Synthesis and characterization of novel poly(ethylene glycol)-lipid conjugates suitable for use in drug delivery

Heyes, James; Hall, Kim; Tailor, Vicky; Lenz, Richard; MacLachlan, Ian

doi:10.1016/j.jconrel.2006.02.012

Cited by 105 publications

(66 citation statements)

References 40 publications

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“…Mean SNALP particle sizes were 72 (0.04 polydispersity) and 72 (0.02 polydispersity) nm for PLK1424-2/A and LUC-U/U, respectively. tions with the C18 analogue PEG-cDSA (50). All SNALP were dialyzed in PBS prior to use and were stable as a wet preparation stored at 4°C for greater than 6 months.…”

Section: Methodsmentioning

confidence: 99%

Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice

Judge¹,

Robbins²,

Tavakoli³

et al. 2009

J. Clin. Invest.

Self Cite

307

251

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siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics.

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Section: Methodsmentioning

confidence: 99%

Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice

Judge¹,

Robbins²,

Tavakoli³

et al. 2009

J. Clin. Invest.

Self Cite

307

251

View full text Add to dashboard Cite

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“…103,104 Finally, the presence of PEG in liposome formulations prevents aggregation, favors the formation of small, monodisperse particles, and increases the EPR effect, due to the extended circulation time and escape from the RES. 105 The practical consequences of these phenomena are evident when the biopharmaceutical profiles of Stealth liposomes and conventional liposomes are contemplated. Stealth liposomes have a longer half-life (which leads to longer blood-circulation times), low systemic plasma clearance, and low volume of distribution (minimal interaction with nondiseased tissue).…”

Section: Liposomes In Nanomedicinementioning

confidence: 99%

Liposomes as nanomedical devices

Bozzuto¹,

Molinari²

2015

IJN

1,794

1,114

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Since their discovery in the 1960s, liposomes have been studied in depth, and they continue to constitute a field of intense research. Liposomes are valued for their biological and technological advantages, and are considered to be the most successful drug-carrier system known to date. Notable progress has been made, and several biomedical applications of liposomes are either in clinical trials, are about to be put on the market, or have already been approved for public use. In this review, we briefly analyze how the efficacy of liposomes depends on the nature of their components and their size, surface charge, and lipidic organization. Moreover, we discuss the influence of the physicochemical properties of liposomes on their interaction with cells, half-life, ability to enter tissues, and final fate in vivo. Finally, we describe some strategies developed to overcome limitations of the “first-generation” liposomes, and liposome-based drugs on the market and in clinical trials.

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“…[27] reported that the pharmacokinetics of the lipid nanoparticles (LNPs) with an ionizable aminolipid, which is largely neutral but changes to a cationic form under acidic conditions, was improved compared to that with a conventional cationic lipid. The LNPs system also succeeded in tumor specific reporter gene expression, and gene silencing in orthotopic and subcutaneous tumors [28,29].…”

Section: Introductionmentioning

confidence: 99%

A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo

Sato

Hatakeyama

Sakurai

et al. 2012

Journal of Controlled Release

273

277

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Modification of liposomal siRNA carriers with polyethylene glycol, i.e., PEGylation, is a generally accepted strategy for achieving in vivo stability and delivery to tumor tissue. However, PEGylation significantly inhibits both cellular uptake and the endosomal escape process of the carriers. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for siRNA delivery and peptide-based functional devices for overcoming the limitations and succeeded in the efficient delivery of siRNA to tumors. In this study, we synthesized a pH-sensitive cationic lipid, YSK05, to overcome the limitations. The Collectively, these data confirm that YSK05 facilitates the endosomal escape of the MEND and thereby enhances the efficacy of siRNA delivery into cytosol and gene silencing.

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Synthesis and characterization of novel poly(ethylene glycol)-lipid conjugates suitable for use in drug delivery

Cited by 105 publications

References 40 publications

Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice

Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice

Liposomes as nanomedical devices

A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo

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