Superselective Targeting Using Multivalent Polymers

Dubacheva, Galina V.; Curk, Tine; Mognetti, Bortolo Matteo; Auzély‐Velty, Rachel; Frenkel, Daan; Richter, Ralf P.

doi:10.1021/ja411138s

Cited by 98 publications

(178 citation statements)

References 26 publications

(55 reference statements)

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“…This aspect of multivalency has recently been described by Frenkel and co-workers and could explain a faster than linear increase of cellbound nanogels with the density of available mannose ligands. [59][60][61] Such trend appears in our present work but requires more in depth investigation.…”

supporting

confidence: 75%

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting

Coen¹,

Vanparijs

Risseeuw³

et al. 2016

Biomacromolecules

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We report on the design of glycosylated nanogels via core-cross-linking of amphiphilic non-watersoluble block copolymers composed of an acetylated glycosylated block and a pentafluorophenyl (PFP) activated ester block prepared by RAFT polymerization. Self-assembly, pH-sensitive corecross-linking and removal of remaining PFP esters and protecting groups is achieved in one-pot yielding fully hydrated sub-100 nm nanogels. Using cell subsets that exhibit high and low expression of the mannose receptor under conditions that suppress active endocytosis, we show that mannosylated but not galactosylated nanogels can efficiently target the mannose receptor (MR) that is expressed on the cell surface of primary dendritic cells (DCs). These nanogels hold promise for immunological applications involving DCs and macrophage subsets.

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supporting

confidence: 75%

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting

Coen¹,

Vanparijs

Risseeuw³

et al. 2016

Biomacromolecules

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“…The box size in the vertical z direction is sufficiently large to ensure that none of the particles ever interacts with the hard ceiling or the floor. The simulations started with the particle center of mass at height R + σ above the membrane and were run for 6·10 6 cycles, where in each cycle on average one translational/rotational move per every bead and particle is attempted.…”

Section: Methodsmentioning

confidence: 99%

“…Such selectivity can be achieved by exploiting multivalency. A series of recent experimental and theoretical papers have shown that multivalent carriers (nanoparticles or polymers) can distinguish target surfaces (cells) on the basis of their receptor concentration, rather than just on the basis of the presence of a suitable receptor (5)(6)(7)(8)(9).…”

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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“…For example, investigations of multivalent binding of polymers to surfaces lacked specificity [e.g., due to polymer-polymer interactions (14,15)] and suffered from poor experimental control over the density of ligands/ receptors on polymer (10, 11) and surface (14,15). With a welldefined model system based on host-guest interactions, we recently overcame these limitations and provided, to our knowledge, the first quantitative experimental demonstration of superselective binding of multivalent polymers to surfaces (16).…”

mentioning

confidence: 99%

Designing multivalent probes for tunable superselective targeting

Dubacheva

Curk

Auzély‐Velty

et al. 2015

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

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Specific targeting is common in biology and is a key challenge in nanomedicine. It was recently demonstrated that multivalent probes can selectively target surfaces with a defined density of surface binding sites. Here we show, using a combination of experiments and simulations on multivalent polymers, that such "superselective" binding can be tuned through the design of the multivalent probe, to target a desired density of binding sites. We develop an analytical model that provides simple yet quantitative predictions to tune the polymer's superselective binding properties by its molecular characteristics such as size, valency, and affinity. This work opens up a route toward the rational design of multivalent probes with defined superselective targeting properties for practical applications, and provides mechanistic insight into the regulation of multivalent interactions in biology. To illustrate this, we show how the superselective targeting of the extracellular matrix polysaccharide hyaluronan to its main cell surface receptor CD44 is controlled by the affinity of individual CD44-hyaluronan interactions.tunability | superselectivity | host-guest multivalent interactions | hyaluronan

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Superselective Targeting Using Multivalent Polymers

Cited by 98 publications

References 26 publications

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting

pH-Degradable Mannosylated Nanogels for Dendritic Cell Targeting

Optimal multivalent targeting of membranes with many distinct receptors

Designing multivalent probes for tunable superselective targeting

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