Transferrin Receptor-Targeted Lipid Nanoparticles for Delivery of an Antisense Oligodeoxyribonucleotide against Bcl-2

Xiao, Yang; Koh, Chee Guan; Liu, Shujun; Pan, Xiaogang; Santhanam, Ramasamy; Yu, Bo; Peng, Yong; Pang, Jiuxia; Golan, Sharon; Talmon, Yeshayahu; Jin, Yan; Muthusamy, Natarajan; Byrd, John C.; Chan, Kenneth K.; Lee, L. James; Marcucci, Guido; Lee, Robert J.

doi:10.1021/mp800149s

Cited by 93 publications

(77 citation statements)

References 29 publications

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“…Cationic liposomes are frequently used for nucleic acid delivery studies due to the multiple cationic groups presented on the surface of the liposomes [24-29]. These cations naturally interact with polyanionic nucleic acids and form lipoplexes.…”

Section: Lipid Nanoparticles Mediated On Deliverymentioning

confidence: 99%

Delivery of oligonucleotides with lipid nanoparticles

Wang

Miao

Satterlee

et al. 2015

Advanced Drug Delivery Reviews

169

119

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Since their inception in the 1980's, oligonucleotide-based (ON-based) therapeutics have been recognized as powerful tools that can treat a broad spectrum of diseases. The discoveries of novel regulatory methods of gene expression with diverse mechanisms of action are still driving the development of novel ON-based therapeutics. Difficulties in the delivery of this class of therapeutics hinder their in vivo applications, which forces drug delivery systems to be a prerequisite for clinical translation. This review discusses the strategy of using lipid nanoparticles as carriers to deliver therapeutic ONs to target cells in vitro and in vivo. A discourse on how chemical and physical properties of the lipid materials could be utilized during formulation and the resulting effects on delivery efficiency constitutes the major part of this review.

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Section: Lipid Nanoparticles Mediated On Deliverymentioning

confidence: 99%

Delivery of oligonucleotides with lipid nanoparticles

Wang

Miao

Satterlee

et al. 2015

Advanced Drug Delivery Reviews

169

119

View full text Add to dashboard Cite

show abstract

“…20 Further details are available in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). A postinsertion method was adopted to incorporate RIT into nanoparticles carrying ODNs.…”

Section: Preparation Of Rituximab-conjugated Liposomal Odn Nanoparticlesmentioning

confidence: 99%

Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia

Mao

et al. 2013

Blood

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• Toll-like receptor-mediated immune stimulation poses major hurdle for antisense oligonucleotides and RNA-based therapies.• A novel targeted delivery strategy that overcomes these immunostimulatory effects while potentiating gene silencing in B-cell malignancies. IntroductionTherapeutic oligonucleotides (ONs), including antisense oligodeoxynucleotides (ODNs), small interfering RNAs (siRNAs), and the more recently discovered miRNAs designed for targeted inhibition of specific mRNA sequences that code for cell survival proteins, are of emerging interest in hematologic malignancies. [1][2][3][4] Despite their promising roles, clinical trials using ONs in hematologic malignancies have shown limited success. Probably the most studied has been the antisense targeting Bcl-2 G3139. Bcl-2 is a well-characterized member of the Bcl-2 family with multiple antiapoptotic functions that prevent cell death from multiple mechanisms. 5,6 Overexpression of Bcl-2 can dramatically increase resistance to therapeutics that promote mitochondrial and endoplasmic reticulum-mediated death in a variety of cancer types. The Bcl-2 protein is dramatically overexpressed in chronic lymphocytic leukemia (CLL) compared with normal B cells and has been shown to promote resistance to fludarabine. [7][8][9] Preclinical studies examining either knock-down (antisense and siRNA) or inhibition of Bcl-2 protein function by small molecules promotes apoptosis in CLL cells, thereby prompting the initiation of clinical trials of G3139 in CLL. Surprisingly, the first phase 1 study of G3139 in CLL identified a lower tolerated dose than in other diseases because of cytokine release syndrome and other immune-activating symptoms unique to CLL. 10 Whereas detailed pharmacodynamics validating target down-modulation of Bcl-2 was not performed in CLL patients, 11 studies done on AML blasts in vivo suggested that the doses were inadequate to effectively inhibit this protein. 12 Despite this lack of pharmacodynamic data, development of G3139 went forth to full phase 3 testing, where it was added to fludarabine and The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 8, 2018. by guest www.bloodjournal.org From cyclophosphamide and compared with chemotherapy alone. 10,13,14 Modest enhancement of clinical activity was observed but was insufficient for regulatory approval. Other attempts to target Bcl-2 family member proteins with BH3 mimetic small molecules such as ABT263 have demonstrated clinical success in trials with objective response rates. 15 Unfortunately, these agents are not selective to one Bcl-2 family member and therefore have unanticipated target effects such as severe thrombocytopenia and cellular immune suppression because of antagonizing Bcl-XL. These findings suggest that more selective targeting of s...

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“…The natural ligand for TfR, Tf, binds to its receptor with a dissociation constant of around 40nM. TfR, also known as CD71, is a dimeric transmembrane glycoprotein (180 kDa) [77]. The receptor for Tf, referred to as TfR1, is ubiquitously expressed at low levels in most normal human tissues.…”

Section: Transferrin Receptormentioning

confidence: 99%