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Nanoparticles and Bioorthogonal Chemistry Joining Forces For Nanoscale Advances View Article Online REVIEW View Journal | View Issue Nanoparticles and bioorthogonal chemistry joining forces for improved biomedical applications Cite this: Nanoscale Adv.,2021,3,1261 ab a ab Javier Idiago-Lopez,´ † Eduardo Moreno-Antol´ın, † Jesus´ M. de la Fuente and Raluca M. Fratila *ab Bioorthogonal chemistry comprises chemical reactions that can take place inside complex biological environments, providing outstanding tools for the investigation and elucidation of biological processes. Its use in combination with nanotechnology can lead to further developments in diverse areas of biomedicine, such as molecular bioimaging, targeted delivery, in situ drug activation, study of cell– nanomaterial interactions, biosensing, etc. Here, we summarise the recent efforts to bring together the unique properties of nanoparticles and the remarkable features of bioorthogonal reactions to create Received 19th October 2020 a toolbox of new or improved biomedical applications. We show how, by joining forces, bioorthogonal Accepted 21st January 2021 chemistry and nanotechnology can overcome some of the key current limitations in the field of DOI: 10.1039/d0na00873g nanomedicine, providing better, faster and more sensitive nanoparticle-based bioimaging and biosensing Creative Commons Attribution-NonCommercial 3.0 Unported Licence. rsc.li/nanoscale-advances techniques, as well as therapeutic nanoplatforms with superior efficacy. 1. Introduction receptors5,6 (active targeting, as opposed to passive accumula- tion of NPs in solid tumours through the enhanced permeation Nanoparticles (NPs) have outstanding physical and chemical and retention -EPR- effect7). It is very oen that both diagnostic properties that have been exploited over the last decades in the and therapeutic functions can be integrated in the same biomedical eld in the quest for advanced tools for the diag- multifunctional nanoplatform, concept known as theragnosis.8 nosis and therapy of various diseases. Some of their unique Moreover, for specic applications (for example, signal ampli- This article is licensed under a optical and magnetic features at the nanoscale enable their use cation for detection or targeted drug delivery purposes), the in detection/biosensing,1 photodynamic therapy or magnetic use of multivalent nanoconjugates with high avidity (high 2,3 density display of biomolecules on the nanoparticle surface) Open Access Article. Published on 21 2021. Downloaded 02/10/2021 12:23:16 . and optical hyperthermia, or as contrast agents in uores- – cence, magnetic resonance, photoacoustic or photo- can be particularly advantageous.9 11 luminescence imaging.1,4 Additionally, suitably engineered NPs Over the past decade, an increasing number of publications (for example liposomes, polymeric or mesoporous NPs) can act reported biomedical applications of nanoparticles based on the as nanocarriers for controlled delivery of therapeutic (bio) use of bioorthogonal chemistries – reactions that can take place molecules,2 providing several advantages over conventional in complex environments, including living systems, with systemic drug delivery, such as high loading capacity, cargo complete specicity and minimal interference with native bio- – protection, improved drug pharmacokinetics, biodistribution logical processes.12 15 Usually, a bioorthogonal reaction involves and bioavailability and controlled release of the cargo (oen the incorporation of a chemical bioorthogonal reporter (see based on the stimuli-responsiveness of the nanocarrier itself). Section 2.2) to the target biomolecule by using the cell's own Besides the use of their intrinsic physicochemical properties, biosynthetic and metabolic mechanisms, followed by covalent many biological and biomedical applications of NPs rely on reaction with an exogenous probe. However, performing bio- their coupling to other molecules, a process known as bio- orthogonal chemistry in vitro and in vivo is not a trivial task, for conjugation. The functionalisation of nanoparticles with rele- several reasons. First, not any chemical motif can function as vant biomolecules (antibodies, aptamers, peptides, a bioorthogonal reporter; in fact, only a handful of them are carbohydrates, etc.) can improve their ability to cross biological truly bioorthogonal (meaning that they do not interfere with barriers and enables specic recognition of cell surface biological functionalities) and possess selective reactivity toward their bioorthogonal partner. Second, bioorthogonal aInstituto de Nanociencia y Materiales de Aragon´ (INMA), CSIC-Universidad de reactions must ful l several stringent requirements, most of “ ” 16 Zaragoza, Zaragoza 50009, Spain. E-mail: [email protected]; [email protected]; which are common to the so-called click reactions. They [email protected]; [email protected] must be water-compatible, not susceptible to the nucleophilic bCentro de Investigacion´ Biom´edica en Red de Bioingenier´ıa, Biomateriales y attack of ubiquitous amine and thiol groups present in Nanomedicina (CIBER-BBN), Spain biomolecules, not sensitive to redox and enzymatic chemistry, † Equal contribution. © 2021 The Author(s). Published by the Royal Society of Chemistry Nanoscale Adv.,2021,3,1261–1292 | 1261 View Article Online Nanoscale Advances Review and must not require heating above 37 C, pressure or the chemistry separately, not so many are available concerning presence of cytotoxic reagents and/or catalysts. Furthermore, biomedical applications involving both bioorthogonal chem- they must be highly selective and have favourable reaction istry and nanotechnology. In our view, this is a eld which will kinetics, given the low concentrations in which many biomol- continue to expand in the coming years and will have a partic- ecules are present inside living systems. To date, diverse bio- ularly strong impact in the development of new or improved orthogonal reactions have proved their usefulness in many biomedical applications. Therefore, in this review we present elds, such as biology, medicine, biomaterials science and our vision on the unique opportunities that the powerful nanotechnology. Examples include in vitro and in vivo imaging combination of bioorthogonal chemistry and nanotechnology of biomolecules (antibodies, enzymes, glycans, etc.),17–19 exo- can provide for bioimaging, biosensing/detection and thera- some20,21 and cell22,23 tracking, nuclear medicine,24,25 manipu- peutic applications. We start by introducing some important lation of protein activity,26 articial cell–cell interactions,27,28 in concepts related to bioorthogonal chemistry, focusing on the vivo tumour targeting,29,30 prodrug activation,31,32 nano- main types of bioorthogonal reporters and bioorthogonal sensing,33 functionalisation of nanomaterials29,34–39 and reactions discussed throughout the review (Section 2). We then biomaterials.40,41 turn our attention to the most promising applications in While plenty of reviews can be found in the literature on the different areas, highlighting relevant examples from the elds topics of biomedical applications of NPs and on bioorthogonal of bioimaging, biosensing/detection and therapy (Section 3). For the sake of clarity and focus, we have curated a selection of representative examples that present clear in vitro and in vivo applications. We apologise in advance for any omission, and we encourage the reader to check Table 1, in which a more comprehensive compilation of references is included. Regarding the biomedical applications herein described, they Creative Commons Attribution-NonCommercial 3.0 Unported Licence. are based on three main combinations of NPs and bio- orthogonal reactions (Fig. 1): (a) “Classical” bioorthogonal in vitro and in vivo coupling of NPs to cells or tissues – in these cases, the living systems are modied to incorporate chemical reporters and the NPs are suitably functionalised with the bioorthogonal partner. (b) Bioorthogonal reactions taking place inside living systems between two building blocks, at least one of them being From left to right : Javier a nanoparticle; they do not necessarily involve a classical This article is licensed under a Idiago-Lo´pez; Jesu´sM: de la labelling of a living system with a bioorthogonal reporter, as in Fuente; Raluca M: Fratila and Eduardo Moreno-Antol´ın the rst case. Note that, in some cases, bioorthogonal reactions falling into this category can be bond-breaking and not bond- Open Access Article. Published on 21 2021. Downloaded 02/10/2021 12:23:16 . Javier Idiago and Eduardo Moreno are currently pursuing their PhD forming reactions (bioorthogonal uncaging, see Section 3.6). under the supervision of Prof Jesus´ M. de la Fuente and Dr (c) Bioorthogonal chemistry approaches for NP functionali- Raluca M. Fratila at Instituto de Nanociencia y Materiales de sation in view of the biomedical application. A comprehensive Aragon´ (INMA, CSIC-University of Zaragoza). Javier's research uses overview of the use of bioorthogonal chemistry for functional- bioorthogonal chemistry for the covalent immobilization of isation of nanomaterials and nanoparticles is beyond the scope magnetic nanoparticles (MNPs) on cell membranes for magnetic of this review; therefore, we only selected examples which are hyperthermia applications. Eduardo works on the development of relevant in light of the biomedical applications of the corre- magnetoliposomes as cell membrane models to study the effect of sponding NPs and we encourage the reader to consult detailed the localised heating produced
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