Illkirch-graffenstaden, France
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Behr J.-P.,University of Strasbourg | Behr J.-P.,Polyplus-transfection
Accounts of Chemical Research | Year: 2012

The discovery of RNA interference has given a new lease on life to both the chemistry of oligonucleotides and chemical approaches for the intracellular delivery of nucleic acids. In particular, delivery of siRNA, whether in vitro for screening and target validation purposes or in humans as a new class of drugs, may revolutionize our approach to therapy. Their impact could equal that of the bioproduction and various uses of monoclonal antibodies today. Unfortunately, global pharmaceutical companies again seem to be waiting to buy the next Genentech or Genzyme of gene silencing rather than investing research and development into this promising area of research.Gene silencing encounters barriers similar to gene addition and hence may benefit from the extra decade of experience brought by gene therapy. "Chemical" transfection of cells in culture has become routine, and this Account discusses some of the reasons this success has not extended to nonviral gene therapy trials, most of which do not progress beyond the phase 2 stage. The author also discusses a (much debated) mechanism of nucleic acid cell entry and subsequent release of the polycationic particles into the cytoplasm. Both topics should be useful to those interested in delivery of siRNA.The move from gene therapy toward siRNA as an oligonucleotide-based therapy strategy provides a much wider range of druggable targets. Even though these molecules are a hundredfold smaller than a gene, they are delivered via similar cellular mechanisms. Their complexes with cationic polymers are less stable than those with a higher number of phosphate groups, which may be compensated by siRNA concatemerization or by chemical conjugation with the cationic carrier. Thus chemistry is again desperately needed. © 2012 American Chemical Society.

French National Center for Scientific Research, University of Strasbourg and Polyplus-transfection | Date: 2015-06-22

The invention relates to oligonucleotide-oligocation molecules A_(i)B_(j)H that can be synthetized via automated phosphoramidite chemistry having oligonucleotides moieties Ai and oligocations moieties Bj, wherein .A_(i )is an i-mer oligonucleotide residue, with i=5 to 50, where nucleotide A is an oligomer with naturally or non naturally occurring nucleobases and/or pentafuranosyl groups and/or native phosphodiester bonds, for example selected from the group comprising deoxyribo, ribo, locked (LNA) nucleotides as well as their chemical modifications or substitutions such as phosphorothioate, 2-fluoro, 2-O-alkyl, or a marker group such as a fluorescent agent, .Bj is a j-mer organic oligocation moiety, with j=1 to 50, where B is selected from the group comprising .HPO_(3)R^(1)(XR^(2)_(n))_(n1)XR^(3)O, where R^(1), R^(2)n and R^(3), identical or different, are lower alkylene, X is NH or NC(NH_(2))_(2), n varies from 1 to 5 and n1=2 to 20, .HPO_(3)R^(4)CH(R^(5)X^(1))R^(6)O, where R^(4 )is lower alkylene, R^(5 )and R^(6), identical or different, are lower alkylene and X^(1 )is putrescine, spermidine or spermine residue, .HPO_(3)R^(7)-(aa)_(n2)-R^(8)O, where R^(7 )is lower alkylene and R^(8 )is lower alkylene, serine, a natural aminoalcohol, (aa)_(n2 )is a peptide containing natural aminoacids with cationic side chains, such as Arginine, Lysine, Ornithine, -Histidine, Diaminopropionic acid and n2=2 to 20.

Transfection is an integral equipment used in investigation studies for gene function and the modulation of gene expression. Thus, it contributes in the advancement of basic cellular research, drug discovery, and target validation. The transfection reagent and equipment market is driven by rising prevalence of infectious disease, utilization of biopharmaceuticals in the production of proteins, growing obese population, and increasing prevalence of cancer. Various government initiative accentuated the growth of transfection reagent and equipment market. However, high cost of transfection reagents and equipment, risk factors during insertion of the reagents and cytotoxic effect associated with transfection technology are the major factors restraining the transfection reagents and equipment market. Transfection is a process that involves production of genetically modified cells with utilization of foreign nucleic acid (DNA and RNA). This technology helps the cells in mutation of cancer cells, protein metabolism by affecting the nuclear genes and regulation of gene therapy. The transfection reagent and equipment market can be segmented on the basis of various methods such as physical methods and biochemical methods. The biochemical method accounts for the largest share in the overall transfection market. The biochemical based method is further segmented as calcium phosphate, DEAE-dextran, lipid mediated transfection (Lipofection), catonic polymers, activated dendrimers and magnetic beads. The physical based method includes electroporation, biolistic technology, microinjection, laserfection and others (gene gun, sonoporation). Electroporation technique is likely to account for the largest share in the equipment based transfection. The transfection reagent market, by application is segmented into biomedical research, protein product, and therapeutic delivery. The biomedical research segment was observed as one of the largest segment of the transfection reagent market. Geographically, North America is the largest transfection reagents and equipment market in the world due to rising prevalence of various cancers (such as cervical cancer, breast cancer, colon cancer, and prostate cancer). Moreover, rising demand for proteomics and genomics technology and upfront initiatives taken by government related to preventive healthcare have supported the growth of transfection reagents and equipment market in this region. Europe was the second largest market due to rising trend of utilization of targeted drug delivery, nanomedicine in diagnostics, clinical trials and drug development studies drive the demand of transfection reagents and equipment market. Asia-Pacific is observed to be an emerging market in transfection reagents and equipment market and is still in the initial stage. One of the important factors driving the growth of transfection reagent and equipment in the Asia-Pacific market is outsourcing of clinical trials to Asian countries by majority of the drug development companies. Moreover, development of in transfection technology, rise in demand of protein therapeutics, developing healthcare infrastructure in emerging markets such as India and China, and increasing demand from applied markets. Latin American countries such as Brazil and Mexico are the regions that have significant potential for growth due to emerging medical infrastructure, high disposable income and rising prevalence of infectious diseases. Transfection equipment and reagents market is in introductory stage especially in Latin American and African countries. Some of the major players in the global transfection reagent and equipment market include Thermo Fisher Scientific, Inc. (U.S.), Promega Corporation (U.S.), Roche Holding AG (Switzerland), Qiagen N.V. (Netherlands), Polyplus-transfection SA (France), Bio-Rad Laboratories (U.S.), Lonza Group (Switzerland), Sigma-Aldrich Corporation (U.S.), Mirus Bio LLC (U.S.), and Maxcyte Inc.(U.S.) others.

Kedinger V.,Polyplus-transfection | Meulle A.,Polyplus-transfection | Zounib O.,Polyplus-transfection | Bonnet M.-E.,Polyplus-transfection | And 7 more authors.
BMC Cancer | Year: 2013

Background: Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.Methods: We used our newly developed sticky siRNA-based technology delivered with linear polyethyleneimine (PEI) to inhibit the expression of survivin and cyclin B1 both in vitro and in vivo, and addressed the effect of this inhibition on B16-F10 murine melanoma tumor development.Results: We confirm that survivin and cyclin B1 downregulation through a RNA interference mechanism induces a blockage of the cell cycle as well as impaired proliferation of B16-F10 cells in vitro. Most importantly, PEI-mediated systemic delivery of sticky siRNAs against survivin and cyclin B1 efficiently blocks growth of established subcutaneaous B16-F10 tumors as well as formation and dissemination of melanoma lung metastases. In addition, we highlight that inhibition of survivin expression increases the effect of doxorubicin on lung B16-F10 metastasis growth inhibition.Conclusion: PEI-mediated delivery of sticky siRNAs targeting genes involved in tumor progression such as survivin and cyclin B1, either alone or in combination with chemotherapeutic drugs, represents a promising strategy for melanoma treatment. © 2013 Kedinger et al.; licensee BioMed Central Ltd.

Yu T.,Wuhan University | Yu T.,Aix - Marseille University | Liu X.,Wuhan University | Liu X.,Aix - Marseille University | And 7 more authors.
Angewandte Chemie - International Edition | Year: 2012

An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimer vectors to deliver a heat shock protein?27 siRNA and produce potent gene silencing and anticancer activity in?vitro and in?vivo in a prostate cancer model (see picture). This dendrimer can be used alternatively for treating various diseases.

Bonnet M.-E.,Polyplus-transfection | Gossart J.-B.,Polyplus-transfection | Benoit E.,Polyplus-transfection | Messmer M.,IBMC | And 8 more authors.
Journal of Controlled Release | Year: 2013

RNA interference allows the design of new inhibitors that target deregulated pathways in cancer. However systemic delivery of siRNA for the treatment of solid tumors still remains an issue. In our study, in order to suppress the progression of lung cancer metastasis in mice, we developed sticky siRNA (ssiRNA) to inhibit survivin and cyclin B1, two candidates involved in cell survival and proliferation. We exploited the linear polyethylenimine (PEI) as potent non-viral carrier to efficiently deliver our inhibitors. As a proof of concept, we have chosen a very aggressive mammary adenocarcinoma model (TSA-Luc cells), which forms lung metastases upon systemic cell injection. We confirmed in vitro, that the ssiRNAs delivered with PEI are not only able to inhibit our target genes at the mRNA and protein levels, but are also able to block the cell cycle and cell proliferation through a mechanism of RNA interference. More importantly, we showed in vivo by luciferase dosage, bioimaging and tissue section, an inhibition of lung tumor metastases after systemic delivery of cyclin B1 and survivin ssiRNA complexed with PEI. Alternating treatment with cisplatin and ssiRNA/PEI showed an additive effect between the two anticancer drugs on lung tumor inhibition leading to a significant increase in animal survival. Moreover a promising window between activity (IC50) and toxic-ity (LD50), essential for therapeutic application, was observed. Our data show that systemic delivery of ssiRNA/PEI complexes targeting the cell cycle is a valuable strategy for the treatment of lung tumor metastasis and that it can be combined with chemotherapy. © 2013 Elsevier B.V. All rights reserved.

Polyplus-transfection | Date: 2010-05-11

Synthetic molecules, namely, synthetic nucleotides and synthetic nucleic acids for scientific research and for laboratory analyses other than for medical or veterinary purposes; diagnostic preparations other than for medical or veterinary purposes; reagents as ingredients of diagnostic products, namely, diagnostic reagents for research use other than for medical or veterinary purposes. Synthetic molecules, namely, synthetic nucleotides and synthetic nucleic acids for medical and veterinary purposes, diagnostic preparations for medical and veterinary use; reagents as ingredients of diagnostic products, namely, diagnostic reagents for medical and veterinary purposes; [ reagents as ingredients of therapeutic products for human and animal use, namely, pharmaceutical and veterinary reagents; reagents as ingredients of vaccination products, namely, vaccines, vaccine adjuvants, vaccine stabilizers; ] chemical reagents for medical or veterinary purposes including for the purposes of medical or veterinary research. [ Software used for the structural design of synthetic molecules, namely, synthetic nucleotides and synthetic nucleic acids; magnetic or optical data media, namely, magnetic disks, optical disks, CD-ROMs, USB sticks being USB hardware, and computer hard discs all containing data concerning the structural design of synthetic molecules, namely, synthetic nucleotides and synthetic nucleic acids ].

Polyplus-transfection | Date: 2014-07-01

The invention relates to compositions comprising double-stranded oligonucleotides of identical or different sequences and/or length, said oligonucleotides having sequences ^(3)N_(1)N_(2 ). . . N_(i-1)N_(i ). . . N_(j)^(5 )wherein^(3)N_(i ). . . N_(j)^(5 )is half of a double-stranded 19-28 mer oligonucleotide of sequence complementary to a target nucleic acid sequence present in a living cell, and^(3)N_(1 ). . . N_(i-1)^(5 )is a 3-50 mer overhang of sequence allowing oligomerisation of said double-stranded oligonucleotide. Compositions of transfection comprising said oligonucleotide compositions and there used for therapeutical application.

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