Liver cancer cells as the model for developing liver-targeted RNAi therapeutics

Hou, Beibei; Qin, Linhui; Huang, Linfeng

doi:10.1016/j.bbrc.2023.01.007

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…The immune system is a crucial component of this coordination, with tissue barriers acting as the first line of defense of the immune system. Within the immune cells, CD4 + factors can secrete cellular tissue to enhance immune response and kill tumor cells, while CD8 + factors can secrete inhibitory cells to suppress CD4 + factors, inhibit B cell synthesis, and thereby inhibit immune response, resulting in decreased immune function [38]. This work compared immune function indicators between patients in different groups and found that the levels of CD3+, CD4+, and CD4+/CD8 + in patients in the Obs group after treatment were much higher, with P < 0.05 to the levels of these indicators in the Ctrl group.…”

Section: Discussionmentioning

confidence: 99%

Assessment of disease control rate and safety of sorafenib in targeted therapy for advanced liver cancer

Zeng,

Yu,

Chen

et al. 2024

World J Surg Onc

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Objective The clinical efficacy and safety of sorafenib in patients with advanced liver cancer (ALC) were evaluated based on transarterial chemoembolization (TACE). Methods 92 patients with ALC admitted to our hospital from May 2020 to August 2022 were randomly rolled into a control (Ctrl) group and an observation (Obs) group, with 46 patients in each. Patients in the Ctrl group received TACE treatment, while those in the Obs group received sorafenib molecular targeted therapy (SMTT) on the basis of the treatment strategy in the Ctrl group (400 mg/dose, twice daily, followed by a 4-week follow-up observation). Clinical efficacy, disease control rate (DCR), survival time (ST), immune indicators (CD3+, CD4+, CD4+/CD8+), and adverse reactions (ARs) (including mild fatigue, liver pain, hand-foot syndrome (HFS), diarrhea, and fever) were compared for patients in different groups after different treatments. Results the DCR in the Obs group (90%) was greatly higher to that in the Ctrl group (78%), showing an obvious difference (P < 0.05). The median ST in the Obs group was obviously longer and the median disease progression time (DPT) was shorter, exhibiting great differences with those in the Ctrl group (P < 0.05). Moreover, no great difference was observed in laboratory indicators between patients in various groups (P > 0.05). After treatment, the Obs group exhibited better levels in all indicators. Furthermore, the incidence of ARs in the Obs group was lower and exhibited a sharp difference with that in the Ctrl group (P < 0.05). Conclusion SMTT had demonstrated good efficacy in patients with ALC, improving the DCR, enhancing the immune response of the body, and reducing the incidence of ARs, thereby promoting the disease outcome. Therefore, it was a treatment method worthy of promotion and application.

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Section: Discussionmentioning

confidence: 99%

Assessment of disease control rate and safety of sorafenib in targeted therapy for advanced liver cancer

Zeng,

Yu,

Chen

et al. 2024

World J Surg Onc

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“…The same procedure was used for the transfection of 0.5 nM siPCSK9 in Hep3B. High asialoglycoprotein receptor (ASGPR) expression in Hep3B allows direct GalNAc-siPCSK9 delivery [ 18 ]. Hep3B cells were incubated with Opti-MEM ™ reduced serum medium containing 100 nM GalNAc-siPCSK9 for 72 h, and samples were collected as described above.…”

Section: Methodsmentioning

confidence: 99%

A highly sensitive stem-loop RT-qPCR method to study siRNA intracellular pharmacokinetics and pharmacodynamics

Chen,

Bosmajian,

Woo

2024

Biology Methods and Protocols

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Small interfering RNA (siRNA) is a powerful tool for sequence-specific silencing of disease-related genes. In this study, we established and validated a stem-loop reverse transcription real-time polymerase chain reaction (RT-qPCR) method applicable for both chemically unmodified and modified siRNA, aiming to elucidate mechanistic intracellular pharmacokinetic and pharmacodynamic (PK/PD) properties of siRNA. We conducted a comprehensive evaluation of factors affecting intracellular siRNA quantification. Our study revealed that immobilization-based siRNA extraction introduced high variation, making it unsuitable for absolute quantification. Conversely, direct cell lysis followed by stem-loop RT-qPCR demonstrated excellent reproducibility, with a quantification range from 0.0002 to 20 femtomole (fmole) for unmodified siRNA and 0.02 to 20 fmole for modified siRNA. The design of a 6-basepair overlapping RT primer facilitated the distinction of full-length antisense from its 3’ metabolites, and pre-annealing of antisense to RT primer enhanced sensitivity and reproducibility. Differences in siRNA loss during storage and sample processing were noted among microcentrifuge tubes from various manufacturers. Endogenous miR-16 served as a reference for normalizing cytoplasmic siRNA, while protein concentration post-immunoprecipitation lysis was used to normalize RISC-loaded siRNA levels. This method successfully enabled a detailed characterization of the time profiles of cytoplasmic and RISC-loaded siRNA, advancing of the in vitro-in vivo translation of siRNA therapeutics.

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Combinatorial Synthesis of Alkyl Chain‐Capped Poly(β‐Amino Ester)s for Effective siRNA Delivery

Chen,

Ren,

Jiang

et al. 2024

Macromolecular Bioscience

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Poly (β‐amino ester) (PBAE) is a class of biodegradable polymers containing ester bonds in their main chain, extensively investigated as cationic polymer carriers for siRNA. Most current PBAE carriers rely on termination with hydrophilic or charged amines. In this study, a polymer platform consisting of 168 PBAE polymers with hydrophobic alkyl chain terminals is constructed through sequential aza‐Michael addition. A large number of effective carriers are identified through in vitro screening of the PBAE platform for siLuc delivery to HeLa‐Luc cells. Specifically, PA8‐C6 and PA8‐C8 achieve remarkable gene knockdown efficacies of up to 80% with low cytotoxicity. Certain materials from the PA2 and PA5 series demonstrate potent siRNA delivery capabilities associated with elevated cytotoxicity. The pKa value of PBAE is predominantly determined by the hydrophilic amine side chains rather than the end‐capping groups. A pKa range of ≈6.2–6.5 may contribute to the excellent delivery capability for PA8 series carriers. The co‐formulation of PBAE carriers with helper lipids leads to the reduced size and surface charges of the polyplex NPs with siRNA, consequently decreasing the cytotoxicity and enhancing siRNA delivery efficacy. These findings hold significant implications for the development of novel degradable polymer carriers for siRNA delivery.

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Liver cancer cells as the model for developing liver-targeted RNAi therapeutics

Cited by 7 publications

References 38 publications

Assessment of disease control rate and safety of sorafenib in targeted therapy for advanced liver cancer

Assessment of disease control rate and safety of sorafenib in targeted therapy for advanced liver cancer

A highly sensitive stem-loop RT-qPCR method to study siRNA intracellular pharmacokinetics and pharmacodynamics

Combinatorial Synthesis of Alkyl Chain‐Capped Poly(β‐Amino Ester)s for Effective siRNA Delivery

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