Amphiphilic polymers show a rich variety of self-assembly behavior in aqueous solutions. In experimental studies, statistical copolymer or block copolymer architectures are usually investigated because of their ease of synthesis or their structural analogy to surfactants. A copolymer structure that links the two architectures is an alternating copolymer, which is easily accessible by polycondensation reactions. Using alternating hydrophilic and hydrophobic building blocks with varying lengths allows a systematic variation between statistical and multiblock architectures. We synthesized alternating amphiphilic copolymers as polyesters using hydrophobic dicarboxylic acids (C4–C20) and hydrophilic poly­(ethylene glycol) (PEG) units (EG3–EG1000). Copolymers with long EG units were made accessible with the help of a newly developed esterification process. The solution properties of amphiphilic copolymers feature a lower critical solution temperature (LCST) behavior in water, which can be systematically varied over a wide range from 3 to 83 °C by adjusting the lengths of the C n and EG m units. We find that the transition temperature depends linearly on the hydrophobic unit length C m and logarithmically on the hydrophilic length EG n . In the one-phase region, PEG copolymer coils are more compact compared to the respective PEG homopolymers due to hydrophobic interactions between the hydrophobic units leading to loop formation. For shorter PEG units, the copolymers form micellar structures consisting only of a few copolymer chains. The micellar cores consist of hydrophobic regions containing only a few dicarboxylic acid units embedded in a PEG-rich and water-poor matrix. The cores are surrounded by a diluted corona of PEG chains. Further decreasing the PEG unit length leads to the formation of highly swollen gels consisting of networks of interconnected micelles. These can self-assemble to form highly ordered liquid crystalline cubic phases. The study demonstrates how the structure of alternating amphiphilic copolymers can be systematically varied to adjust the thermal solution properties such as the LCST over a wide range, as well as the self-assembly properties varying between single chains, micelles, gels, and highly ordered lyotropic liquid crystals.

The translocation of biologically active macromolecules through cell membranes is of vital importance for cells and is a key process for drug delivery. Proteins exploit specific conformational changes in their secondary structure to facilitate membrane translocation. For the large class of biological and synthetic macromolecules, where such conformational adaptions are not possible, guidelines to tailor the structure of monomers and macromolecules to aid membrane translocation and cross-membrane drug delivery would be highly desirable. Here, we use alternating amphiphilic macromolecules to systematically investigate the relation between polarity, polymer chain length, lipid chain length, polymer concentration, and temperature on membrane partition and translocation rate. We employed pulse field gradient NMR and confocal fluorescence microscopy to determine membrane adsorption and desorption rate constants and partitioning coefficients. We find that translocation is a two-step process involving a fast adsorption and membrane insertion process and a slower desorption process. Membrane insertion is a key step that determines the molecular weight, concentration, and temperature dependences. Passive translocation is possible on time scales from minutes to hours. Macromolecules with different adapted hydrophilic/hydrophobic comonomer sequences show the same translocation rate, indicating that common optimized translocation conditions can be realized with a variety of monomer chemical structures. The investigated copolymers are biocompatible, biodegradable, and capable of transporting a hydrophobic payload through the lipid membrane. This detailed understanding of the macromolecular translocation mechanism enables to better tailor the delivery of active agents using macromolecular carriers.