A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth <i>In vivo</i>

Yagi, Nobuhiro; Manabe, Ichiro; Tottori, Tsuneaki; Ishihara, Atsushi; Ogata, Fusa; Kim, Jong Heon; Nishimura, Satoshi; Fujiu, Katsuhito; Oishi, Yumiko; Itaka, Keiji; Kato, Yasuki; Yamauchi, Masahiro; Nagai, Ryozo

doi:10.1158/0008-5472.can-08-3945

Cited by 88 publications

(71 citation statements)

References 16 publications

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“…To improve the particle size of siRNA and to prevent its degradation by nucleases, nanoparticles (50-200 nm) were specifically designed to mitigate tumor growth in mouse models (56)(57)(58). These nanoparticles, which are formed by conjugating biologically inert polymers directly to siRNA or by preparing liposomes that encapsulate siRNA, were shown to be effective in stabilizing siRNA in the serum.…”

Section: Strategies For Improving the Pharmacokinetics Of Therapeuticmentioning

confidence: 99%

RNA interference therapeutics for cancer: Challenges and opportunities (Review)

Bora¹

2012

Mol Med Report

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Abstract. RNA interference (RNAi) is a sequence-specific, post-transcriptional gene silencing mechanism in animals and plants, which is mediated by double-stranded RNA (dsRNA). There has recently been an increasing interest in harnessing the gene silencing activity of dsRNA to develop novel drugs for the treatment of various diseases, such as cancer, neurological disorders, age-related macular degeneration and viral infections. Small interfering RNA (siRNA)-based drugs have distinct advantages over conventional small molecule or protein-based drugs, including high specificity, higher potency and reduced toxicity. However, there are several technical obstacles to overcome before siRNA-based drugs reach the clinic. Delivery of siRNA to the target tissues and stability in the serum remain a major challenge and are the main focus of current research and development efforts. This review focused primarily on the progress made in developing RNAi as therapeutics for cancer and the challenges associated with its clinical development. Use of ligands recognizing cell-specific receptors to achieve tumor-specific delivery of siRNA, methods for enhanced siRNA delivery, improving the bioavailability and pharmacokinetic properties of siRNA and reducing the off-target effects and non-specific gene silencing are discussed in the light of current evidence.

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Section: Strategies For Improving the Pharmacokinetics Of Therapeuticmentioning

confidence: 99%

RNA interference therapeutics for cancer: Challenges and opportunities (Review)

Bora¹

2012

Mol Med Report

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“…[146][147][148][149] Researchers have recently constrained siRNA between a cationic core composed of DOTAP and an outer lipid bilayer of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol-2000) and egg phosphatidylcholine obtaining a bloodstream circulation time of up to 20 hours after injection. 150 A novel approach has been proposed by Tanaka et al 144 involving a multistage delivery system composed of two biodegradable and biocompatible carriers. The first-stage carriers are mesoporous, microscale, biodegradable silicon particles that enable loading and release of the second-stage nanocarriers, ie, dioleoyl phosphatidylcholine nanoliposomal siRNA.…”

Section: New Combination Approachesmentioning

confidence: 99%

Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy

Gulino¹

2012

IJN

114

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During recent decades there have been remarkable advances and profound changes in cancer therapy. Many therapeutic strategies learned at the bench, including monoclonal antibodies and small molecule inhibitors, have been used at the bedside, leading to important successes. One of the most important advances in biology has been the discovery that small interfering RNA (siRNA) is able to regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). RNAi is one of the most rapidly growing fields of research in biology and therapeutics. Much research effort has gone into the application of this new discovery in the treatment of various diseases, including cancer. However, even though these molecules may have potential and strong utility, some limitations make their clinical application difficult, including delivery problems, side effects due to off-target actions, disturbance of physiological functions of the cellular machinery involved in gene silencing, and induction of the innate immune response. Many researchers have attempted to overcome these limitations and to improve the safety of potential RNAi-based therapeutics. Nanoparticles, which are nanostructured entities with tunable size, shape, and surface, as well as biological behavior, provide an ideal opportunity to modify current treatment regimens in a substantial way. These nanoparticles could be designed to surmount one or more of the barriers encountered by siRNA. Nanoparticle drug formulations afford the chance to improve drug bioavailability, exploiting superior tissue permeability, payload protection, and the "stealth" features of these entities. The main aims of this review are: to explain the siRNA mechanism with regard to potential applications in siRNA-based cancer therapy; to discuss the possible usefulness of nanoparticlebased delivery of certain molecules for overcoming present therapeutic limitations; to review the ongoing relevant clinical research with its pitfalls and promises; and to evaluate critically future perspectives and challenges in siRNA-based cancer therapy.

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“…Of these, the polyethylene glycol (PEG)ylated lipidic systems show promise, with early reports demonstrating their effectiveness in various cancer models. [4][5][6] The formulation procedures used in those studies, however, are labour intensive and require specialized equipments and skills. The resulting end products, being in aqueous states, are also not suitable for longterm storage.…”

Section: Introductionmentioning

confidence: 99%

“…The importance of this was demonstrated in a recently published study on neutral lipid-coated wrapsome formulation. 6 Although their particles exhibited excellent pharamacokinetic profile, with 20% of the particles still circulating in the bloodstream at 24 h after administration, it was found that frequent administration of relatively high dose of siRNA (2.5-7.5 mg kg À1 , 7-10 doses) was required for effective gene-silencing and anti-tumour effect. In contrast to this, we required much lower doses of siRNA to produce a comparable outcome from our HFDM-formulated particles (2 mg kg À1 , three doses) (Figure 5a).…”

Section: Introductionmentioning

confidence: 99%

“…It must be noted, however, that siRNAs were administered into mice when tumour burden was small in our study. Although similar approaches have been used in other studies, 6,32 it is important in the future to establish the optimal treatment time points and dosing schedule for our HFDM-formulated particles in this TC-1 tumour model. This can be achieved via performing a detailed pharmacokinetic and pharmacodynamic study on these particles, which will in turn improve our understanding of the clinical applicability of these siRNA-entrapped HFDM-formulated particles.…”

Section: Introductionmentioning

confidence: 99%

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Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models

Singhania

Burgess

et al. 2010

Gene Ther

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Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA.

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A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo

Abstract: Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the

Cited by 88 publications

References 16 publications

RNA interference therapeutics for cancer: Challenges and opportunities (Review)

RNA interference therapeutics for cancer: Challenges and opportunities (Review)

Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models

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