A liquid crystalline phase in spermidine-condensed DNA

Over a large range of salt and spermidine concentrations, short DNA fragments precipitated by spermidine (a polyamine) sediment in a pellet from a dilute isotropic supernatant. We report here that the DNA-condensed phase consists of a cholesteric liquid crystal in equilibrium with a more concentrated phase. These results are discussed according to Flory's theory for the ordering of rigid polymers. The liquid crystal described here corresponds to an ordering in the presence of attractive interactions, in contrast with classical liquid crystalline DNA. Polyamines are often used in vitro to study the functional properties of DNA. We suggest that the existence of a liquid crystalline state in spermidine-condensed DNA is relevant to these studies

Non-conventional trans-platinum complexes functionalized with RDG peptides: chemical and cytototoxicity studies

In order to target platinum complexes to cancer cells, trans-Pt(II) or trans-Pt(IV) complexes were bioconjugated to the cyclic peptide cRGDfK (cRGD), with affinity for αvβ3 integrin receptors, through their 4-picolinic acid spectator ligands. To tackle this goal, the Pt(II) and Pt(IV) precursors were activated at their carboxylic acid function and futher reacted with the cRGDfK peptide, to afford the bioconjugates Pt(II)-cRGD and Pt(IV)-cRGD, respectively. Pt(II)-cRGD was studied by 195Pt-NMR that confirmed the presence of the Pt(II) center. In contrast, the characterization of Pt(IV)-cRGD was not possible due to the tendency of this complex to undergo reduction to Pt(II) in solution. Thus, only the Pt(II)-cRGD complex was used for further biological studies, and it exhibited some cytotoxic activity against the HUVEC cell line, with the highest levels of αvβ3 expression. However, no improved effects were observed with respect to the Pt(II)-pic precursor. Studies by ICP-MS showed enhanced intracellular accumulation for Pt(II)-cRGD with respect to Pt(II)-pic in cancer cells. Overall, these results show that while Pt(II) bioconjugation enhances compound's uptake, it did not translate into an increase in cytotoxicity

Drug development in oncology assisted by noninvasive optical imaging.

International audienceEarly and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology

Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells

Invited for the cover of this issue is Olivier Renaudet and co-workers at the Université Grenoble Alpes and funded by the European Research Council (CoG “LEGO′” no. 647938). The image illustrates a synthetic chemist playing with supramolecular structures to kill cancer cells by using natural antibodies present in the blood stream. Read the full text of the article at 10.1002/chem.201903327

Impact of antigen density on recognition by monoclonal antibodies

Understanding antigen-antibody interactions is important to many emerging medical and bioanalytical applications. In particular, the levels of antigen expression at the cell surface may determine antibody-mediated cell death. This parameter has a clear effect on outcome in patients undergoing immunotherapy. In this context, CD20 which is expressed in the membrane of B cells has received significant attention as target for immunotherapy of leukemia and lymphoma using the monoclonal antibody rituximab. To systematically study the impact of CD20 density on antibody recognition, we designed self-assembled monolayers that display tunable CD20 epitope densities. For this purpose, we developed in situ click chemistry to functionalize SPR sensor chips. We find that the rituximab binding affinity depends sensitively and non-monotoneously on CD20 surface density. Strongest binding, with an equilibrium dissociation constant (KD = 32 nM) close to values previously reported from in vitro analysis with B cells (apparent KD between 5 and 19 nM), was obtained for an average inter-antigen spacing of 2 nm. This distance is required for improving rituximab recognition, and in agreement with the known requirement of CD20 to form clusters to elicit a biological response. More generally, this study offers an interesting outlook in the understanding of the necessity of epitope clusters for effective mAb recognition

Synthesis and photophysical studies of a multivalent photoreactive RuII-calix[4]arene complex bearing RGD-containing cyclopentapeptides

peer reviewe

PET imaging of αvβ3 integrin expression in tumours with 68Ga-labelled mono-, di- and tetrameric RGD peptides

Contains fulltext : 97195.pdf (publisher's version ) (Closed access)PURPOSE: Due to the restricted expression of alpha(v)beta(3) in tumours, alpha(v)beta(3) is considered a suitable receptor for tumour targeting. In this study the alpha(v)beta(3)-binding characteristics of (68)Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their (111)In-labelled counterparts. METHODS: A monomeric (E-c(RGDfK)), a dimeric (E-[c(RGDfK)](2)) and a tetrameric (E{E[c(RGDfK)](2)}(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (68)Ga. In vitro alpha(v)beta(3)-binding characteristics were determined in a competitive binding assay. In vivo alpha(v)beta(3)-targeting characteristics of the compounds were assessed in mice with subcutaneously growing SK-RC-52 xenografts. In addition, microPET images were acquired using a microPET/CT scanner. RESULTS: The IC(50) values for the Ga(III)-labelled DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2) and DOTA-E{E[c(RGDfK)](2)}(2) were 23.9 +/- 1.22, 8.99 +/- 1.20 and 1.74 +/- 1.18 nM, respectively, and were similar to those of the In(III)-labelled mono-, di- and tetrameric RGD peptides (26.6 +/- 1.15, 3.34 +/- 1.16 and 1.80 +/- 1.37 nM, respectively). At 2 h post-injection, tumour uptake of the (68)Ga-labelled mono-, di- and tetrameric RGD peptides (3.30 +/- 0.30, 5.24 +/- 0.27 and 7.11 +/- 0.67%ID/g, respectively) was comparable to that of their (111)In-labelled counterparts (2.70 +/- 0.29, 5.61 +/- 0.85 and 7.32 +/- 2.45%ID/g, respectively). PET scans were in line with the biodistribution data. On all PET scans, the tumour could be clearly visualised. CONCLUSION: The integrin affinity and the tumour uptake followed the order of DOTA-tetramer > DOTA-dimer > DOTA-monomer. The (68)Ga-labelled tetrameric RGD peptide has excellent characteristics for imaging of alpha(v)beta(3) expression with PET

Molecular imaging of angiogenesis with SPECT

Single-photon emission computed tomography (SPECT) and position emission tomography (PET) are the two main imaging modalities in nuclear medicine. SPECT imaging is more widely available than PET imaging and the radionuclides used for SPECT are easier to prepare and usually have a longer half-life than those used for PET. In addition, SPECT is a less expensive technique than PET. Commonly used gamma emitters are: 99mTc (Emax 141 keV, T1/2 6.02 h), 123I (Emax 529 keV, T1/2 13.0 h) and 111In (Emax 245 keV, T1/2 67.2 h). Compared to clinical SPECT, PET has a higher spatial resolution and the possibility to more accurately estimate the in vivo concentration of a tracer. In preclinical imaging, the situation is quite different. The resolution of microSPECT cameras (<0.5 mm) is higher than that of microPET cameras (>1.5 mm). In this report, studies on new radiolabelled tracers for SPECT imaging of angiogenesis in tumours are reviewed

Design of peptide vectors through chemoselective ligations

International audienceThe identification of molecular markers that can differentiate a tumor from healthy tissue is essential for the development of more successful diagnostic methods and more effective antitumoral agents. Integrins such as αVβ3 are attractive therapeutic targets as these receptors are cell surface proteins that are highly expressed on tumor microenvironment. A characteristic feature of this receptor is its high binding affinity for the ubiquitous triad sequence arginine-glycine-aspartic acid (RGD). The design of numerous RGD-containing cyclopeptides has led to highly selective synthetic ligands with enhanced binding affinities.1 We have shown that clustered RGD-containing compounds offer an interesting outlook for biological applications. These compounds are based on a cyclic decapeptide scaffold containing two independent functional domains: (I) a clustered ligand domain and (II) an effector domain for supplementary function. Access to such biomolecular compounds may become a challenging task. We recently developed methodologies using chemoselective ligations to achieve sophisticated macromolecules 2 with desirable biological properties such as tumor imaging, drug delivery and cell capture.3____[1] M. Pfaff, K. Tangemann, B. Müller, M. Gurrath, G. Müller, H. Kessler, R. Timpl and J. Engel, J. Biol. Chem. 1994, 269, 20233 ; W. Arap, R. Pasqualini and E. Ruoslahti, Science 1998, 279, 377.[2] M. Galibert, O. Renaudet, P. Dumy, and D. Boturyn, Angew. Chem. Int. Ed. 2011, 50, 1901.[3] C. H. F. Wenk, F. Ponce, S. Guillermet, C. Tenaud, D. Boturyn, et al., Cancer Lett. 2013, 334, 188 ; A. Karageorgis, M. Claron, R. Jugé, C. Aspord, C. Leloup, et al., Mol. Ther. 2017, 25, 534 ; M. Degardin, D. Thakar, M. Claron, R. P. Richter, L. Coche-Guérente and D. Boturyn. J. Mat. Chem. B 2017, 5, 4745

Design and synthesis of peptide vectors: towards antibody mimics

International audienc