Imporved biological activity of antisense oligonucleotides conjugated to a fusogenic peptide

Bongartz, J P; Aubertin, Anne-Marie; Milhaud, Pierre G.; Lebleu, Bernard

doi:10.1093/nar/22.22.4681

Cited by 153 publications

(95 citation statements)

References 37 publications

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“…Strategies that can enable rapid release of contents from tissue-accumulated or cellular-internalized liposomes for molecular targeting must be developed. In combination with fusogenic peptide (Bongartz et al, 1994) or releasing agents to trigger intracellular drug release, CPP may still be able to improve the antitumor activity of liposomal drugs. In addition, many antibodies and their derivative immunoliposomes cannot be internalized (Goren et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Translocation of Liposomes into Cancer Cells by Cell-Penetrating Peptides Penetratin and Tat: A Kinetic and Efficacy Study

2002

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Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide-and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 g/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.

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Section: Discussionmentioning

confidence: 99%

Translocation of Liposomes into Cancer Cells by Cell-Penetrating Peptides Penetratin and Tat: A Kinetic and Efficacy Study

2002

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“…On a molecular level, significant research has been devoted toward creating materials incorporating peptides and oligonucleotides because these types of chimeric structures have been shown to increase the knockdown of target proteins (34)(35)(36)(37)(38)(39)(40)(41)(42)(43). However, molecular methods of preparing these materials are relatively inefficient, limit sequence diversity because of incompatible chemistries, require orthogonal protecting groups on nucleosides and amino acids (44), and can generate undesired side products (45).…”

mentioning

confidence: 99%

Peptide antisense nanoparticles

Patel

Giljohann

Seferos

et al. 2008

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

103

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We have designed a heterofunctionalized nanoparticle conjugate consisting of a 13-nm gold nanoparticle (Au NP) containing both antisense oligonucleotides and synthetic peptides. The synthesis of this conjugate is accomplished by mixing thiolated oligonucleotides and cysteine-terminated peptides with gold nanoparticles in the presence of salt, which screens interactions between biomolecules, yielding a densely functionalized nanomaterial. By controlling the stoichiometry of the components in solution, we can control the surface loading of each biomolecule. The conjugates are prepared easily and show perinuclear localization and an enhanced gene regulation activity when tested in a cellular model. This heterofunctionalized structure represents a new strategy for preparing nanomaterials with potential therapeutic applications.gene regulation ͉ gold nanoparticles ͉ heterofunctional

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“…Peptides derived from the N-terminal sequence of the influenza virus hemagglutinin subunit HA-2, or prepared synthetically, such as GALA or KALA are pH-sensitive fusogenic, which can use the acidic pH of the endosome to induce their rupture (545,546). These peptides change conformation at acidic pH and destabilize the endosomal membrane resulting in an increased cytoplasmic delivery of ODNs.…”

Section: Fusogenic Peptide Conjugationmentioning

confidence: 99%

“…These peptides change conformation at acidic pH and destabilize the endosomal membrane resulting in an increased cytoplasmic delivery of ODNs. Bongartz et al (545) conjugated a peptide derived from HA-2 to an antisense PO-ODN targeting the AUG initiation site of the HIV TAT protein via a disulfide or thioether bond and observed as 5 to 10 fold improvement of the anti HIV activities, respectively. However, no sequence specificity was obtained and the fusogenic peptide possessed some antiviral activities on its own (IC50: 6 μM).…”

Section: Fusogenic Peptide Conjugationmentioning

confidence: 99%

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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Imporved biological activity of antisense oligonucleotides conjugated to a fusogenic peptide

Cited by 153 publications

References 37 publications

Translocation of Liposomes into Cancer Cells by Cell-Penetrating Peptides Penetratin and Tat: A Kinetic and Efficacy Study

Translocation of Liposomes into Cancer Cells by Cell-Penetrating Peptides Penetratin and Tat: A Kinetic and Efficacy Study

Peptide antisense nanoparticles

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

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