Synthesis and Biological Evaluation of a Bioresponsive and Endosomolytic siRNA−Polymer Conjugate

Meyer, Martin; Dohmen, Christian; Philipp, Alexander; Kiener, Daniel; Maiwald, G.; Scheu, Christina; Ogris, Manfred; Wagner, Ernst

doi:10.1021/mp9000124

Cited by 165 publications

(139 citation statements)

References 43 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…However, liposomes have not been the only platform used for delivering siRNA. Polymeric micelles [542][543][544][545][546], polymer conjugates [547][548][549][550], and polymeric nanoparticles [551][552][553][554][555][556][557] have also shown promising efficacy as non-viral carriers for the delivery of siRNAs in the treatment of different diseases.…”

Section: C) Polymeric Nanoparticles In Cancer Gene Therapymentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,460

754

View full text Add to dashboard Cite

Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vasculatization and, in time, adquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastasic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, like the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic Código de campo cambiado

show abstract

Section: C) Polymeric Nanoparticles In Cancer Gene Therapymentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,460

754

View full text Add to dashboard Cite

show abstract

“…46,55 The successful modification and reversibility of the disulfide bonds are documented in Supporting Information, Figure S1.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Sequence Defined Disulfide-Linked Shuttle for Strongly Enhanced Intracellular Protein Delivery

2012

Self Cite

View full text Add to dashboard Cite

Intracellular protein transduction technology is opening the door for a promising alternative to gene therapy. Techniques have to address all critical steps, like efficient cell uptake, endolysosomal escape, low toxicity, while maintaining full functional activity of the delivered protein.Here, we present the use of a chemically precise, structure defined threearm cationic oligomer carrier molecule for protein delivery. This carrier of exact and low molecular weight combines good cellular uptake with efficient endosomal escape and low toxicity. The protein cargo is covalently attached by a bioreversible disulfide linkage. Murine 3T3 fibroblasts could be transduced very efficiently with cargo nlsEGFP, which was tagged with a nuclear localization signal. We could show subcellular delivery of the nlsEGFP to the nucleus, confirming cytosolic delivery and expected subsequent subcellular trafficking. Transfection efficiency was concentration-dependent in a directly linear mode and 20-fold higher in comparison with HIV-TAT-nlsEGFP containing a functional TAT transduction domain. Furthermore, β-galactosidase as a model enzyme cargo, modified with the carrier oligomer, was transduced into neuroblastoma cells in enzymatically active form.

show abstract

“…Different types of covalent conjugates of siRNA with cationic polymers have been synthesized, with the polycations neutralizing the negative oligonucleotide charges and, after cellular uptake by endocytosis, promoting escape from endosomes into the cytosol. 26,27 Such 'dynamic polyconjugates' (Fig. 3B) may incorporate several functions (targeting ligands, surface shielding with poly(ethylene glycol) (PEG), endosomolytic domains), however present structures significantly larger than a single siRNA molecule.…”

Section: The Chemistry Approachmentioning

confidence: 99%

Biomaterials in RNAi therapeutics: quo vadis?

Wagner

2013

Biomater. Sci.

Self Cite

View full text Add to dashboard Cite

The fifteen years of utilizing RNAi present a surprise story, ranging from the unexpected discovery and publication of RNA interference in 1998, rewarded by the nobel prize in 2006, the introduction of synthetic short siRNAs for the specific gene silencing in mammalian cells in 2001, or the discovery of more than 1600 human microRNAs naturally regulating about one third of our genes. Therapeutic applications started amazingly fast and resulted in the first recent successes in therapy. Synthetic siRNAs are under evaluation for knocking down disease-associated target mRNAs, microRNA mimics for turning on or antagonists (antagomirs) for turning off microRNA activity. Modified oligonucleotides comprise a special class of therapeutics with a new chemical profile; the precise synthetic molecules are much smaller than protein or gene vector drugs, but they are larger than conventional drugs and thus cannot passively diffuse into their target cells. The main current strategies for solving the delivery problem are discussed.We now face the interesting question of alternative future directions: should oligonucleotide molecules be chemically further minimized into small drug-like chemical entities? Or should multiple RNAi molecules be wrapped up into larger virus-like nanoparticles for delivery? Biomaterials in therapeutic RNA interference, quo vadis?

show abstract

Synthesis and Biological Evaluation of a Bioresponsive and Endosomolytic siRNA−Polymer Conjugate

Cited by 165 publications

References 43 publications

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Sequence Defined Disulfide-Linked Shuttle for Strongly Enhanced Intracellular Protein Delivery

Biomaterials in RNAi therapeutics: quo vadis?

Contact Info

Product

Resources

About