FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2071770842> ?p ?o ?g. }

• W2071770842 endingPage "855" @default.
• W2071770842 startingPage "853" @default.
• W2071770842 abstract "NanomedicineVol. 4, No. 8 EditorialFree AccessRNAi nanoparticles in the service of personalized medicineRanit Kedmi and Dan PeerRanit KedmiLaboratory of Nanomedicine, Department of Cell Research & Immunology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel and Center for Nanoscience & Nanotechnology, Tel Aviv University, Tel Aviv, 69978, IsraelSearch for more papers by this author and Dan Peer† Author for correspondenceLaboratory of Nanomedicine, Department of Cell Research & Immunology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel and Center for Nanoscience & Nanotechnology, Tel Aviv University, Tel Aviv, 69978, Israel. Search for more papers by this authorEmail the corresponding author at peer@post.tau.ac.ilPublished Online:4 Dec 2009https://doi.org/10.2217/nnm.09.74AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit The understanding of cancer molecular origins and the different intracellular signaling pathways that are perturbed in the various types of malignancies have laid the foundation to realize why patients react diversely to therapy. For example, in colon cancer, an efficient treatment of EGF-receptor blockade with monoclonal antibody was found not to benefit patients with tumors positive for the K-ras mutation [1]. This slowly but steadily brought a shift from a ‘one size fits all’ therapy approach to a more personalized attitude, in which each patient is treated according to their tumor-specific genetic defects. To support this new approach, a substantial effort is invested in developing a new class of molecular diagnostic tools identifying patients’ tumor-personal gene-expression signatures, as well as mutation profiles.RNA interference (RNAi) is a is a ubiquitous, highly specific, endogenous mechanism of gene silencing that can be activated by incorporating small interfering (si)RNAs into the cell cytoplasm to reduce gene-expression level in a sequence-specific manner. siRNA represents a drug platform, owing to its sequence-specific gene silencing that enables the use of different sequences to reduce distinct genes while keeping the chemical similarity of synthetic 19–21 nucleotide RNA duplexes. In addition, siRNAs can reduce gene expression from the mutated allele whilst keeping the normal one active [2], therefore, siRNAs are extremely suitable as a drug platform in personalized cancer therapy. However, major obstacles concerning systemic delivery and intracellular off-target effects, as well as immune response, hindered the desired therapeutic goal, bringing uncertainty to its realization. Owing to the poor cellular uptake of naked siRNA and rapid serum RNase clearance, systemic nanocarriers have been developed. The most widely used vehicles are based on positively charged reagents, which encapsulate or complex with the negatively charged nucleic acid. Electrostatic interactions between the carriers and the cell membrane enable intracellular entrance, typically by endocytosis, which requires siRNA release from the endosome to the cytoplasm. Still, accumulating evidence indicates a response of the innate immune system for such particles, leading to toxicity associated with extreme cytokine release. The siRNA entry into the endosome where Toll-like receptor (TLR)7/8 are present probably activates the immune response through the NF-κB pathway by upregulating expression of IFN-α and proinflammatory cytokines. Using a broad-based siRNA screening strategy, it was demonstrated that TLR7/8 immunogenicity is determined mainly by siRNA sequence motifs and thermodynamic properties of the duplexes [3]. However, chemical modifications of the siRNA duplexes, such as 2´-O-methyl uridines, are recognized with high affinity by TLR7/8, but do not induce downstream signaling and can be used to completely avoid the immune effects [4–6]. siRNA can also be recognized by TLR3, which is located in intracellular compartments, such as the endosome [7], or on the surface of certain cell types, such as blood endothelial cells. Although it was thought that TLR3 initiates signals in response to virus-derived dsRNA with a minimal length of 40–50 bp [8], Kleinman et al. showed in endothelial cells that TLR3 is activated by 21 nucleotide siRNA [9]. The TLR3 pathway is functional in different types of tumors and its activation shows various and even opposing effects. Mainly, it was found to induce a type-I interferon response as well as inflammatory cytokine and chemokine production. In addition to TLR-based systems, mammalian cells have evolved a number of non-TLR mechanisms induced by dsRNA-binding protein kinase or retinoic acid-inducible gene 1 proteins that are reviewed elsewhere [10,11]. Most published work concerning the innate immune response of siRNA disregards the off-target effect of using carriers to deliver siRNA. In cell culture models, the carrier is used for siRNA internalization to the cell cytoplasm, while in animal models the carrier is responsible for systemic delivery, coping with greater challenges besides internalization, such as rapid RNA clearance and targeting the carrier to a particular cell type in a specific tissue. Recent evidence indicates that cationic lipids, which have been extensively used as carriers, activate various cellular cascades, including the activation of inflammatory TLR4 signaling by diC14-amidine liposomes [12], increased expression of dendritic cell costimulatory molecules, CD80 and CD86 [13], and upregulation of CCL2, -3 and -4 chemokine genes caused by treatment with DOTAP, a cationic lipid [14] (for a detailed review see [15]). These indications necessitate a revisit of previous conclusions regarding siRNA triggering an immune response, owing to the use of such cationic carriers. Increasing our knowledge on the exact influence of different carriers on various tumors may lead to a wise exploitation of transporters in personalized cancer therapy. Divergent side effects caused by carriers can, in some tumors, promote tumor aggressiveness, while in others they might reduce malignancy and actually contribute to the therapeutic outcome. Chronic inflammation has long been identified to be associated with cancer. Ex vivo TLR4 triggering by lipopolysaccharides in human head and neck squamous cell carcinoma supports cancer progression by promoting tumor cell proliferation and inducing tumor cell resistance to drug-mediated apoptosis [16,17]. However, there are indications that cationic liposome side effects might support cancer therapy. For example, certain cationic lipids elevate intracellular calcium, which is known to function in the regulation of cell death [18,19] and, hence, might be used to eradicate tumor cells [20]. Induction of the CCL3 gene by cationic carriers might also be used to promote therapy in certain tumors. Nakashima et al. demonstrated reduced tumorigenicities in vivo in adenocarcinoma cells transfected with CCL3 [21]. Others have demonstrated that CCL3 plays a role in multiple myeloma progression as a downstream target of FGF receptor 3 [22]. This reflects the complexity and variability in using cationic carriers in cancer therapy. Therefore, a detailed intensive study should be conducted to examine the effect of various cationic carriers on different categories of tumors in distinct individuals.An additional strategy for dealing with a carrier’s off-target effect is to engineer nontoxic immune-privilege carriers. We have recently constructed liposomes made from neutral phospholipids and coated with hyaluronan, a naturally accruing glycosaminoglycan, in order to prevent an immune response. The hyaluronan coating endows these carriers with long-circulating properties and stabilizes the carriers in vivo. The hyaluronan coating was also used as a scaffold for monoclonal antibody binding to direct the carriers to specific leukocyte cell type [23].Distinct classes of tumors and the variations between individuals facilitate the need for personalized medicine. In fact, a higher level of complexity relies on tumor subpopulation composition. Cells in the tumor differ in their function and contribution, as well as in their gene expression, mutation profile and cell-surface markers. Such subpopulations may include cancer stem cells [24], metastatic cells, as well as cells from the microenvironment contributing to tumor progression, such as macrophages [25]. The future vision for siRNA-based personalized medicine is a specific cell-type therapy, in which a range of carriers encapsulated with different siRNA sequences will tackle the tumor subpopulations by exploiting the different cell surface markers to release a distinct cargo best suited for those specific cells in a particular patient.Financial & competing interests disclosureThis work was supported by grants from the Alon Foundation (D Peer), Marie Curie IRG FP07, European Union (D Peer) and the Lewis family trust for Cancer Research (D Peer). R Kedmi is a recipient of the Stem Cell PhD Fellowship (Tel Aviv University, Israel). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Jiang Y, Kimchi ET, Staveley-O’Carroll KF, Cheng H, Ajani JA: Assessment of K-ras mutation: a step toward personalized medicine for patients with colorectal cancer. Cancer115,3609–3617 (2009).Crossref, Medline, CAS, Google Scholar2 Zhang Z, Jiang G, Yang F, Wang J: Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells. Cancer Biol. Ther.5,1481–1486 (2006).Crossref, Medline, CAS, Google Scholar3 Goodchild A, Nopper N, King A et al.: Sequence determinants of innate immune activation by short interfering RNAs. BMC Immunol.10,40 (2009).Crossref, Medline, Google Scholar4 Tluk S, Jurk M, Forsbach A et al.: Sequences derived from self-RNA containing certain natural modifications act as suppressors of RNA-mediated inflammatory immune responses. Int. Immunol.21,607–619 (2009).Crossref, Medline, CAS, Google Scholar5 Sioud M, Furset G, Cekaite L: Suppression of immunostimulatory siRNA-driven innate immune activation by 2´-modified RNAs. Biochem. Biophys. Res. Commun.361,122–126 (2007).Crossref, Medline, CAS, Google Scholar6 Judge AD, Bola G, Lee AC, MacLachlan I: Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol. Ther.13,494–505 (2006).Crossref, Medline, CAS, Google Scholar7 Fukuda K, Watanabe T, Tokisue T et al.: Modulation of double-stranded RNA recognition by the N-terminal histidine-rich region of the human toll-like receptor 3. J. Biol. Chem.283,22787–22794 (2008).Crossref, Medline, CAS, Google Scholar8 Liu L, Botos I, Wang Y et al.: Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science320,379–381 (2008).Crossref, Medline, CAS, Google Scholar9 Kleinman ME, Yamada K, Takeda A et al.: Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature452,591–597 (2008).Crossref, Medline, CAS, Google Scholar10 Robbins M, Judge A, MacLachlan I: siRNA and innate immunity. Oligonucleotides19,89–102 (2009).Crossref, Medline, CAS, Google Scholar11 Judge A, MacLachlan I: Overcoming the innate immune response to small interfering RNA. Hum. Gene Ther.19,111–124 (2008).Crossref, Medline, CAS, Google Scholar12 Tanaka T, Legat A, Adam E et al.: DiC14-amidine cationic liposomes stimulate myeloid dendritic cells through Toll-like receptor 4. Eur. J. Immunol.38,1351–1357 (2008).Crossref, Medline, CAS, Google Scholar13 Vangasseri DP, Cui Z, Chen W, Hokey DA, Falo LD Jr, Huang L: Immunostimulation of dendritic cells by cationic liposomes. Mol. Membr. Biol.23,385–395 (2006).Crossref, Medline, CAS, Google Scholar14 Yan W, Chen W, Huang L: Mechanism of adjuvant activity of cationic liposome: phosphorylation of a MAP kinase, ERK and induction of chemokines. Mol. Immunol.44,3672–3681 (2007).Crossref, Medline, CAS, Google Scholar15 Lonez C, Lensink MF, Vandenbranden M, Ruysschaert JM: Cationic lipids activate cellular cascades. Which receptors are involved?. Biochim. Biophys. Acta1790,425–430 (2009).Crossref, Medline, CAS, Google Scholar16 Szczepanski MJ, Czystowska M, Szajnik M et al.: Triggering of Toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res.69,3105–3113 (2009).Crossref, Medline, CAS, Google Scholar17 Huang B, Zhao J, Li H et al.: Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res.65,5009–5014 (2005).Crossref, Medline, CAS, Google Scholar18 Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R: Calcium and apoptosis: ER–mitochondria Ca2+ transfer in the control of apoptosis. Oncogene27,6407–6418 (2008).Crossref, Medline, CAS, Google Scholar19 Ouali M, Ruysschaert JM, Lonez C, Vandenbranden M: Cationic lipids involved in gene transfer mobilize intracellular calcium. Mol. Membr. Biol.24,225–232 (2007).Crossref, Medline, CAS, Google Scholar20 Jackisch C, Hahm HA, Tombal B et al.: Delayed micromolar elevation in intracellular calcium precedes induction of apoptosis in thapsigargin-treated breast cancer cells. Clin. Cancer Res.6,2844–2850 (2000).Medline, CAS, Google Scholar21 Nakashima E, Oya A, Kubota Y et al.: A candidate for cancer gene therapy: MIP-1α gene transfer to an adenocarcinoma cell line reduced tumorigenicity and induced protective immunity in immunocompetent mice. Pharm. Res.13,1896–1901 (1996).Crossref, Medline, CAS, Google Scholar22 Masih-Khan E, Trudel S, Heise C et al.: MIP-1a (CCL3) is a downstream target of FGFR3 and RAS–MAPK signaling in multiple myeloma. Blood108,3465–3471 (2006).Crossref, Medline, CAS, Google Scholar23 Peer D, Park EJ, Morishita Y, Carman CV, Shimaoka M: Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science319,627–630 (2008).Crossref, Medline, CAS, Google Scholar24 Read TA, Fogarty MP, Markant SL et al.: Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell15,135–147 (2009).Crossref, Medline, CAS, Google Scholar25 Kim S, Takahashi H, Lin WW et al.: Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature457,102–106 (2009).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByAnti-viral RNAi nanoparticles protect shrimp against white spot disease1 January 2018 | Molecular Systems Design & Engineering, Vol. 3, No. 1Mechanisms of cellular uptake and endosomal escape of calcium-siRNA nanocomplexesInternational Journal of Pharmaceutics, Vol. 515, No. 1-2Multifunctional Nanoparticles for Personalized Medicine1 February 2012Promise and Challenge of RNA Interference–Based Therapy for CancerJournal of Clinical Oncology, Vol. 29, No. 6Induction of therapeutic gene silencing in leukocyte-implicated diseases by targeted and stabilized nanoparticles: A mini-reviewJournal of Controlled Release, Vol. 148, No. 1The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activationBiomaterials, Vol. 31, No. 26RNAi nanomedicines: challenges and opportunities within the immune system13 May 2010 | Nanotechnology, Vol. 21, No. 23 Vol. 4, No. 8 STAY CONNECTED Metrics History Published online 4 December 2009 Published in print December 2009 Information© Future Medicine LtdFinancial & competing interests disclosureThis work was supported by grants from the Alon Foundation (D Peer), Marie Curie IRG FP07, European Union (D Peer) and the Lewis family trust for Cancer Research (D Peer). R Kedmi is a recipient of the Stem Cell PhD Fellowship (Tel Aviv University, Israel). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
• W2071770842 created "2016-06-24" @default.
• W2071770842 creator A5038855686 @default.
• W2071770842 creator A5045716103 @default.
• W2071770842 date "2009-12-01" @default.
• W2071770842 modified "2023-09-28" @default.
• W2071770842 title "RNAi nanoparticles in the service of personalized medicine" @default.
• W2071770842 cites W1488201155 @default.
• W2071770842 cites W1493051695 @default.
• W2071770842 cites W1975499385 @default.
• W2071770842 cites W1992517046 @default.
• W2071770842 cites W2004062771 @default.
• W2071770842 cites W2016014815 @default.
• W2071770842 cites W2016806021 @default.
• W2071770842 cites W2020368715 @default.
• W2071770842 cites W2027268325 @default.
• W2071770842 cites W2029271422 @default.
• W2071770842 cites W2034277378 @default.
• W2071770842 cites W2038660811 @default.
• W2071770842 cites W2039023207 @default.
• W2071770842 cites W2042368231 @default.
• W2071770842 cites W2043693109 @default.
• W2071770842 cites W2054139397 @default.
• W2071770842 cites W2058914749 @default.
• W2071770842 cites W2060056553 @default.
• W2071770842 cites W2114208662 @default.
• W2071770842 cites W2131243283 @default.
• W2071770842 cites W2131387907 @default.
• W2071770842 cites W2142414417 @default.
• W2071770842 cites W2150736048 @default.
• W2071770842 cites W2161091841 @default.
• W2071770842 doi "https://doi.org/10.2217/nnm.09.74" @default.
• W2071770842 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19958219" @default.
• W2071770842 hasPublicationYear "2009" @default.
• W2071770842 type Work @default.
• W2071770842 sameAs 2071770842 @default.
• W2071770842 citedByCount "9" @default.
• W2071770842 countsByYear W20717708422012 @default.
• W2071770842 countsByYear W20717708422016 @default.
• W2071770842 countsByYear W20717708422018 @default.
• W2071770842 crossrefType "journal-article" @default.
• W2071770842 hasAuthorship W2071770842A5038855686 @default.
• W2071770842 hasAuthorship W2071770842A5045716103 @default.
• W2071770842 hasConcept C104317684 @default.
• W2071770842 hasConcept C144133560 @default.
• W2071770842 hasConcept C162853370 @default.
• W2071770842 hasConcept C166703698 @default.
• W2071770842 hasConcept C2780378061 @default.
• W2071770842 hasConcept C32220436 @default.
• W2071770842 hasConcept C41008148 @default.
• W2071770842 hasConcept C54355233 @default.
• W2071770842 hasConcept C60644358 @default.
• W2071770842 hasConcept C67705224 @default.
• W2071770842 hasConcept C86803240 @default.
• W2071770842 hasConceptScore W2071770842C104317684 @default.
• W2071770842 hasConceptScore W2071770842C144133560 @default.
• W2071770842 hasConceptScore W2071770842C162853370 @default.
• W2071770842 hasConceptScore W2071770842C166703698 @default.
• W2071770842 hasConceptScore W2071770842C2780378061 @default.
• W2071770842 hasConceptScore W2071770842C32220436 @default.
• W2071770842 hasConceptScore W2071770842C41008148 @default.
• W2071770842 hasConceptScore W2071770842C54355233 @default.
• W2071770842 hasConceptScore W2071770842C60644358 @default.
• W2071770842 hasConceptScore W2071770842C67705224 @default.
• W2071770842 hasConceptScore W2071770842C86803240 @default.
• W2071770842 hasIssue "8" @default.
• W2071770842 hasLocation W20717708421 @default.
• W2071770842 hasLocation W20717708422 @default.
• W2071770842 hasOpenAccess W2071770842 @default.
• W2071770842 hasPrimaryLocation W20717708421 @default.
• W2071770842 hasRelatedWork W2071770842 @default.
• W2071770842 hasRelatedWork W2148069575 @default.
• W2071770842 hasRelatedWork W2166284356 @default.
• W2071770842 hasRelatedWork W2237638674 @default.
• W2071770842 hasRelatedWork W2349647957 @default.
• W2071770842 hasRelatedWork W2351245884 @default.
• W2071770842 hasRelatedWork W2388091871 @default.
• W2071770842 hasRelatedWork W2531624620 @default.
• W2071770842 hasRelatedWork W4236704548 @default.
• W2071770842 hasRelatedWork W6514224 @default.
• W2071770842 hasVolume "4" @default.
• W2071770842 isParatext "false" @default.
• W2071770842 isRetracted "false" @default.
• W2071770842 magId "2071770842" @default.
• W2071770842 workType "article" @default.