLA) were characterized by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) measurements to gain structural information regarding the particle morphology, core–shell size, and aggregation number. The structural information at this quasi-equilibrium state can also be used as a reference when studying the kinetics of polymer micellization