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1. Multicompartmental Microcapsules with Orthogonal Programmable Two‐Way Sequencing of Hydrophobic and Hydrophilic Cargo Release

   https://doi.org/10.1002/ange.201600383  

   Xu, Weinan ; Ledin, Petr A. ; Iatridi, Zacharoula ; Tsitsilianis, Constantinos ; Tsukruk, Vladimir V. ( March 2016 , Angewandte Chemie)

   Multicompartmental responsive microstructures with the capability for the pre‐programmed sequential release of multiple target molecules of opposite solubility (hydrophobic and hydrophilic) in a controlled manner have been fabricated. Star block copolymers with dual‐responsive blocks (temperature for poly(N‐isopropylacrylamide) chains and pH for poly(acrylic acid) and poly(2‐vinylpyridine) arms) and unimolecular micellar structures serve as nanocarriers for hydrophobic molecules in the microcapsule shell. The interior of the microcapsule can be loaded with water‐soluble hydrophilic macromolecules. For these dual‐loaded microcapsules, a programmable and sequential release of hydrophobic and hydrophilic molecules from the shell and core, respectively, can be triggered independently by temperature and pH variations. These stimuli affect the hydrophobicity and chain conformation of the star block copolymers to initiate out‐of‐shell release (elevated temperature), or change the overall star conformation and interlayer interactions to trigger increased permeability of the shell and out‐of‐core release (pH). Reversing stimulus order completely alters the release process.
2. Single-Micelle-Templated Synthesis of Hollow Barium Carbonate Nanoparticle for Drug Delivery

   https://doi.org/10.3390/polym15071739  

   Bastakoti, Bishnu Prasad ; Bhattarai, Nischal ; Ashie, Moses D. ; Tettey, Felix ; Yusa, Shin-ichi ; Nakashima, Kenichi ( April 2023 , Polymers)

   A laboratory-synthesized triblock copolymer poly(ethylene oxide-b-acrylic acid-b-styrene) (PEG-PAA-PS) was used as a template to synthesize hollow BaCO3 nanoparticles (BC-NPs). The triblock copolymer was synthesized using reversible addition–fragmentation chain transfer radical polymerization. The triblock copolymer has a molecular weight of 1.88 × 104 g/mol. Transmission electron microscopy measurements confirm the formation of spherical micelles with a PEG corona, PAA shell, and PS core in an aqueous solution. Furthermore, the dynamic light scattering experiment revealed the electrostatic interaction of Ba2+ ions with an anionic poly(acrylic acid) block of the micelles. The controlled precipitation of BaCO3 around spherical polymeric micelles followed by calcination allows for the synthesis of hollow BC-NPs with cavity diameters of 15 nm and a shell thickness of 5 nm. The encapsulation and release of methotrexate from hollow BC-NPs at pH 7.4 was studied. The cell viability experiments indicate the possibility of BC-NPs maintaining biocompatibility for a prolonged time.
3. Co-assembly of sugar-based amphiphilic block polymers to achieve nanoparticles with tunable morphology, size, surface charge, and acid-responsive behavior

   https://doi.org/10.1039/C8QM00353J  

   Lin, Yen-Nan ; Su, Lu ; Smolen, Justin ; Li, Richen ; Song, Yue ; Wang, Hai ; Dong, Mei ; Wooley, Karen L. ( November 2018 , Materials Chemistry Frontiers)

   The development of next-generation smart nanocarriers that can be tailored for specific applications requires precise control over physiochemical properties, yet modulation of nanostructures solely through synthetic routes is a time-consuming and labor-intensive process. In this work, co-assembly of two degradable glucose-based amphiphilic block polymers is demonstrated as a means to control nanoparticle size, surface charge, and stimuli-responsive properties, allowing optimization of these constructs for cytosolic drug delivery applications. Polymeric particles with varying weight fractions of carboxylate- and histamine-modified poly( dl- lactide)- b -poly( d -glucose carbonate)s (PDLLA- b -PDGC) were obtained with diameters ranging from ca. 30 nm to 3 μm and zeta potential values ranging from ca. −35 mV to −1.6 mV in nanopure water. Histamine moieties imparted pH-responsive behavior due to protonation below pH 7, whereas the carboxylates imparted colloidal stability and anionic character. Blending the acid- and histamine-functionalized polymers produced co-assemblies with different pH-dependent surface charge profiles. In particular, co-assemblies with 60 wt% histamine-modified PDLLA- b -PDGC ( f histamine = 0.6) swelled upon acidification from physiological pH (7.4) to endolysosomal pH (5.5), which is anticipated to enable drug release within endolysosomal compartments. The accessible procedures presented here for engineering highly tunable nanoparticles from glucose-based, functional, degradablemore »polymers offer versatile strategies for accelerating the development and clinical implementation of such stimuli-responsive, tailored nanocarriers.« less
4. Selective hydrogen bonding controls temperature response of layer-by-layer upper critical solution temperature micellar assemblies

   https://doi.org/10.1039/d0sm01997f  

   Aliakseyeu, Aliaksei ; Albright, Victoria ; Yarbrough, Danielle ; Hernandez, Samantha ; Zhou, Qing ; Ankner, John F. ; Sukhishvili, Svetlana A. ( March 2021 , Soft Matter)

   This work establishes a correlation between the selectivity of hydrogen-bonding interactions and the functionality of micelle-containing layer-by-layer (LbL) assemblies. Specifically, we explore LbL films formed by assembly of poly(methacrylic acid) (PMAA) and upper critical solution temperature block copolymer micelles (UCSTMs) composed of poly(acrylamide- co -acrylonitrile) P(AAm- co -AN) cores and polyvinylpyrrolidone (PVP) coronae. UCSTMs had a hydrated diameter of ∼380 nm with a transition temperature between 45 and 50 °C, regardless of solution pH. Importantly, micelles were able to hydrogen-bond with PMAA, with the critical interaction pH being temperature dependent. To better understand the thermodynamic nature of these interactions, in depth studies using isothermal titration calorimetry (ITC) were conducted. ITC reveals opposite signs of enthalpies for binding of PMAA with micellar coronae vs. with the cores. Moreover, ITC indicates that pH directs the interactions of PMAA with micelles, selectively enabling binding with the micellar corona at pH 4 or with both the corona and the core at pH 3. We then explore UCSTM/PMAA LbL assemblies and show that the two distinct modes of PMAA interaction with the micelles ( i.e. whether or not PMAA binds with the core) had significant effects on the film composition, structure, and functionality. Consistent withmore »PMAA hydrogen bonding with the P(AAm- co -AN) micellar cores, a significantly higher fraction of PMAA was found within the films assembled at pH 3 compared to pH 4 by both spectroscopic ellipsometry and neutron reflectometry. Selective interaction of PMAA with PVP coronae of the assembled micelles, achieved by the emergence of partial ionization of PMAA at pH 4 was critical for preserving film functionality demonstrated as temperature-controlled swelling and release of a model small molecule, pyrene. The work done here can be applied to a multitude of assembled polymer systems in order to predict suppression/retention of their stimuli-responsive behavior.« less
5. Multi-responsive polypeptide hydrogels derived from N-carboxyanhydride terpolymerizations for delivery of nonsteroidal anti-inflammatory drugs

   https://doi.org/10.1039/C7OB00931C  

   Fan, Jingwei ; Li, Richen ; Wang, Hai ; He, Xun ; Nguyen, Tan P. ; Letteri, Rachel A. ; Zou, Jiong ; Wooley, Karen L. ( January 2017 , Organic & Biomolecular Chemistry)

   A polypeptide-based hydrogel system, when prepared from a diblock polymer with a ternary copolypeptide as one block, exhibited thermo-, mechano- and enzyme-responsive properties, which enabled the encapsulation of naproxen (Npx) during the sol–gel transition and its release in the gel state. Statistical terpolymerizations of l -alanine (Ala), glycine (Gly) and l -isoleucine (Ile) NCAs at a 1 : 1 : 1 feed ratio initiated by monomethoxy monoamino-terminated poly(ethylene glycol) afforded a series of methoxy poly(ethylene glycol)- block -poly( l -alanine- co -glycine- co - l -isoleucine) (mPEG- b -P(A-G-I)) block polymers. β-Sheets were the dominant secondary structures within the polypeptide segments, which facilitated a heat-induced sol-to-gel transition, resulting from the supramolecular assembly of β-sheets into nanofibrils. Deconstruction of the three-dimensional networks by mechanical force (sonication) triggered the reverse gel-to-sol transition. Certain enzymes could accelerate the breakdown of the hydrogel, as determined by in vitro gel weight loss profiles. The hydrogels were able to encapsulate and release Npx over 6 days, demonstrating the potential application of these polypeptide hydrogels as an injectable local delivery system for small molecule drugs.