Polyoxazoline-Based Nanovaccine Synergizes with Tumor-Associated Macrophage Targeting and Anti-PD-1 Immunotherapy against Solid Tumors.

Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co-delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)-ß expression using a polyoxazoline (POx)-poly(lactic-co-glycolic) acid (PLGA) nanovaccine, while modulating the tumor-associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti-programmed cell death protein 1 (PD-1) can constitute an alternative approach for cancer immunotherapy. POx-Mannose (Man) nanovaccines generate antigen-specific T-cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)-Man nanovaccines. This anti-tumor effect induced by the POx-Man nanovaccines is mediated by a CD8+ -T cell-dependent mechanism, in contrast to the PEG-Man nanovaccines. POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.

Surface Functionalization of Poly(l-lactide-co-glycolide) Membranes with RGD-Grafted Poly(2-oxazoline) for Periodontal Tissue Engineering.

Bone tissue defects resulting from periodontal disease are often treated using guided tissue regeneration (GTR). The barrier membranes utilized here should prevent soft tissue infiltration into the bony defect and simultaneously support bone regeneration. In this study, we designed a degradable poly(l-lactide-co-glycolide) (PLGA) membrane that was surface-modified with cell adhesive arginine-glycine-aspartic acid (RGD) motifs. For a novel method of membrane manufacture, the RGD motifs were coupled with the non-ionic amphiphilic polymer poly(2-oxazoline) (POx). The RGD-containing membranes were then prepared by solvent casting of PLGA, POx coupled with RGD (POx_RGD), and poly(ethylene glycol) (PEG) solution in methylene chloride (DCM), followed by DCM evaporation and PEG leaching. Successful coupling of RGD to POx was confirmed spectroscopically by Raman, Fourier transform infrared in attenuated reflection mode (FTIR-ATR), and X-ray photoelectron (XPS) spectroscopy, while successful immobilization of POx_RGD on the membrane surface was confirmed by XPS and FTIR-ATR. The resulting membranes had an asymmetric microstructure, as shown by scanning electron microscopy (SEM), where the glass-cured surface was more porous and had a higher surface area then the air-cured surface. The higher porosity should support bone tissue regeneration, while the air-cured side is more suited to preventing soft tissue infiltration. The behavior of osteoblast-like cells on PLGA membranes modified with POx_RGD was compared to cell behavior on PLGA foil, non-modified PLGA membranes, or PLGA membranes modified only with POx. For this, MG-63 cells were cultured for 4, 24, and 96 h on the membranes and analyzed by metabolic activity tests, live/dead staining, and fluorescent staining of actin fibers. The results showed bone cell adhesion, proliferation, and viability to be the highest on membranes modified with POx_RGD, making them possible candidates for GTR applications in periodontology and in bone tissue engineering.

Capillary Microfluidic-Assisted Surface Structuring.

A facile and universal oxygen-tolerant, capillary microfluidic-derived, controlled radical polymerization for surface structuring (gradient and patterned polymer brushes) is reported. A syringe pump and a filter paper sheet are used as capillary microfluidic to supply the reaction solution (monomer, solvent, and ligand) to a sandwich-shaped setup by placing a flat copper plate onto an ATRP initiator-modified substrate and resulting in gradient polymer brush formation with controlled thickness, steepness, and grafting area, polymers are showing the high chain-end fidelity. Two different polymer brushes (binary polymer brushes) can be simultaneously grown from both ends of the initiator modified substrate by using this method, which can be used to study the interfacial properties of different polymer brushes.

Facile Fabrication of Bio- and Dual-Functional Poly(2-oxazoline) Bottle-Brush Brush Surfaces.

Poly(2-oxazoline)s (POx) bottle-brush brushes have excellent biocompatible and lubricious properties, which are promising for the functionalization of surfaces for biomedical devices. Herein, a facile synthesis of POx is reported which is based bottle-brush brushes (BBBs) on solid substrates. Initially, backbone brushes of poly(2-isopropenyl-2-oxazoline) (PIPOx) were fabricated via surface initiated Cu0 plate-mediated controlled radical polymerization (SI-Cu0 CRP). Poly(2-methyl-2-oxazoline) (PMeOx) side chains were subsequently grafted from the PIPOx backbone via living cationic ring opening polymerization (LCROP), which result in ≈100 % increase in brush thickness (from 58 to 110 nm). The resultant BBBs shows tunable thickness up to 300 nm and high grafting density (σ) with 0.42 chains nm-2 . The synthetic procedure of POx BBBs can be further simplified by using SI-Cu0 CRP with POx molecular brush as macromonomer (Mn =536 g mol-1 , PDI=1.10), which results in BBBs surface up to 60 nm with well-defined molecular structure. Both procedures are significantly superior to the state-of-art approaches for the synthesis of POx BBBs, which are promising to design bio-functional surfaces.

Polymer Brushes on Hexagonal Boron Nitride.

Direct covalent functionalization of large-area single-layer hexagonal boron nitride (hBN) with various polymer brushes under mild conditions is presented. The photopolymerization of vinyl monomers results in the formation of thick and homogeneous (micropatterned, gradient) polymer brushes covalently bound to hBN. The brush layer mechanically and chemically stabilizes the material and allows facile handling as well as long-term use in water splitting hydrogen evolution reactions.

One step 3D printing of surface functionalized composite scaffolds for tissue engineering applications.

their surface properties. A main challenge in this area is the development of processing routes enabling for a simple but efficient surface design of complex shaped geometries. Against this background, this work aimed at the implementation of self-assembly principles for surface functionalization of 3D-printed poly(lactic-co-glycolic acid) (PLGA)-based constructs with macro- and microporous geometries via precision extruding deposition. METHODS: Three-component melts from PLGA, CaCO3 and amphiphilic polymers (poly(2-oxazoline) block copolymer) were printed and their bulk and surface properties were studied. RESULTS: Melts with up to 30 mass % of CaCO3 could be successfully printed with homogeneously distributed mineral particles. PLGA degradation during the printing process was temperature and time dependent: the molecular weight reached 10 to 15% of the initial values after ca. 120 min of heat exposure. Filament surfaces from melts containing CaCO3 show an increasing microroughness along with increasing CaCO3 content. Surface roughness and amphiphilic polymer content improve scaffold wettability with both factors showing synergistic effects. The CaCO3 content of the melts affected the inner filament structure during in vitro degradation in PBS, resulting in a homogeneous mineral particle-associated microporosity for mineral contents of 20 mass % and above. CONCLUSIONS: These results provide novel insights into the behavior of three-component melts from PLGA, CaCO3 and amphiphilic polymers during precision extruding deposition and show for the first time that self-assembly processes can be used to tailor scaffolds surface properties under such processing conditions.

Poly(2-oxazoline)s based biomaterials: A comprehensive and critical update.

Poly(2-oxazoline)s have been investigated for decades as biomaterials. Pioneering early work suggested that hydrophilic poly(2-oxazoline)s are comparable to poly(ethylene glycol) regarding their potential as biomaterials, but the ready commercial availability of the latter has led to its meteoric rise to become the gold standard of hydrophilic synthetic biomaterials. In contrast, poly(2-oxazoline)s almost fell into oblivion. However, in the last decade, this family of polymers has gained much more interest in general and as biomaterials in particular. The rich chemistry and comparably straightforward synthesis of poly(2-oxazoline)s gives many opportunities for tailoring the properties of the resulting biomaterials, allowing the chemist to explore new conjugation chemistry, and to fine-tune the molar mass, hydrophilic-lipophilic balance as well as architecture. Thus, the wide range of demands for various applications of biomaterials can be suitably addressed. This review aims to give a comprehensive and critical update of the development of poly(2-oxazoline) based biomaterials, focusing on the last 5 years, which have seen an explosive increase of interest. We believe that the research regarding this diverse family of polymers will remain strong and will keep growing, in particular after the promising first-in-human studies of a poly(2-oxazoline) drug conjugate. This review aims at researchers and students new to this polymer family and seasoned poly(2-oxazoline) experts alike and attempts to showcase how the chemical diversity of poly(2-oxazoline)s allows a relatively facile and broad access to biomaterials of all kinds.

Patterned Polypeptoid Brushes.

Patterned polypeptoid brushes on gold and oxide substrates are synthesized by surface-initiated polymerization of N-substituted glycine N-carboxyanhydrides. Their biofouling resistance is shown by protein and cell adhesion experiments. The accessibility of the system to common patterning protocols is demonstrated by UV-lithography and a µCP approach. Moreover, the terminal secondary amine group of the polypeptoid brushes is functionalized with different fluorescent dyes to demonstrate their chemical accessibility.

Drug-induced morphology switch in drug delivery systems based on poly(2-oxazoline)s.

Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drug-polymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core.