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Click Chemistry for Drug Delivery Nanosystems

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

“The reaction must be modular wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific (but not necessarily enantioselective). The required process characteristics include simple reaction conditions (ideally, the process should be insensitive to oxygen and water), readily available starting materials and reagents, the use of no solvent or a solvent that is benign (such as water) or easily removed, and simple product isolation. Purification—if required—must be by nonchromatographic methods, such as crystallization or distillation, and the product must be stable under physiological conditions… Click processes proceed rapidly to completion and also tend to be highly selective for a single product: we think of these reactions as being “spring-loaded” for a single trajectory”. H. C. Kolb, M. G. Finn and K. B. Sharpless. Angew. Chem., Int. Ed. 40: 2004–2021 (2001).

ABSTRACT

The purpose of this Expert Review is to discuss the impact of click chemistry in nanosized drug delivery systems. Since the introduction of the click concept by Sharpless and coworkers in 2001, numerous examples of click reactions have been reported for the preparation and functionalization of polymeric micelles and nanoparticles, liposomes and polymersomes, capsules, microspheres, metal and silica nanoparticles, carbon nanotubes and fullerenes, or bionanoparticles. Among these click processes, Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) has attracted most attention based on its high orthogonality, reliability, and experimental simplicity for non-specialists. A renewed interest in the use of efficient classical transformations has been also observed (e.g., thiol-ene coupling, Michael addition, Diels-Alder). Special emphasis is also devoted to critically discuss the click concept, as well as practical aspects of application of CuAAC to ensure efficient and harmless bioconjugation.

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Abbreviations

AAC:

azide-alkyne cycloaddition

AgNP:

silver nanoparticle

AIBN:

azobisisobutyronitrile

Alk:

alkyne

ATRP:

atom transfer radical polymerization

AuNP:

gold nanoparticle

Az:

azide

BNP:

bionanoparticle

BPDS:

bathophenanthroline disulphonated disodium salt

CD:

cyclodextrin

CMC:

critical micelle concentration

CNT:

carbon nanotube

CPMV:

cowpea mosaic virus

CTA:

chain transfer agent

CuAAC:

Cu(I)-catalyzed azide-alkyne cycloaddition

DBU:

1,8-diazabicyclo[5.4.0]undec-7-ene

DDS:

drug delivery system

DIPEA:

N,N-diisopropylethylamine

DOTA:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

DOX:

doxorubicin

EGF:

epidermal growth factor

EGFP:

enhanced green fluorescent protein

EPL:

expressed protein ligation

EPR:

enhanced permeability and retention

FA:

folic acid

FPLC:

fast protein liquid chromatography

FR:

folate receptor

FRET:

fluorescence resonance energy transfer

GFP:

green fluorescent protein

HABA:

2-(4-hydroxyphenylazo)benzoic acid

HEMA:

2-hydroxyethyl methacrylate

LA:

lactic acid

LbL:

layer-by-layer

MAA:

methacrylic acid

MBP:

maltose binding protein

MNP:

magnetic nanoparticle

MRI:

magnetic resonance imaging

MWCNT:

multi-walled carbon nanotube

NHS:

N-hydroxysuccinimide

NP:

nanoparticle

PAA:

poly(acrylic acid)

PACA:

poly(alkyl cyanocrylate)

PBD:

poly(butadiene)

PCL:

poly(ε-caprolactone)

PCN:

polymer-caged nanobin

PDMA:

poly(N,N-dimethylacrylamide)

PEG:

poly(ethylene glycol)

PEI:

poly(ethylene imine)

PEO:

poly(ethylene oxide)

PET:

position emission tomography

PGA:

poly-L-glutamic acid

PIC:

polyion complex

PLL:

poly-L-lysine

PMA:

poly(methacrylate)

PMDETA:

N,N,N′,N′,N″-pentamethyldiethylenetriamine

PMPC:

poly(2-methyl-2-carboxyl-propylene carbonate)

PNIPAM:

poly (N-isopropylacrylamide)

PrMA:

propyl methacrylate

PS:

poly(styrene)

PTMCC:

poly(2-methyl-2-carboxytrimethylene carbonate)

PtNP:

platinum nanoparticle

PTQY:

photoluminescence quantum yield

PVP:

poly(vinyl pyrrolidone)

QD:

quantum dot

RAFT:

reversible addition-fragmentation chain transfer

RGD:

Arg-Gly-Asp

ROS:

reactive oxygen species

SiNP:

silica nanoparticle

SPAAC:

strain-promoted azide-alkyne cycloaddition

SPION:

superparamagnetic iron oxide nanoparticle

STEM:

scanning transmission electron microscopy

SWCNT:

single-walled carbon nanotube

TBTA:

tris(benzyltriazolylmethyl)amine

TCEP:

tris(carboxyethyl)phosphine

TEC:

thiol-ene coupling

THPTA:

tris(hydroxypropyltriazolylmethyl)amine

TMS:

trimethylsilyl

VNP:

viral nanoparticle

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ACKNOWLEDGMENTS & DISCLOSURES

This work was financially supported by the Spanish Ministry of Science and Innovation (CTQ2009-10963 and CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR).

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  1. Department of Organic Chemistry, Center for Research in Biological Chemistry & Molecular Materials (CIQUS), University of Santiago de Compostela, Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain

    Enrique Lallana, Ana Sousa-Herves, Francisco Fernandez-Trillo, Ricardo Riguera & Eduardo Fernandez-Megia

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  1. Enrique Lallana
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Correspondence to Eduardo Fernandez-Megia.

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Lallana, E., Sousa-Herves, A., Fernandez-Trillo, F. et al. Click Chemistry for Drug Delivery Nanosystems. Pharm Res 29, 1–34 (2012). https://doi.org/10.1007/s11095-011-0568-5

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