Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide

Rodrigueza, Wendi V.; Woolliscroft, Michael J.; Ebrahim, Abdul Shukkur; Forgey, Robert; McGovren, Patrick J.; Endert, Gerold; Wagner, Alexandra; Holewa, Danielle; Aboukameel, Amro; Gill, Richard; Bisgaier, Charles L.; Messmann, Richard A.; Whitehead, Christopher; Izbicka, Elzbieta; Streeper, Robert T.; Wick, Michael; Stiegler, Gabriela; Stein, C. A.; Monsma, David J.; Webb, Craig P.; Sooch, Mina P.; Panzner, Steffen; Mohammad, Ramzi M.; Goodwin, Neal; Al‐Katib, Ayad

doi:10.1007/s00280-014-2476-y

Cited by 22 publications

(25 citation statements)

References 47 publications

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“…ProNAi Therapeutics has developed a liposome-based ON formulation that demonstrated anti-tumor efficacy in vivo [100]. The therapeutic ON is a 24-mer, chemically unmodified DNA nucleotide sequence, which is designed to be complementary to a non-coding, non-transcribed region of the BCL-2 gene.…”

Section: Therapeutic Applications Of Onsmentioning

confidence: 99%

“…A formulation composed of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC)/ 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)/ cholesteryl hemisuccinate (CHEMS)/ cholesteryl-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutanoate (MOCHOL) (6:24:23:47 mol ratio) was selected based on the antitumor activity tested in a PC-3 tumor-bearing animal model when used in combination with docetaxel. Since the formulation was developed for clinical evaluation, sophisticated optimization studies were conducted to test the dosing schedules, dose-escalation, and the resulting pharmacokinetics, pharmacodynamics, and immune response [100]. …”

Section: Therapeutic Applications Of Onsmentioning

confidence: 99%

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Delivery of oligonucleotides with lipid nanoparticles

Wang

Miao

Satterlee

et al. 2015

Advanced Drug Delivery Reviews

170

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: Therapeutic Applications Of Onsmentioning

confidence: 99%

Section: Therapeutic Applications Of Onsmentioning

confidence: 99%

Delivery of oligonucleotides with lipid nanoparticles

Wang

Miao

Satterlee

et al. 2015

Advanced Drug Delivery Reviews

170

119

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“…We recently reported on the development, physiochemical characterization and activity of the DNAi, PNT2258 [28]. PNT2258, a 24 base-single stranded, unmodified phosphodiester DNA oligonucleotide (PNT100) encapsulated in specialized liposomes (SMARTICLES ® ), was designed to target an untranslated region of BCL-2 to block transcription.…”

Section: Introductionmentioning

confidence: 99%

PNT2258, a novel deoxyribonucleic acid inhibitor, induces cell cycle arrest and apoptosis via a distinct mechanism of action: a new class of drug for non-Hodgkin's lymphoma

et al. 2016

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Current therapy for BCL-2-associated tumors such as Non-Hodgkin Lymphomas (NHL) is inadequate. The DNAi PNT2258, a 24 base single-stranded phosphodiester DNA oligodeoxynucleotide (PNT100) encapsulated in a protective liposome, was precisely designed to treat cancers that over-express BCL-2. PNT2258 strongly inhibited BCL-2 promoter activity, confirming its predicted mechanism of action. BCL-2 mRNA and protein expression were significantly downregulated in a follicular small cleaved cell lymphoma (WSU-FSCCL) cell line. 2.5μM PNT2258 induced an initial S- phase arrest followed by a gradual increase in the sub-G0 (apoptosis) compartment and a reciprocal progressive decrease of the S phase. Terminal deoxynucleotidyl transferase (TdT)-positive populations and cleaved caspase-3 and PARP were also increased. The data are consistent with the idea that BCL-2 inhibition by PNT2258 activates apoptotic pathways in WSU-FSCCL cells. This is the first report to address the distinct mechanism of action underlying the anti-BCL-2 functions of PNT2258. Growth inhibition in two other cell lines, WSU-DLCL2 and WSU-WM, supports broad applicability of BCL-2 DNAi to treatment of B-cell NHL.

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“…19 LNPs have been evaluated in several pipelines of clinical trials as stable nucleic acid lipid particles (SNALP). 20, 21 Rodrigueza et al reported the preparation of lipid-based nanoparticle (PNT2258) loading of a 24-base DNA oligonucleotide using a one-step method that is similar to the method of SNALP preparation, 22 and such nanoparticles have been evaluated in clinical trials. 22,23 Though there is no distinct definition of lipoplexes and LNPs, we herein define lipoplexes as electrostatic polyelectrolyte complexes formed by mixing preformed cationic liposomes with siRNA in an aqueous environment, while LNPs are formed by mixing an aqueous siRNA solution with an alcoholic lipid solution in one step.…”

Section: Introductionmentioning

confidence: 99%

“…20, 21 Rodrigueza et al reported the preparation of lipid-based nanoparticle (PNT2258) loading of a 24-base DNA oligonucleotide using a one-step method that is similar to the method of SNALP preparation, 22 and such nanoparticles have been evaluated in clinical trials. 22,23 Though there is no distinct definition of lipoplexes and LNPs, we herein define lipoplexes as electrostatic polyelectrolyte complexes formed by mixing preformed cationic liposomes with siRNA in an aqueous environment, while LNPs are formed by mixing an aqueous siRNA solution with an alcoholic lipid solution in one step. In this study, we prepared two types of siRNA-loaded carrier (lipoplexes and LNPs) with similar particle sizes from components of the same composition using different preparation methods, and evaluated the impact of structure on cellular uptake and immune stimulation.…”

Section: Introductionmentioning

confidence: 99%

Effect of the nanoformulation of siRNA-lipid assemblies on their cellular uptake and immune stimulation

Kubota¹,

Onishi²,

Sawaki³

et al. 2017

IJN

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Two lipid-based nanoformulations have been used to date in clinical studies: lipoplexes and lipid nanoparticles (LNPs). In this study, we prepared small interfering RNA (siRNA)-loaded carriers using lipid components of the same composition to form molecular assemblies of differing structures, and evaluated the impact of structure on cellular uptake and immune stimulation. Lipoplexes are electrostatic complexes formed by mixing preformed cationic lipid liposomes with anionic siRNA in an aqueous environment, whereas LNPs are nanoparticles embedding siRNA prepared by mixing an alcoholic lipid solution with an aqueous siRNA solution in one step. Although the physicochemical properties of lipoplexes and LNPs were similar except for small increases in apparent size of lipoplexes and zeta potential of LNPs, siRNA uptake efficiency of LNPs was significantly higher than that of lipoplexes. Furthermore, in the case of LNPs, both siRNA and lipid were effectively incorporated into cells in a co-assembled state; however, in the case of lipoplexes, the amount of siRNA internalized into cells was small in comparison with lipid. siRNAs in lipoplexes were thought to be more likely to localize on the particle surface and thereby undergo dissociation into the medium. Inflammatory cytokine responses also appeared to differ between lipoplexes and LNPs. For tumor necrosis factor-α, release was mainly caused by siRNA. On the other hand, the release of interleukin-1β was mainly due to the cationic nature of particles. LNPs released lower amounts of tumor necrosis factor-α and interleukin-1β than lipoplexes and were thus considered to be better tolerated with respect to cytokine release. In conclusion, siRNA-loaded nanoformulations effect their cellular uptake and immune stimulation in a manner that depends on the structure of the molecular assembly; therefore, nanoformulations should be optimized before extending studies into the in vivo environment.

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Development and antitumor activity of a BCL-2 targeted single-stranded DNA oligonucleotide

Cited by 22 publications

References 47 publications

Delivery of oligonucleotides with lipid nanoparticles

Delivery of oligonucleotides with lipid nanoparticles

PNT2258, a novel deoxyribonucleic acid inhibitor, induces cell cycle arrest and apoptosis via a distinct mechanism of action: a new class of drug for non-Hodgkin's lymphoma

Effect of the nanoformulation of siRNA-lipid assemblies on their cellular uptake and immune stimulation

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