Analysis of nanoparticle delivery to tumours

Wilhelm, Stefan; Tavares, Anthony J.; Dai, Qing; Ohta, Seiichi; Audet, Julie; Dvorak, Harold F.; Chan, Warren C. W.

doi:10.1038/natrevmats.2016.14

Cited by 4,004 publications

(3,716 citation statements)

References 114 publications

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“…Although the EPR effect has not yet been fully proven in humans, nanoparticles (including small EVs) can escape from the vasculature through leaky endothelial tissue via the EPR effect, and this constitutes an important mechanism for size-dependent “passive targeting” [152,153]. However, according to previous studies of their biodistribution, less than 5% of systemically administered nanoparticles reach tumour tissues [154,155]. Remarkably, most exosomes and small-sized microvesicles distribute to the liver, and less than 2% of the injected vesicles were found to accumulate in tumour tissues after systemic administration [156].…”

Section: Limitations and Factors That Should Be Overcome For The Thermentioning

confidence: 99%

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

Yang

Hong

Cho

et al. 2018

J of Extracellular Vesicle

190

148

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Membrane proteins are of great research interest, particularly because they are rich in targets for therapeutic application. The suitability of various membrane proteins as targets for therapeutic formulations, such as drugs or antibodies, has been studied in preclinical and clinical studies. For therapeutic application, however, a protein must be expressed and purified in as close to its native conformation as possible. This has proven difficult for membrane proteins, as their native conformation requires the association with an appropriate cellular membrane. One solution to this problem is to use extracellular vesicles as a display platform. Exosomes and microvesicles are membranous extracellular vesicles that are released from most cells. Their membranes may provide a favourable microenvironment for membrane proteins to take on their proper conformation, activity, and membrane distribution; moreover, membrane proteins can cluster into microdomains on the surface of extracellular vesicles following their biogenesis. In this review, we survey the state-of-the-art of extracellular vesicle (exosome and small-sized microvesicle)-based therapeutics, evaluate the current biological understanding of these formulations, and forecast the technical advances that will be needed to continue driving the development of membrane protein therapeutics.

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Section: Limitations and Factors That Should Be Overcome For The Thermentioning

confidence: 99%

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

Yang

Hong

Cho

et al. 2018

J of Extracellular Vesicle

190

148

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“…Over the past 20 y many nanoparticle-based targeting methods have been developed. However, thus far, effective tumor drug delivery is hampered by the lack of reliable, unique markers (1,2).…”

mentioning

confidence: 99%

Optimal multivalent targeting of membranes with many distinct receptors

Curk

Dobnikar

Frenkel

2017

Proc. Natl. Acad. Sci. U.S.A.

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Cells can often be recognized by the concentrations of receptors expressed on their surface. For better (targeted drug treatment) or worse (targeted infection by pathogens), it is clearly important to be able to target cells selectively. A good targeting strategy would result in strong binding to cells with the desired receptor profile and barely binding to other cells. Using a simple model, we formulate optimal design rules for multivalent particles that allow them to distinguish target cells based on their receptor profile. We find the following: (i) It is not a good idea to aim for very strong binding between the individual ligands on the guest (delivery vehicle) and the receptors on the host (cell). Rather, one should exploit multivalency: High sensitivity to the receptor density on the host can be achieved by coating the guest with many ligands that bind only weakly to the receptors on the cell surface.(ii) The concentration profile of the ligands on the guest should closely match the composition of the cognate membrane receptors on the target surface. And (iii) irrespective of all details, the effective strength of the ligand-receptor interaction should be of the order of the thermal energy k B T, where T is the absolute temperature and k B is Boltzmann's constant. We present simulations that support the theoretical predictions. We speculate that, using the above design rules, it should be possible to achieve targeted drug delivery with a greatly reduced incidence of side effects.T he fact that most cells can be recognized from the outside is advantageous for the normal functioning of an organism, but it can be a disadvantage when specific cells are being targeted by pathogens. Cells betray their identity (and state of health) by the composition profile of molecules that are exposed on their outer surface. In what follows, we call these molecules "receptors," irrespective of whether they are receptors in the biological sense (they are receptors for the ligands that will be used to recognize them). It would clearly be advantageous if diseased cells could be selectively targeted by a drug-delivery vehicle on the basis of their receptor profile. Here, the crucial word is "selective": We wish to target only those cells that have the correct receptor profile, as binding of drug-delivery vehicles to other cells may lead to undesired side effects.Targeted drug delivery is based on identifying a specific marker (peptide, sugar) that is unique to the targeted group of cells. Binding to a single marker type can be effective if this molecule is presented in sufficient quantities on the outer surface of the targeted cell. However, in many cases of practical importance (e.g., many types of cancer), the markers that are known are not unique to cancer cells, but just overexpressed. Over the past 20 y many nanoparticle-based targeting methods have been developed. However, thus far, effective tumor drug delivery is hampered by the lack of reliable, unique markers (1, 2).To recognize the simultaneous presence of a mixture o...

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“…In general, targeted drug delivery should allow optimal dosages only in disease-affected areas, thus reducing toxic side effects. However, in a specific example of cancer treatment, recent analysis shows that only a small fraction of the administered drug dose is delivered to a solid tumour 26 because of immune system response and organ competition mechanisms that shorten nanoparticle circulation in blood. At the same time, a prolonged circulation could cause premature drug release.…”

Section: Nature Catalysismentioning

confidence: 99%

Magnetic field remotely controlled selective biocatalysis

et al. 2017

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M aterials that efficiently release biological molecules or therapeutic chemicals on demand using exposure to remotely controlled and safe external sources of energy, such as magnetic fields, could find applications for drug delivery 1 , biotechnology 2,3 and biosensors 4 . Because live tissue and synthetic polymers are not responsive to weak magnetic fields, the development of magnetic-field-responsive soft materials has been reported by combining magnetic nanoparticles and stimuli-responsive soft materials 5 . Magnetic nanoparticles interact with magnetic fields and transduce magnetic field energy into physical or chemical changes in the soft material. Materials that control enzymatic processes are one example of such soft materials. Enzymes are extensively used to change or degrade colloidal particles, capsules, and their assemblies to trigger release of the cargo via biocatalytic reactions 6,7 .In all eukaryotes, metabolic pathways are precisely organized and regulated. This precise control is based in part on the high selectivity of biocatalytic reactions and controlled transport of chemicals and biomacromolecules across membranes that compartmentalize cells, organelles and organs. Highly selective biocatalysis alone cannot orchestrate complex systems of biochemical reactions without the supporting role of signal-triggered synthesis, release, secretion, conversion and degrading processes that take place in different compartments in cells and organs. Despite being highly selective, enzymes cannot provide 100% selectivity. In particular, enzymes could interact with a number of substrates of a similar chemical structure (for example, proteases are highly promiscuous catalysts), be degraded by other enzymes or even by self-digestion upon secretion into a complex biological environment, or undergo undesired aggregation, crystallization or nonspecific adsorption, which would strongly damage the efficiency of the biocatalytic process. However, the overall high specificity of biocatalytic processes is strengthened by localizing the enzymatic reactions within a specific environment and spatial compartments.Inspired by this hierarchical design in live systems, diverse stimuli-responsive functional materials have been reported, involving various architectures that respond to changes in magnetic fields [8][9][10] . However, it remains challenging to create a reactive system that preserves enzyme molecules from destructive environments and undesired interactions while being able to initiate the designated reaction when needed. Different approaches have been developed to preserve enzymes for storage and delivery before activating them on demand in a magnetic field at the targeted location. A number of studies aimed at controlling the kinetics of biocatalytic reactions in model systems [11][12][13][14][15] have explored magnetic-field-triggered changes of the local concentration and mobility of enzymes. However, it is difficult to apply many of such approaches to live tissue because of limitations associated with degradat...

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Analysis of nanoparticle delivery to tumours

Cited by 4,004 publications

References 114 publications

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

Optimal multivalent targeting of membranes with many distinct receptors

Magnetic field remotely controlled selective biocatalysis

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