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Representative examples of bifunctional dendrimers. Adapted with permission from (a) ref. (23); (b) ref. (24); and (c) ref. (25).
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During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagn...
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... collaboration between the groups of Finn, Fokin, Sharp- less, and Hawker demonstrated the usefulness of CuAAC for the preparation of Janus-type dendrimers, where protected and unprotected 2,2-bis(hydroxymethyl)propionic acid (bis- MPA) dendrons were connected through their focal points via triazole linkages [Cu (PPh 3 ) 3 Br, DIPEA, THF, 50°C] ( Fig. 2a) (23). In addition, an adequate selection of protect- ing groups allowed the stepwise CuAAC functionalization of the resulting dendrimers (CuSO 4 , ascorbate, THF-H 2 O) with 16 mannose units on one side of the dendrimer, and 2 coumarin dyes on the other. The resulting glycodendrimer showed a 240-fold increase affinity towards lectin ...
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... to monomeric mannose which entails a rich future for these structures in antiadhesive therapy. In a similar fashion, the group of Sanyal has reported the preparation of bifunctional Janus-type dendrimers based on a Diels-Alder cycloaddition (benzene, 85°C) between furan-functionalized Fréchet dendrons and maleimide-functionalized bis-MPA dendrons (Fig. 2b) ...
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... handles. As described by Malkoch and coworkers, this strategy has allowed the preparation of bifunctional dendrimers of generation 1-3 (G1-G3) bearing up to 24 hydroxyl groups at the periphery and 21 internal alkyne/ azide groups distributed throughout the dendrimer backbone, which were amenable for further functionalization by means of CuAAC (Fig. 2c) ...
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... and other synthetic multivalent glycocon- jugates with the ability to interact with target lectins and hence, to promote/inhibit natural carbohydrate-receptor interactions (37). Pioneering examples on the preparation of glycodendrimers from unprotected carbohydrates came from the groups of Liskamp/Pieters (38), Finn/Fokin/ Sharpless/Hawker (23) (Fig. 2a), and Fernandez-Megia/ Riguera ( Fig. 4) (39,40). It is worth to note that, while the first two reports relied on alkynated dendrimers, the group of Fernandez-Megia and Riguera employed gallic acid- triethylene glycol (GATG) dendrimers incorporating termi- nal azide groups on their periphery. This way, glyco- dendrimers and ...
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... this first report illustrated the advantage of combining precise chemistries in this field. Application of the same principle was later reported by Weck and coworkers for the simultaneous click functionali- zation of a poly(norbornene) with a nucleoside and biotin by means of CuAAC and hydrazone linkages (CuSO 4 , ascorbate, DMF or DMSO, 25°C) (Fig. 9b) ...
Citations
... Click chemistry is defined as the chemical reactions that take place spontaneously between two different reactants at the mild condition in a highly selective manner affording high product yields. This method includes different sub-categories such as alkyneazide click reactions, Diels-Alder (DA), cycloaddition, and thiolene addition reactions [78][79][80]. ...
... Click chemistry is defined as the chemical reactions that take place spontaneously between two different reactants at the mild condition in a highly selective manner affording high product yields. This method includes different sub-categories such as alkyne-azide click reactions, Diels-Alder (DA), cycloaddition, and thiolene addition reactions [78][79][80]. ...
Polysaccharides-based injectable hydrogels are a unique group of biodegradable and biocompatible materials that have shown great potential in the different biomedical fields. The biomolecules or cells can be simply blended with the hydrogel precursors with a high loading capacity by homogenous mixing. The different physical and chemical crosslinking approaches for preparing polysaccharide-based injectable hydrogels are reviewed. Additionally, the review highlights the recent work using polysaccharides-based injectable hydrogels as stimuli-responsive delivery vehicles for the controlled release of different therapeutic agents and viscoelastic matrix for cell encapsulation. Moreover, the application of polysaccharides-based injectable hydrogel in regenerative medicine as tissue scaffold and wound healing dressing is covered.
... Early dendrimers were commonly based on a poly(aminoamine), PAMAM, core, generated by successive, exhaustive aza-Michael addition of ethylenediamine to methacrylate [226], and more recently have been synthesised using efficient click chemistry reactions [227][228][229] with multifunctional centres such as hyperbranched polyglycerols [230] and pentaerythritol [225,[231][232][233]. The PAMAM family of dendrimer has been associated with toxic effects, due to their small size and cationic nature leading to interactions with cell membranes eventually leading to cell lysis [234,235]. ...
The sustained and/or targeted delivery of hydrophilic drugs is an important field within drug delivery, presenting unique challenges when compared to that of hydrophobic drugs. Yet relatively few comprehensive reviews specific to hydrophilic drug delivery have been published recently. In this review, therefore, we seek to establish the recent trends in the delivery of hydrophilic drugs in particular, and recent developments including electrospun core-shell nanofibrous materials, stimuli-responsive hydrogel carriers, amphiphilic drug-drug conjugates (ADDCs), and nanomaterials including polymer nanoparticles (PNPs), solid lipid nanoparticles (SLNs), micelles, liposomes, and mesoporous silica nanoparticles (MSNs). A recurring trend in the field has been the relatively slow translation of novel technologies into viable pharmaceutical products, with few reaching clinical trial phase. Furthermore, we consider the bench-to-bedside potential of these novel technologies, taking into account the capabilities of these concepts to overcome the technical, legislative, and commercial requirements that must be met in order for a viable device to be adopted in the real world.
... In recent years, approaches of click chemistry 3 and bioorthogonal chemistry 4 have been widely applied in drug delivery, broadly defined, with very exciting results. Along this line, there have been reviews addressing specific aspects of click chemistry in drug delivery including cell engineering and drug delivery 5 ; cell tracking and tissue engineering 6 ; polymers, dendrimers, and hydrogels for drug delivery 7 ; as well as other general topics [8][9][10] . ...
Neurodegenerative disease (ND) is a clinical condition in which neurons degenerate with a consequent loss of functions in the affected brain region. Parkinson’s disease (PD) is the second most progressive ND after Alzheimer’s disease (AD), which affects the motor system and is characterized by the loss of dopaminergic neurons from the nigrostriatal pathway in the midbrain, leading to bradykinesia, rigidity, resting tremor, postural instability and non-motor symptoms such as cognitive declines, psychiatric disturbances, autonomic failures, sleep difficulties, and pain syndrome. Coconut oil (CO) is an edible oil obtained from the meat of Cocos nucifera fruit that belongs to the palm family and contains 92% saturated fatty acids. CO has been shown to mediate oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis and excitotoxicity-induced effects in PD in various in vitro and in vivo models as a multi-target bioagent. CO intake through diet has also been linked to a decreased incidence of PD in people. During digestion, CO is broken down into smaller molecules, like ketone bodies (KBs). The KBs then penetrate the blood–brain barrier (BBB) and are used as a source of energy its ability to cross BBB made this an important class of natural remedies for the treatment of ND. The current review describes the probable neuroprotective potential pathways of CO in PD, either prophylactic or therapeutic. In addition, we briefly addressed the important pathogenic pathways that might be considered to investigate the possible use of CO in neurodegeneration such as AD and PD.
... In recent years, approaches of click chemistry 3 and bioorthogonal chemistry 4 have been widely applied in drug delivery, broadly defined, with very exciting results. Along this line, there have been reviews addressing specific aspects of click chemistry in drug delivery including cell engineering and drug delivery 5 ; cell tracking and tissue engineering 6 ; polymers, dendrimers, and hydrogels for drug delivery 7 ; as well as other general topics 8e10 . ...
Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls.
... This might be the reason for an obsolete opinion that dendrimer fabrication is complicated, sluggish, and expensive. However, many recent changes have been made to improve and accelerate the formulation of dendrimers that include but not limited to the use of (1) orthogonal chemistries to eliminate the necessity for group safety and thus to minimize the numerous reaction steps; (2) advanced "click" synthesis for irrevocable, rapid, and high-yielding processes; and (3) hyper-cores and hyper-monomers for rapid increment in the size [78][79][80][81][82]. ...
18.1 Introduction Cancer is the second predominant cause of mortality, after cardiovascular diseases, emphasizing the significance of cancer research [1]. Among all types of cancers, breast cancer remains the leading cause of death in women in developed countries. This is not a common disorder and includes several distinct biochemical entities with varying pathological characteristics and clinical consequences [2]. There is sufficient proof about frequent variations in the biochemical and histological features of breast cancer that have resulted in limited success from the conventional treatment, which emphasizes the need for intensive research and the development of newer therapeutic approaches [3]. Breast carcinoma in women is a highly prevalent disease , affecting 2.1 million individuals per year, leading to the highest proportion of cancer-related mortality. As reported, nearly 627,000 people died due to breast cancer, around 15% of all cancer-related mortality among women, in 2018 [4]. Although breast cancer incidence is significantly higher among women in developed countries, incidence rates have also increased in almost every corner of the globe. Physicians usually experience many challenges during breast cancer diagnosis and therapy. Such problems include understanding and collating between data from various medical imaging modalities, which classify cancers and anticipate the fate of tumor cells during different clinical stagging techniques [5]. The existing breast cancer treatment methodology involves chemotherapy, which prompts the shrinking of cancerous cells. This is accompanied by surgical intervention to excise tumor cells andfollowed by hormonal treatment, radiation CHAPTER Targeted Nanomedicine for Breast Cancer Therapy. https://doi.
... 148 The idea was to confine the whole range of chemical transformations to a set of reactions with a high thermodynamic driving force, allowing the efficient and easy transformation of "spring-loaded" starting materials into new structures with useful properties. 149 The impact of click chemistry has been significant in polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. 150 Among the click reactions, the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) has emerged as the archetypal example owing to its high orthogonality, and reactivity and regioselectivity, leading exclusively to 1,4-disubstituted 1,2,3-triazoles. ...
... Polymer Chemistry use of biorthogonal coupling reactions, namely the strain-promoted azide-alkyne cycloaddition or thiol-ene, among others, represents a powerful strategy for the synthesis and covalent decoration of dendrimers in the absence of metal catalysts, additives and organic solvents. 149 The possibility of developing biocompatible and biodegradable smart dendrimer-containing LbL nanoassemblies is particularly attractive for the nanoencapsulation of living cells, aiming to protect them and their cargo from extreme conditions in the biological environment and enable their on-demand delivery at the target site. Furthermore, those smart biocompatible and biodegradable nanoassemblies also open new pathways in coating core-shell particles and produce hollow multilayered nano/micro-capsules able to bind and release payloads on-demand and be used for cellular uptake. ...
Dendrimers are powerful synthetic macromolecular architectures for a wide variety of bioapplications owing to their unique and superior features, including monodispersity, well-defined and highly branched architecture, multivalency, tunable size and shape, good water solubility, bioavailability, and precisely controllable size at the nanometer-scale. However, the cationic and higher-generation dendrimers have generally proven to raise cytotoxicity concerns, which leads to the disruption of cell membranes and cell death, thus extensively limiting their use. Hence, the chemical functionalization of dendrimers’ surface with desired functional moieties and their incorporation within supramolecular Layer-by-Layer (LbL) assemblies has been reported as an effective strategy to circumvent the safety issues and improve their biological performance. Herein, we systematically review the multitude of intermolecular interactions behind the build-up of supramolecular dendrimer-containing multifunctional LbL nanoensembles with improved properties and enhanced functionalities for being used in a wide variety of bioapplications. We envisage that such diversity of intermolecular interactions may increase the number of building blocks that can be combined with dendrimers and processed into robust supramolecular multifunctional nanoarchitectures across multiple length scales well-suited to be applied in biological and biomedical scenarios, including in controlled drug/therapeutics/nucleic acid delivery, gene therapy, biosensing, bioimaging, and tissue engineering and regenerative medicine. The review also provides a glimpse on the integration of the bottom-up LbL assembly technology with other bottom-up or top-down approaches for shaping increasingly complex and sophisticated dendrimer-based supramolecular multifunctional devices with high capability for being translated into practical bioapplications.
... Bioorthogonal reactions rely on introduction into the polymers of functional groups different from those found in amino acid side chains, able to chemoselectively react in mild conditions with high yields. Among them, the so-called click chemistry [24][25][26][27], based, for example, on Huisgen-type cycloaddition [28], Staudinger reaction [29,30], Diels-Alder [31][32][33], thiol-ene addition [34,35], and carbonyl/oxime-hydrazone chemistry [36,37], has been proposed over recent years. The main drawback of bioorthogonal reactions arises from the need for a two-step process, involving first the introduction of orthogonal functional groups, either by chemical or enzymatic reactions [38] or protein engineering [39] approaches. ...
Gelatin is a costless polypeptide material of natural origin, able to form hydrogels that are potentially useful in biomaterial scaffold design for drug delivery, cell cultures, and tissue engineering. However, gelatin hydrogels are unstable at physiological conditions, losing their features only after a few minutes at 37 °C. Accordingly, treatments to address this issue are of great interest. In the present work, we propose for the first time the use of bi- and trifunctional tetrazoles, most of them unknown to date, for photoinduced gelatin cross-linking towards the production of physiologically stable hydrogels. Indeed, after UV-B irradiation, aryl tetrazoles generate a nitrilimine intermediate that is reactive towards different functionalities, some of them constitutively present in the amino acid side chains of gelatin. The efficacy of the treatment strictly depends on the structure of the cross-linking agent used, and substantial improved stability was observed by switching from bifunctional to trifunctional cross-linkers.
... 53,199 A related challenge is the modification of the polymer material, for which it can be difficult to create multifunctionalized structures that have the cargo and ligands in precise proportions and binding sites. 200 This can cause a need for optimizing peptide conjugations to ensure both the peptide and the cargo maintain their original functionality. ...
Polymeric biomaterials have been used in a variety of applications, like cargo delivery and tissue scaffolding, because they are easily synthesized and can be adapted to many systems. However, there is still a need to further enhance and improve their functions to progress their use in the biomedical field. A promising solution is to modify the polymer surfaces with peptides that can increase biocompatibility, cellular interactions, and receptor targeting. In recent years, peptide modifications have been used to overcome many challenges to polymer biomaterial development. This review discusses recent progress in developing peptide-modified polymers for therapeutic applications including cell-specific targeting and tissue engineering. Furthermore, we will explore some of the most frequently studied base components of these biomaterials.
... To provide modularity, we propose a synthetic route involving a PEG-alkyne intermediate scaffold. In this way, the desired functional group or biomolecule can be easily incorporated into the polymerisable unit by means of the Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) [38,39], (Fig. 1). Multivalency will be therefore achieved through the polymerization of a well-characterised carbohydrate-derivative monomer. ...
Carbohydrate multivalent interactions play a key role in nature as efficient recognition tools for controlling a plethora of physiological and pathological events. These interactions are weak but the presence of multiple copies of ligands and receptors on biological surfaces leads to a multivalent recognition with enhanced selectivity and exponentially increased affinity. Here we report a simple and straightforward methodology for multivalent presentation of both simple monosaccharide ligands and complex dendritic glycostructures using polymeric nanogels (NGs). The interaction between the glycoNGs and a model lectin has been analysed by DLS and UV–Vis agglutination assays, showing that the introduction of glycodendrons with 3 and 9 mannose residues into the NGs results in a strong enhancement of the multivalency.
... For example, CuAAC allows for facile labelling of particles, polymers, and biomolecules such as enzymes and proteins. [35][36][37][38][39] Several reports have used CuAAC for the functionalization of large branched, grafted, and globular polymers, 37 but very few are found for the functionalization of short-chain mPEG. ...
... For example, CuAAC allows for facile labelling of particles, polymers, and biomolecules such as enzymes and proteins. [35][36][37][38][39] Several reports have used CuAAC for the functionalization of large branched, grafted, and globular polymers, 37 but very few are found for the functionalization of short-chain mPEG. ...
Many small-molecule drugs exhibit poor aqueous solubility, and various approaches have been developed to improve the solubility and delivery. Chemical conjugation of an insoluble drug to a hydrophilic polymer can...
