Development of Morphologically Discrete PEG–PDLLA Nanotubes for Precision Nanomedicine

Precise control over the morphological features of nanoparticles is an important requisite for their application in nanomedical research. Parameters such as size and shape have been identified as critical features for effective nanotherapeutic technologies due to their role in circulation, distribution, and internalization in vivo. Tubular PEG-PDLLA polymersomes (nanotubes) exhibit an interesting morphology with potential for immunotherapeutics, as the elongated shape can affect cell-particle interactions. Developing methodologies that permit control over the precise form of such nanotubes is important for their biomedical implementation due to the stringent physicochemical constraints for efficacious performance. Through careful control over the engineering process, we demonstrate the generation of well-defined nanotubes based on polymersomes as small as 250 and 100 nm, which can be successfully shape transformed. The quality of the resulting nanostructures was established by physical characterization using AF4-MALS and cryo-TEM. Moreover, we show the successful loading of such nanotubes with model payloads (proteins and drugs). These findings provide a promising platform for implementation in biomedical applications in which discrete structure and functionality are essential features

Hybrid Biodegradable Nanomotors through Compartmentalized Synthesis

Designer particles that are embued with nanomachinery for autonomous motion have great potential for biomedical applications; however, their development is highly demanding with respect to biodegradability/compatibility. Previously, biodegradable propulsive machinery based on enzymes has been presented. However, enzymes are highly susceptible to proteolysis and deactivation in biological milieu. Biodegradable hybrid nanomotors powered by catalytic inorganic nanoparticles provide a proteolytically stable alternative to those based upon enzymes. Herein we describe the assembly of hybrid biodegradable nanomotors capable of transducing chemical energy into motion. Such nanomotors are constructed through a process of compartmentalized synthesis of inorganic MnO2 nanoparticles (MnPs) within the cavity of organic stomatocytes. We show that the nanomotors remain active in cellular environments and do not compromise cell viability. Effective tumor penetration of hybrid nanomotors is also demonstrated in proof-of-principle experiments. Overall, this work represents a new prospect for engineering of nanomotors that can retain their functionality within biological contexts

Self-recovering dual cross-linked hydrogels based on bioorthogonal click chemistry and ionic interactions

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Self-recovering dual cross-linked hydrogels based on bioorthogonal click chemistry and ionic interactions

The biocompatible, injectable and high water-swollen nature of hydrogels makes them a popular candidate to imitate the extracellular matrix (ECM) for tissue engineering both in vitro and in vivo. However, commonly used covalently cross-linked hydrogels, despite their stability and tunability, are elastic and deteriorate as bulk material degrades which would impair proper cell function. To improve these deficiencies, here, we present a self-recovering cross-linked hydrogel formed instantaneously with functionalized poly(ethylene glycol) as a basis. We combine covalent cross-links introduced via a strain-promoted azide-alkyne cycloaddition (SPAAC) click reaction and non-covalent links between phosphonate groups and calcium ions. By adjusting the ratios of non-covalent and covalent cross-links, we synthesized these dual cross-linked (DC) hydrogels that displayed storage moduli below ∼2000 Pa and relaxation times from seconds to minutes. The gels recovered to 41-96% of their initial mechanical properties after two subsequent strain failures. Cryo-scanning electron microscopy revealed that DC hydrogels containing approximately equal amounts of covalent and non-covalent cross-links displayed phase separation. Finally, we functionalized the DC hydrogels by incorporating an integrin binding motif, RGDS, to provide a biocompatible environment for human mesenchymal stem cells (HMSCs) by facilitating adhesion inside the gel network. Inside these DC gels HSMCs displayed a viability up to 73% after five days of cell culture

Reversibly self-assembled pH-responsive PEG-p(CL-g-TMC) polymersomes

Polymersomes have gained much interest within the biomedical field as drug delivery systems due to their ability to transport and protect cargo from the harsh environment inside the body. For an improved drug efficacy, control over cargo release is however also an important factor to take into account. An often employed method is to incorporate pH sensitive groups in the vesicle membrane, which induce disassembly and content release when the particles have reached a target site in the body with the appropriate pH, such as the acidic microenvironment of tumor tissue or the endosome. In this paper, biodegradable poly(ethylene glycol)-poly(caprolactone-gradient-trimethylene carbonate)-based polymeric vesicles have been developed with disassembly features at mild acidic conditions. Modifying the polymer backbone with imidazole moieties results in vesicle disassembly upon protonation due to the lowered pH. Furthermore, upon increasing the pH efficient re-assembly into vesicles is observed due to the switchable amphiphilic nature of the polymer. When this re-assembly process is conducted in presence of cargo, enhanced encapsulation is achieved. Furthermore, the potency of the polymeric system for future biomedical applications such as adjuvant delivery is demonstrated

ATP-mediated transient behavior of stomatocyte nanosystems

In nature, dynamic processes are ubiquitous and often characterized by adaptive, transient behavior. Herein, we present the development of a transient bowl-shaped nanoreactor system, or stomatocyte, the properties of which are mediated by molecular interactions. In a stepwise fashion, we couple motility to a dynamic process, which is maintained by transient events; namely, binding and unbinding of adenosine triphosphate (ATP). The surface of the nanosystem is decorated with polylysine (PLL), and regulation is achieved by addition of ATP. The dynamic interaction between PLL and ATP leads to an increase in the hydrophobicity of the PLL–ATP complex and subsequently to a collapse of the polymer; this causes a narrowing of the opening of the stomatocytes. The presence of the apyrase, which hydrolyzes ATP, leads to a decrease of the ATP concentration, decomplexation of PLL, and reopening of the stomatocyte. The competition between ATP input and consumption gives rise to a transient state that is controlled by the out-of-equilibrium process

Pathway dependent shape-transformation of azide-decorated polymersomes

Here we report the shape transformation of poly(ethylene glycol)-polystyrene (PEG-PS) polymersomes into ordered inverse morphologies, directed by the salt concentration of the medium and the presence of azide groups on the polymersome surface. The azide moieties introduced at the chain ends of the PEG blocks induce a difference in hydrodynamic volume of the hydrophilic domains at the inner and outer side of the vesicular membrane, allowing control over its spontaneous curvature and hence the pathway of shape deformation. This simple modification enables access to intricate morphologies which are traditionally only accessible via the application of complex polymer building blocks

Biomorphic engineering of multifunctional polylactide stomatocytes toward therapeutic nano-red blood cells

Morphologically discrete nanoarchitectures, which mimic the structural complexity of biological systems, are an increasingly popular design paradigm in the development of new nanomedical technologies. Herein, engineered polymeric stomatocytes are presented as a structural and functional mimic of red blood cells (RBCs) with multifunctional therapeutic features. Stomatocytes, comprising biodegradable poly(ethylene glycol)-block-poly(D,L-lactide), possess an oblate-like morphology reminiscent of RBCs. This unique dual-compartmentalized structure is augmented via encapsulation of multifunctional cargo (oxygen-binding hemoglobin and the photosensitizer chlorin e6). Furthermore, stomatocytes are decorated with a cell membrane isolated from erythrocytes to ensure that the surface characteristics matched those of RBCs. In vivo biodistribution data reveal that both the uncoated and coated nano-RBCs have long circulation times in mice, with the membrane-coated ones outperforming the uncoated stomatoctyes. The capacity of nano-RBCs to transport oxygen and create oxygen radicals upon exposure to light is effectively explored toward photodynamic therapy, using 2D and 3D tumor models; addressing the challenge presented by cancer-induced hypoxia. The morphological and functional control demonstrated by this synthetic nanosystem, coupled with indications of therapeutic efficacy, constitutes a highly promising platform for future clinical application

Photoactivated nanomotors via aggregation induced emission for enhanced phototherapy

Aggregation-induced emission (AIE) has, since its discovery, become a valuable tool in the field of nanoscience. AIEgenic molecules, which display highly stable fluorescence in an assembled state, have applications in various biomedical fields—including photodynamic therapy. Engineering structure-inherent, AIEgenic nanomaterials with motile properties is, however, still an unexplored frontier in the evolution of this potent technology. Here, we present phototactic/phototherapeutic nanomotors where biodegradable block copolymers decorated with AIE motifs can transduce radiant energy into motion and enhance thermophoretic motility driven by an asymmetric Au nanoshell. The hybrid nanomotors can harness two photon near-infrared radiation, triggering autonomous propulsion and simultaneous phototherapeutic generation of reactive oxygen species. The potential of these nanomotors to be applied in photodynamic therapy is demonstrated in vitro, where near-infrared light directed motion and reactive oxygen species induction synergistically enhance efficacy with a high level of spatial control

Biodegradable polymersomes with structure Inherent fluorescence and targeting capacity for enhanced photo-dynamic therapy

Biodegradable nanostructures displaying aggregation-induced emission (AIE) are desirable from a biomedical point of view, due to the advantageous features of loading capacity, emission brightness, and fluorescence stability. Herein, biodegradable polymers comprising poly (ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-P(CLgTMC)), with tetraphenylethylene pyridinium-TMC (PAIE) side chains have been developed, which self-assembled into well-defined polymersomes. The resultant AIEgenic polymersomes are intrinsically fluorescent delivery vehicles. The presence of the pyridinium moiety endows the polymersomes with mitochondrial targeting ability, which improves the efficiency of co-encapsulated photosensitizers and improves therapeutic index against cancer cells both in vitro and in vivo. This contribution showcases the ability to engineer AIEgenic polymersomes with structure inherent fluorescence and targeting capacity for enhanced photodynamic therapy