Preliminary preclinical study of Chol-DsiRNA polyplexes formed with PLL[30]-PEG[5K] for the RNAi-based therapy of breast cancer

Ye, Zhen; Abdelmoaty, Mai Mohamed; Ambardekar, Vishakha V.; Curran, Stephen; Dyavar, Shetty Ravi; Arnold, Lora L.; Cohen, Samuel M.; Kumar, Devendra; Alnouti, Yazen; Coulter, Don W.; Singh, Rakesh K.; Vetro, Joseph A.

doi:10.1016/j.nano.2021.102363

Cited by 5 publications

(37 citation statements)

References 34 publications

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“…To determine if the activities of 5'-overlapping siSTAT3 and DsiSTAT3 sequences against STAT3 mRNA are similar in murine syngeneic breast cancer epithelial cells, we electroporated 4T1 cells with equimolar concentrations of siSTAT3, DsiSTAT3 (3'-extension of the siSTAT3 sequence that suppresses 81%of murine STAT3 mRNA in 4T1 cells 48 h after electroporation [2]), inactive siCTRL, or inactive DsiCTRL and compared normalized murine STAT3 mRNA copy numbers vs. electroporated 4T1 cells at 24, 48, and 72 h after treatment by RT-ddPCR (Fig. 2A).…”

Section: Activities Of 5'-overlapping Sistat3 and Dsistat3 Sequences In Murine Syngeneic 4t1 Breast Cancer Epithelial Cellsmentioning

confidence: 99%

“…Results are representative of at least two independent experiments. Data for DsiCTRL, DsiSTAT3, Chol-DsiCTRL, and Chol-DsiSTAT3 taken from [2].…”

Section: Activities Of 5'-overlapping Sistat3 and Dsistat3 Sequences In Murine Syngeneic 4t1 Breast Cancer Epithelial Cellsmentioning

confidence: 99%

“…RNA interference (RNAi) is a natural, intracellular process that selectively decreases the expression of a specific protein at the mRNA level through complementary base-pair binding of gene-specific dsRNA molecules including microRNA (miRNA), small, interfering RNA (siRNA), or dicer-substrate siRNA (DsiRNA) ("RNAi molecules") [1,2]. Several proteins have been identified in tumor or tumor-associated cells where suppression may produce a therapeutic effect and/or increase the efficacy of other cancer treatments [2,3]. Thus, RNAi molecules have tremendous potential for improving cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…administration [2.5 mg Chol-RNAi/kg] over three days without affecting body weight [4,8]. Chol-DsiRNA Polyplexes, however, maintain LUC mRNA suppression ~48 hours longer after the final dose than Chol-siRNA Polyplexes [4,8], have higher loading (50 wt% vs. 25 wt%), provide greater protection against RNase degradation in 90% murine serum, and are well tolerated by healthy female BALB/c mice to at least 50 mg Chol-DsiRNA/kg [2]. This suggests that Chol-DsiRNA Polyplexes are a more promising formulation candidate than Chol-siRNA Polyplexes for RNAi therapy of breast and possibly other solid tumors.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to suppression of stably expressed LUC mRNA in 4T1-Luc tumors, we recently found that Chol-DsiRNA Polyplexes targeting STAT3, a more widely expressed and therapeutically relevant mRNA, maintain suppression of STAT3 mRNA in primary 4T1 breast tumors less than 24 h after a single lower dose of Chol-DsiSTAT3 [0.5 mg/kg] [2]. Thus, it remains unclear whether or under what conditions Chol-DsiRNA Polyplexes also maintain the suppression of therapeutically relevant mRNA in primary 4T1 tumors for a longer duration than Chol-siRNA Polyplexes.…”

Section: Introductionmentioning

confidence: 99%

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Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC

Ye¹,

Abdelmoaty²,

Curran³

et al. 2021

Preprint

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RNA interference (RNAi) molecules have tremendous potential for cancer therapy but are limited by insufficient potency after i.v. administration. We previously found that polymer complexes (polyplexes) formed between 3’-cholesterol-modified siRNA (Chol-siRNA) or DsiRNA (Chol-DsiRNA) and the cationic diblock copolymer PLL[30]-PEG[5K] greatly increase RNAi potency against stably expressed LUC mRNA in primary syngeneic murine breast tumors after daily i.v. dosing. Chol-DsiRNA Polyplexes, however, maintain LUC mRNA suppression ~48 h longer after the final dose than Chol-siRNA Polyplexes, suggesting they are a better candidate formulation. Here, we directly compared the activities of Chol-siRNA and Chol-DsiRNA Polyplexes in primary murine 4T1 breast tumors against STAT3, a therapeutically relevant target gene overexpressed in many solid tumors including breast cancer. We found that Chol-siSTAT3 Polyplexes suppressed STAT3 mRNA in 4T1 tumors with similar potency (half-maximal ED50 0.3 mg/kg) and kinetics over 96 hours as Chol-DsiSTAT3 Polyplexes but with slightly lower activity against total Stat3 protein (29% vs. 42% suppression) and tumor growth (11.5% vs. 8.6% rate-based T/C ratio) after repeated i.v. administration of tumor-saturating doses every other day. Thus, both Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes may be suitable clinical candidates for RNAi therapy of breast cancer and other solid tumors.

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Section: Activities Of 5'-overlapping Sistat3 and Dsistat3 Sequences In Murine Syngeneic 4t1 Breast Cancer Epithelial Cellsmentioning

confidence: 99%

“…Results are representative of at least two independent experiments. Data for DsiCTRL, DsiSTAT3, Chol-DsiCTRL, and Chol-DsiSTAT3 taken from [2].…”

Section: Activities Of 5'-overlapping Sistat3 and Dsistat3 Sequences In Murine Syngeneic 4t1 Breast Cancer Epithelial Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC

Ye¹,

Abdelmoaty²,

Curran³

et al. 2021

Preprint

Self Cite

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Non‐Viral Nucleic Acid Delivery System for RNA Therapeutics

Liu

Zhou

et al. 2023

Advanced Therapeutics

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Nucleic acid drugs can treat diseases caused by defective or abnormal genes. Herein, the mechanism of non‐viral vectors for nucleic acid drug delivery is described. This review introduce non‐viral vectors for nucleic acid drug delivery, including the nucleic acid‐carrier conjugate, proteins and peptides‐based nanoparticles, polysaccharides, and other biological macromolecules‐based nanoparticles consisting of lipid nanoparticles, synthetic polymers‐based nanoparticles, inorganic nanoparticles, and organic–inorganic hybrid nanoparticles. Finally, the challenges and prospects of non‐viral vectors for nucleic acid drug delivery are discussed.

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Self-Assembled Oleic Acid-Modified Polyallylamines for Improved siRNA Transfection Efficiency and Lower Cytotoxicity

Salvador

Andreozzi

Romero

et al. 2023

ACS Appl. Bio Mater.

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Small interference RNA (siRNA) is a tool for gene modulation, which can silence any gene involved in genetic disorders. The potential of this therapeutic tool is hampered by RNA instability in the blood stream and difficulties to reach the cytosol. Polyamine-based nanoparticles play an important role in gene delivery. Polyallylamine hydrochloride (PAH) is a polycation displaying primary amines that can be easily chemically modified to match the balance between cell viability and siRNA transfection. In this work, PAH has been covalently functionalized with oleic acid at different molar ratios by carbodiimide chemistry. The substituted polymers form polyplexes that keep positive surface charge and fully encapsulate siRNA. Oleic acid substitution improves cell viability in the pulmonary cell line A549. Moreover, 6 and 14% of oleic acid substitution show an improvement in siRNA transfection efficiency. CD47 is a ubiquitous protein which acts as “don’t eat me signal.” SIRPα protein of macrophages recognizes CD47, leading to tumor cell phagocytosis by macrophages. By knocking down CD47 with siRNA, cancer cells become vulnerable to be eliminated by the immune system. PAH–oleic acid substitutes show high efficacy in silencing the CD47 protein, making them a potential candidate for immunotherapy.

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Preliminary preclinical study of Chol-DsiRNA polyplexes formed with PLL[30]-PEG[5K] for the RNAi-based therapy of breast cancer

Cited by 5 publications

References 34 publications

Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC

Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC

Non‐Viral Nucleic Acid Delivery System for RNA Therapeutics

Self-Assembled Oleic Acid-Modified Polyallylamines for Improved siRNA Transfection Efficiency and Lower Cytotoxicity

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