A bivalent cyclic RGD–siRNA conjugate enhances the antitumor effect of apatinib via co-inhibiting VEGFR2 in non-small cell lung cancer xenografts

Liao, Lumin; Cen, Bohong; Li, Guoxian; Wei, Yiran; Wang, Zhen; Huang, Wen; He, Shuai; Yuan, Yawei; Ji, Aimin

doi:10.1080/10717544.2021.1937381

Cited by 8 publications

(6 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach has demonstrated a significant inhibitory effect on tumor growth in both in vitro and in vivo studies. Subsequently, the uptake of siRNA in GBM and non-small cell lung cancer was further enhanced by incorporating a bivalent cRGD peptide modification [ 51 , 52 ]. Additionally, co-administration of Gelofusine helped mitigate renal damage caused by siRNA accumulation in the kidneys [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Chen,

Liu,

Fang

et al. 2024

J Transl Med

Self Cite

View full text Add to dashboard Cite

Background Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5’-C; antisense strand, 3’-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy. Methods IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5’-C; antisense strand, 3’-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-β and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection. Results IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-β and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors. Conclusions This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5’-C; antisense strand, 3’-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field.

show abstract

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Chen,

Liu,

Fang

et al. 2024

J Transl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…RGD peptides are derived from natural proteins, which may trigger an immune response in some patients (Table 1, Figure 3). This could lead to the production of antibodies against the RGD peptide, potentially reducing the effectiveness of the therapy or causing adverse reactions 77–80 . Peptides, including RGD peptides, can be susceptible to degradation by proteases in the body.…”

Section: Rgd Peptides: Challengesmentioning

confidence: 99%

RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions

Javid,

Oryani,

Rezagholinejad

et al. 2024

Cancer Medicine

View full text Add to dashboard Cite

RGD peptide can be found in cell adhesion and signaling proteins, such as fibronectin, vitronectin, and fibrinogen. RGD peptides' principal function is to facilitate cell adhesion by interacting with integrin receptors on the cell surface. They have been intensively researched for use in biotechnology and medicine, including incorporation into biomaterials, conjugation to medicinal molecules or nanoparticles, and labeling with imaging agents. RGD peptides can be utilized to specifically target cancer cells and the tumor vasculature by engaging with these integrins, improving drug delivery efficiency and minimizing adverse effects on healthy tissues. RGD‐functionalized drug carriers are a viable option for cancer therapy as this focused approach has demonstrated promise in the future. Writing a review on the RGD peptide can significantly influence how drugs are developed in the future by improving our understanding of the peptide, finding knowledge gaps, fostering innovation, and making drug design easier.

show abstract

“…The vascular endothelial growth factor receptor 2 (VEGFR2) is a promising target for the treatment of angiogenesis of non-small cell lung cancer. Liao et al design the bivalent cyclic RGD-siRNA conjugates to enhance the apatinib anti-tumor potential to inhibit VEGFR2 in NSCLC xenografts [ 219 ]. Interestingly, biRGD-siVEGFR2 reduced the nephrotoxicity of apatinib [ 219 ].…”

Section: Chemical Modification Of Sirna For Oral Deliverymentioning

confidence: 99%

“…Liao et al design the bivalent cyclic RGD-siRNA conjugates to enhance the apatinib anti-tumor potential to inhibit VEGFR2 in NSCLC xenografts [ 219 ]. Interestingly, biRGD-siVEGFR2 reduced the nephrotoxicity of apatinib [ 219 ]. This study proposed the low-dose apatinib as a clinical anti-tumor therapy.…”

Section: Chemical Modification Of Sirna For Oral Deliverymentioning

confidence: 99%

Oral delivery of RNAi for cancer therapy

Afrin

Bai

Kumar

et al. 2023

Cancer Metastasis Rev

View full text Add to dashboard Cite

Cancer is a major health concern worldwide and is still in a continuous surge of seeking for effective treatments. Since the discovery of RNAi and their mechanism of action, it has shown promises in targeted therapy for various diseases including cancer. The ability of RNAi to selectively silence the carcinogenic gene makes them ideal as cancer therapeutics. Oral delivery is the ideal route of administration of drug administration because of its patients’ compliance and convenience. However, orally administered RNAi, for instance, siRNA, must cross various extracellular and intracellular biological barriers before it reaches the site of action. It is very challenging and important to keep the siRNA stable until they reach to the targeted site. Harsh pH, thick mucus layer, and nuclease enzyme prevent siRNA to diffuse through the intestinal wall and thereby induce a therapeutic effect. After entering the cell, siRNA is subjected to lysosomal degradation. Over the years, various approaches have been taken into consideration to overcome these challenges for oral RNAi delivery. Therefore, understanding the challenges and recent development is crucial to offer a novel and advanced approach for oral RNAi delivery. Herein, we have summarized the delivery strategies for oral delivery RNAi and recent advancement towards the preclinical stages.

show abstract

A bivalent cyclic RGD–siRNA conjugate enhances the antitumor effect of apatinib via co-inhibiting VEGFR2 in non-small cell lung cancer xenografts

Cited by 8 publications

References 34 publications

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions

Oral delivery of RNAi for cancer therapy

Contact Info

Product

Resources

About