Dendritic surface functionalization of nanomaterials: controlling properties and functions for biomedical applications

Uma grande variedade de nanomateriais tem demonstrado aplicações médicas promissoras, tais como liberação de fármacos e em imagens. Nestas aplicações, a superfície química dos materiais é crítica, uma vez que exerce papel importante na determinação da toxicidade e comportamento de biodistribuição do material. Aqui, nós revisamos a funcionalização de nanomateriais, como dendrons, como método eficiente de alterar a superfície química destes compostos, introduzindo novas propriedades e funções. Descritos aqui estão nanopartículas superparamagnéticas de óxido de ferro (do inglês, SPIO), com guanidinas dendríticas para aumentar seu transporte para o interior das células, úteis em imagens de ressonância magnética. A introdução de dendrons contendo hidroxilas, aminas, guanidinas, carboidratos e quelatos de Gd(III) periféricos em vesículas poliméricas (polymersomes) também está descrita. Esses grupos dendríticos permitem a modulação de toxicidade, captura celular, ligação à proteína e eficiência como agente de contraste, enquanto que, ao mesmo tempo, permitem a manutenção da estabilidade das vesículas poliméricas. Assim, essa abordagem é promissora para o desenvolvimento de grande variedade de materiais multifuncionais para aplicações farmacêuticas.A wide variety of nanomaterials have demonstrated promise in medical applications such as drug delivery and imaging. In these applications, the surface chemistry of the materials is critical as it plays an important role in determining the toxicity and biodistribution behavior of the material. We review here the functionalization of nanomaterials with dendrons as an efficient method to alter the surface chemistry of the materials, introducing new properties and functions. Described here is the functionalization of superparamagnetic iron oxide nanoparticles (SPIO) with dendritic guanidines to enhance their transport into cells for magnetic resonance imaging applications. The introduction of dendrons bearing peripheral hydroxyls, amines, guanidines, carbohydrates and Gd(III) chelates to polymer vesicles (polymersomes) is also described. These dendritic moieties allow for modulation of toxicity, cell uptake, protein binding, and contrast agent efficiency, while at the same time allowing the stabilities of the polymersomes to be maintained. Thus, this approach holds promise for the development of a wide range of multifunctional materials for pharmaceutical applications

Synthesis, properties, and degradation of polyisobutylene-polyester graft copolymers

The development of copolymers is a promising approach for combining the favorable properties of two polymers and obtaining new properties of the combination. In this work, graft copolymers of polyisobutylene (PIB) and polycaprolactone (PCL) or poly(D,L-lactide) (PDLLA) were synthesized and studied. Amine terminated polyesters were synthesized and were grafted onto an activated PIB backbone synthesized from butyl rubber, a copolymer of isobutylene and 2 mol % isoprene. The polyester content was tuned from 15 to 44 wt % by varying the molar mass of the polyester blocks and the number of molar equivalents used in the grafting reaction. The graft copolymers with higher polyester content underwent nanoscale phase separation, as demonstrated by differential scanning calorimetry and atomic force microscopy imaging. This was found to provide enhanced mechanical properties such as increased tensile strength and Young’s modulus relative to the starting rubber or physical blends. Despite the significant polyester content of the graft copolymers and the susceptibility of the polyesters to degradation, the graft copolymers underwent negligible mass loss in 5 M NaOH over a period of 8 weeks. These results suggest that polyesters can be incorporated into PIB to tune and enhance its properties, while maintaining high chemical stability

Controlled Polymerization of Ethyl Glyoxylate Using Alkyllithium and Alkoxide Initiators

The synthesis of poly(ethyl glyoxylate)s (PEtGs) by anionic polymerization was explored. PEtGs are a subclass of stimuli-responsive self-immolative polymers with promising properties for applications as coatings, sensors, and drug delivery vehicles. In this report, a new purification procedure for the preparation of highly pure ethyl glyoxylate (EtG), suitable for anionic polymerization reactions, and the first successful examples of controlled polymerization of EtG are described. n-BuLi, PhLi, and t-BuLi were employed as initiators under different experimental conditions and their behavior was examined using NMR spectroscopy, size exclusion chromatography, and thermal analysis to develop an optimized procedure. As functional alkoxide initiators, propargyl alkoxide was employed in optimization studies and poly(ethylene glycol) (PEG) dialkoxide was utilized for the direct synthesis of PEtG-PEG-PEtG copolymers. The new polymerization method revealed many features of controlled polymerization reactions, yielding PEtGs with predictable molar masses and relatively low dispersity values

Self-Healing Polyphosphonium Ionic Networks

Self healing, ionically crosslinked networks were prepared from poly(acrylic acid) (PAA) and poly(triethyl(4-vinylbenzyl)phosphonium chloride (P-Et-P) and their properties were studied. Three different ratios of PAA/P-Et-P were incorporated into the networks by varying the addition orders of the components. Swelling of the networks increased with increasing NaCl concentration when they were immersed in aqueous solution. All networks retained their structural integrity in 0.1 M NaCl. Studies of the rheological and tensile properties of the networks swelled in 0.1 M NaCl showed that PAA\u3eP-Et-Pexhibited high elongation and viscoelastic properties suitable for self-healing with a relaxation time of ~30 s, whereas the other networks exhibited predominantly elastic behavior. The moduli were similar to those of soft tissues. Self-healing of PAA\u3eP-Et-Pin 0.1 M NaCl was demonstrated through repair of a 0.5 mm diameter puncture in the material whereas healing was incomplete for the other networks and also for PAA\u3eP-Et-Pin the absence of NaCl. Healing after completely severing a tensile testing sample showed significant recovery of the modulus, strength, and elongation. The properties of these materials and their ability to self-heal in low and physiologically relevant salt concentrations make them promising candidates for a variety of applications, particularly in the biomedical area

Designing polymers with stimuli-responsive degradation for biomedical applications

Early biomedical applications of polymers were in areas such as joint replacements and often involved durable polymers. However, biodegradable polymers are increasingly being used to perform temporary functions such as drug delivery or supporting cells, after which they can break down and be eliminated from the body. Polymers that degrade specifically in response to stimuli offer additional opportunities to control when and where this degradation occurs, enabling enhanced functions such as site-specific drug release and the early detection of disease. In this article, we will discuss recent advancements in the design, preparation, and application of stimuli-responsive polymer degradation. In particular, we will highlight the introduction of new linkers, and advanced multifunctional systems. Recent approaches towards maximizing the responses to stimuli, including self-immolative and self-amplifying polymers, will also be highlighted. Finally, some of the challenges in applying these more complex, functional polymers will be discussed, along with important areas for future research

Depolymerization of Trityl End-capped Poly(ethyl glyoxylate): Potential Applications in Smart Packaging

The temperature-dependent depolymerization of self-immolative poly(ethyl glyoxylate) (PEtG) capped with triphenylmethyl (trityl) groups was studied and its potential application for smart packaging was explored. PEtGs with four different trityl end-caps were prepared and found to undergo depolymerization to volatile products from the solid state at different rates depending on temperature and the electron-donating substituents on the trityl aromatic rings. Through the incorporation of hydrophobic dyes including Nile red and IR-780, the depolymerization was visualized as a color change of the dye as it changed from a dispersed to aggregated state. The ability of this platform to provide information on thermal history through an easily readable signal makes it promising in smart packaging applications for sensitive products such a food and other cargo that is susceptible to degradation

Self-Immolative Hydrogels with Stimulus-Mediated On-Off Degradation.

Hydrogels are of interest for a wide range of applications from sensors to drug delivery and tissue engineering. Self-immolative polymers, which depolymerize from end-to-end following a single backbone or end-cap cleavage, offer advantages such as amplification of the stimulus-mediated cleavage event through a cascade degradation process. It is also possible to change the active stimulus by changing only a single end-cap or linker unit. However, there are very few examples of self-immolative polymer hydrogels, and the reported examples exhibited relatively poor stability in their nontriggered state or slow degradation after triggering. Described here is the preparation of hydrogels composed of self-immolative poly(ethyl glyoxylate) (PEtG) and poly(ethylene glycol) (PEG). Hydrogels formed from 2 kg/mol 4-arm PEG and 1.2 kg/mol PEtG with a light-responsive linker end-cap had high gel content (90%), an equilibrium water content of 89%, and a compressive modulus of 26 kPa. The hydrogel degradation could be turned on and off repeatedly through alternating cycles of irradiation and dark storage. Similar cycles could also be used to control the release of the anti-inflammatory drug celecoxib. These results demonstrate the potential for self-immolative hydrogels to afford a high degree of control over responses to stimuli in the context of smart materials for a variety of applications

Neutral, water-soluble poly(ester amide) hydrogels for cell encapsulation

© 2020 Elsevier Ltd Hydrogels are of significant interest for cell encapsulation and delivery in regenerative medicine. Poly(ester amide)s (PEAs) are a class of biodegradable polymers that exhibit promise for biomedical applications due to the degradability of the ester and amide linkages in their backbones, their preparation from biomolecules such as amino acids, and the ability to readily tune their properties through a modular synthesis approach. Water-soluble PEAs containing cationic arginine moieties have previously been developed, but to the best of our knowledge, neutral water-soluble PEAs based on non-charged amino acids have not been reported. Using a poly(ethylene glycol) (PEG)-based macromonomer, we describe here the syntheses of water-soluble amino acid-containing PEAs containing crosslinkable alkenes in their backbones. These PEAs were converted into hydrogels through photoinitiated crosslinking and their properties were compared, including gel content, water content, swelling, and Young\u27s moduli. Subsequent cell culture studies on a subset of hydrogels confirmed that human adipose-derived stromal cells (ASCs) showed \u3e 75% viability at 24 h post-encapsulation. To explore the potential of the hydrogels as cell delivery systems for applications in soft tissue regeneration, adipogenic differentiation of the encapsulated ASCs was probed in vitro at 7 days. Analysis of glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity and intracellular lipid accumulation indicated that the hydrogels provided a supportive environment for ASC adipogenesis. Overall, these PEAs provide a new platform that warrants further development for regenerative medicine applications

Vascular grafting strategies in coronary intervention

© 2014 Knight, Gillies and Mequanint. With the growing need for coronary revascularizations globally, several strategies to restore blood flow to the heart have been explored. Bypassing the atherosclerotic coronary arteries with autologous grafts, synthetic prostheses, and tissue-engineered vascular grafts continue to be evaluated in search of a readily available vascular graft with clinically acceptable outcomes. The development of such a vascular graft including tissue engineering approaches both in situ and in vitro is herein reviewed, facilitating a detailed comparison on the role of seeded cells in vascular graft patency

Hybrid Polyester Self-Immolative Polymer Nanoparticles for Controlled Drug Release

© 2018 American Chemical Society. Delivery systems have been developed to address problematic properties of drugs, but the specific release of drugs at their targets is still a challenge. Polymers that depolymerize end-to-end in response to the cleavage of stimuli-responsive end-caps from their termini, commonly referred to as self-immolative polymers, offer high sensitivity to stimuli and have potential for the development of new high-performance delivery systems. In this work, we prepared hybrid particles composed of varying ratios of self-immolative poly(ethyl glyoxylate) (PEtG) and slowly degrading poly(d,l-lactic acid) (PLA). These systems were designed to provide a dual release mechanism consisting of a rapid burst release of drug from the PEtG domains and a slower release from the PLA domains. Using end-caps responsive to UV light and reducing thiols, it was found that triggered particles exhibited partial degradation, as indicated by a reduction in their dynamic light-scattering count rate that depended on the PEtG:PLA ratio. The particles were also shown to release the hydrophobic dye Nile red and the drug celecoxib in a manner that depended on triggering and the PEtG:PLA ratio. In vitro toxicity assays showed an effect of the stimuli on the toxicity of the celecoxib-loaded particles but also suggested it would be ideal to replace the sodium cholate surfactant that was used in the particle synthesis procedure in order to reduce the background toxicity of the delivery system. Overall, these hybrid systems show promise for tuning and controlling the release of drugs in response to stimuli