Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles

Pittella, Frederico; Cabral, Horacio; Maeda, Yoshinori; Mi, Peng; Watanabe, Shigekazu; Takemoto, Hiroyuki; Kim, Hyun Jin; Nishiyama, Nobuhiro; Miyata, Kanjiro; Kataoka, Kazunori

doi:10.1016/j.jconrel.2014.01.008

Cited by 111 publications

(70 citation statements)

References 34 publications

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“…In recent years, great efforts have been made in the development of various siRNA carriers. Polymeric materials [5][6][7][8][9][10][11][12][13][14][15][16][17], liposomes [18,19], inorganic platforms [20] and hybrid systems [21][22][23][24] all showed their potential [25]. However, systemic delivery of siRNA directed to the tumor site remains a major limitation.…”

Section: Introductionmentioning

confidence: 99%

Tumoral gene silencing by receptor-targeted combinatorial siRNA polyplexes

Lee

Kessel

et al. 2016

Journal of Controlled Release

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Section: Introductionmentioning

confidence: 99%

Tumoral gene silencing by receptor-targeted combinatorial siRNA polyplexes

Lee

Kessel

et al. 2016

Journal of Controlled Release

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“…Pittella et al developed a nanoparticle system for siRNA delivery based on calcium phosphate [155, 156]. A PEG-block-charge-conversional polymer (PEG-CCP), which undergoes anionic to cationic conversion in acidic endosomes, forms hybrid micelles with calcium phosphate and siRNA.…”

Section: Inorganic Sirna Delivery Systemsmentioning

confidence: 99%

“…The cationic PEG-CCP destabilizes endosome, and siRNA will be released into cytoplasm. This system was able to deliver about 40-ng siRNA per gram of tumor tissue, and the target gene was silenced in Hela-Luc tumors [156]. Besides those examples discussed above, iron oxide nanoparticles [157] and layered double hydroxide nanoparticles [158] have been employed for siRNA delivery.…”

Section: Inorganic Sirna Delivery Systemsmentioning

confidence: 99%

Recent In Vivo Evidences of Particle-Based Delivery of Small-Interfering RNA (siRNA) into Solid Tumors

Wen

Meng

2014

J Pharm Innov

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Small-interfering RNA (siRNA) is both a powerful tool in research and a promising therapeutic platform to modulate expression of disease-related genes. Malignant tumors are attractive disease targets for nucleic acid-based therapies. siRNA directed against oncogenes, and genes driving metastases or angiogenesis have been evaluated in animal models and in some cases, in humans. The outcomes of these studies indicate that drug delivery is a significant limiting factor. This review provides perspectives on in vivo validated nanoparticle-based siRNA delivery systems. Results of recent advances in liposomes and polymeric and inorganic formulations illustrate the need for mutually optimized attributes for performance in systemic circulation, tumor interstitial space, plasma membrane, and endosomes. Physiochemical properties conducive to efficient siRNA delivery are summarized and directions for future research are discussed.

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“…18 pH-sensitive degradable micelles have attracted great interest for tumor-targeted drug delivery because there exists a natural pH gradient in the tumor microenvironment as well as inside the tumor cells (e.g., in the endo/lysosomal compartments). 19,20 Various pH-sensitive degradable micelles have been developed based on different acid-labile bonds such as ortho ester, 21,22 hydrazone, 23,24 cis-aconitic amide, 25,26 and acetal. 27 In particular, acetal bond is interesting due to its great pH sensitivity.…”

Section: ■ Introductionmentioning

confidence: 99%

Micelles Based on Acid Degradable Poly(acetal urethane): Preparation, pH-Sensitivity, and Triggered Intracellular Drug Release

et al. 2015

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Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degradation. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepared from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-containing diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N-dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with average sizes of about 90-120 nm in water. The dynamic light scattering (DLS) measurements revealed fast swelling and disruption of micelles under acidic pH. UV/vis spectroscopy corroborated that acetal degradation was accelerated at pH 4.0 and 5.0. The in vitro release studies showed that doxorubicin (DOX) was released in a controlled and pH-dependent manner, in which ca. 96%, 73%, and 30% of drug was released within 48 h at pH 4.0, 5.0, and 7.4, respectively. Notably, MTT assays displayed that DOX-loaded PEG-PAU-PEG micelles had a high in vitro antitumor activity in both RAW 264.7 and drug-resistant MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments demonstrated that PEG-PAU-PEG micelles mediated efficient cytoplasmic delivery of DOX. Importantly, blank PEG-PAU-PEG micelles were shown to be nontoxic to RAW 264.7 and MCF-7/ADR cells even at a high concentration of 1.5 mg/mL. Hence, micelles based on poly(acetal urethane) have appeared as a new class of biocompatible and acid-degradable nanocarriers for efficient intracellular drug delivery.

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Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles

Cited by 111 publications

References 34 publications

Tumoral gene silencing by receptor-targeted combinatorial siRNA polyplexes

Tumoral gene silencing by receptor-targeted combinatorial siRNA polyplexes

Recent In Vivo Evidences of Particle-Based Delivery of Small-Interfering RNA (siRNA) into Solid Tumors

Micelles Based on Acid Degradable Poly(acetal urethane): Preparation, pH-Sensitivity, and Triggered Intracellular Drug Release

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