Dendrimers and nanomedicine: multivalency in action

Rolland, Olivier; Turrin, Cédric‐Olivier; Caminade, Anne‐Marie; Majoral, Jean‐Pierre

doi:10.1039/b901054h

Cited by 177 publications

(136 citation statements)

References 162 publications

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“…Dendrimers are highly branched synthetic polymers that are made using a step-by-step reaction and are highly useful in drug delivery (Rolland et al 2009, Tekade et al 2009). They can be synthesised in a variety of sizes, often referred to as generations, which represent the number of branching points in the polymer from the central core (Tekade et al 2009).…”

Section: Dendrimersmentioning

confidence: 99%

The state-of-play and future of platinum drugs

Apps

Choi

Wheate

2015

Endocrine-Related Cancer

233

142

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The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects.

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Section: Dendrimersmentioning

confidence: 99%

The state-of-play and future of platinum drugs

Apps

Choi

Wheate

2015

Endocrine-Related Cancer

233

142

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“…9 Some dendrimers are both water-soluble and biodegradable such as poly(2,2-bis(hydroxymethyl)-propionic acids (bisMPA), 10 poly(L-lysine) dendrimers (PLL), 11 polyester structures (PGLSA−OH), 12 and polyamidoamine derivatives (PAMAM), 2b among others. 13 For example, a fourth generation polyester dendron attached to a trisphenolic core derived from the monomeric unit bis-MPA has been evaluated for drug delivery applications. 14 Cell proliferation studies have suggested that the dendritic scaffold did not exhibit a significant toxic effect.…”

Section: ■ Introductionmentioning

confidence: 99%

Enhancement of Cytotoxicity by Combining Pyrenyl-Dendrimers and Arene Ruthenium Metallacages

et al. 2012

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Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyr Gn )or alcohol (pyr Gn-OH )( n =1 −3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, 6 (OO∩OO) 3 (tpt) 2 ] 6+ (OO∩OO = 5, [1] 6+ and 6,11-dioxydo-5,12-naphtacenedionato (dotq) [2] 6+ ; tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host−guest properties of [guest⊂1] 6+ and [guest⊂2] 6+ were studied in solution by NMR and UV−vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these watersoluble host−guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells. ■ INTRODUCTIONThe synthesis of dendrimers with defined structures is now well established, 1 employing divergent, 2 convergent, 3 and the somewhat less exploited double-stage convergent 4 routes. Since these routes allow dendrimers to be prepared with precise sizes and shapes, and since dendrimers are relatively easy to functionalize, 5 and possess other interesting properties, 6 they have been studied as potential drug delivery vectors. Water-soluble dendrimers have been shown to improve drug solubility, increase drug circulation time, and prolong drug residence in tumors, thus reducing toxicity. 7 Biodegradability is an important criteria in order to avoid cellular accumulation leading to lysosomal storage disease in patients. 8 Most dendrimers are based on ester or amide linkages which degrade by chemical hydrolysis or enzymatic cleavage under physiological conditions. 9 Some dendrimers are both water-soluble and biodegradable such as poly(2,2-bis(hydroxymethyl)-propionic acids (bisMPA), 10 poly(L-lysine) dendrimers (PLL), 11 polyester structures (PGLSA−OH), 12 and polyamidoamine derivatives (PAMAM), 2b among others. 13 For example, a fourth generation polyester dendron attached to a trisphenolic core derived from the monomeric unit bis-MPA has been evaluated for drug delivery applications. 14 Cell proliferation studies have suggested that the dendritic scaffold did not exhibit a significant toxic effect. The attachment of poly(ethylene glycol) to the surface of this type of dendrimer has also been successful for therapeutic applications, 10b,15 and structure− activity relationships have shown that both generation and steric effect are important. 7 Recently, we have reported the synthesis of host−guest systems composed of water-soluble arene ruthenium metallaprisms and pyrenyl-functionalized dendrimers. 16 In these systems, assessment of the biological activity of the pyrenylfunctionalized dendrimers was not possible due to their hydrophobic nature, and consequently, only the antiproliferative activity of the host−guest systems was evaluated. These studies showed that the host−guest systems inhibit the growth of both sensitive and cisplatin resistant cancer cells (A2780 and A2780cisR) with IC 50 values comparable to those of the empty metallaprisms, thus questioning the role of the den...

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“…drug-delivery | nano-medicine | cancer treatment | guest-host | adsorption O ne of the key challenges in nano-medicine is to acquire the ability to design supramolecular constructs that can target surfaces that display a motif or receptor above a threshold concentration while leaving surfaces with lower coverage of such receptors unaffected (1)(2)(3)(4). Experiments indicate that such selective behavior can be obtained using multivalency (5)(6)(7)(8).…”

mentioning

confidence: 99%

“…Mammen et al (9) recognized the importance of this type of system more than ten years ago. Since then, the concept of multivalency has found numerous applications in cell biology (7,11), supramolecular chemistry (10), nano-medicine (4,6), immunology (12,13), and cancer treatment (2,3,5,14), to name but a few examples. The work of Davis et al (3) provides a striking illustration of selective targeting achieved with multivalency: multivalent siRNA nano-particles administered to human patients were found to be selective in targeting cancer cells because the latter overexpress human-transferringprotein receptors.…”

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confidence: 99%

Designing super selectivity in multivalent nano-particle binding

Martínez-Veracoechea

Frenkel

2011

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

302

479

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A key challenge in nano-science is to design ligand-coated nanoparticles that can bind selectively to surfaces that display the cognate receptors above a threshold (surface) concentration. Nanoparticles that bind monovalently to a target surface do not discriminate sharply between surfaces with high and low receptor coverage. In contrast, "multivalent" nano-particles that can bind to a larger number of ligands simultaneously, display regimes of "super selectivity" where the fraction of bound particles varies sharply with the receptor concentration. We present numerical simulations that show that multivalent nano-particles can be designed such that they approach the "on-off" binding behavior ideal for receptor-concentration selective targeting. We propose a simple analytical model that accounts for the super selective behavior of multivalent nano-particles. The model shows that the super selectivity is due to the fact that the number of distinct ligand-receptor binding arrangements increases in a highly nonlinear way with receptor coverage. Somewhat counterintuitively, our study shows that selectivity can be improved by making the individual ligand-receptor bonds weaker. We propose a simple rule of thumb to predict the conditions under which super selectivity can be achieved. We validate our model predictions against the Monte Carlo simulations.ne of the key challenges in nano-medicine is to acquire the ability to design supramolecular constructs that can target surfaces that display a motif or receptor above a threshold concentration while leaving surfaces with lower coverage of such receptors unaffected (1-4). Experiments indicate that such selective behavior can be obtained using multivalency (5-8). During multivalent interactions a type of particle (henceforth referred to as the "guest") uses multiple ligands to bind simultaneously to several of the receptors displayed by another type of particle or surface (the "host") (9, 10). Mammen et al. (9) recognized the importance of this type of system more than ten years ago. Since then, the concept of multivalency has found numerous applications in cell biology (7, 11), supramolecular chemistry (10), nano-medicine (4, 6), immunology (12, 13), and cancer treatment (2,3,5,14), to name but a few examples. The work of Davis et al. There is a substantial body of theoretical work that aims to explain the pronounced enhancement in binding strength that certain multivalent systems can present in comparison with their monovalent counterparts (15-17). In particular, Kitov and Bundle (18) have pointed out that the strength of multivalent binding can be enhanced if there are many possible permutations in the binding pattern of receptors and ligands. The role of steric repulsion and conformational entropy in multivalent systems have been studied using molecular theories (19) and Monte Carlo (MC) simulations (20, 21). However, a unified picture that explains why high selectivity is observed in some experimental realizations of multivalent systems but not in others is still lacki...

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Dendrimers and nanomedicine: multivalency in action

Cited by 177 publications

References 162 publications

The state-of-play and future of platinum drugs

The state-of-play and future of platinum drugs

Enhancement of Cytotoxicity by Combining Pyrenyl-Dendrimers and Arene Ruthenium Metallacages

Designing super selectivity in multivalent nano-particle binding

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