Recent Advancements in the Design of Nanodelivery Systems of siRNA for Cancer Therapy

Yadav, Dokkari Nagalaxmi; Ali, Mohammad Sadik; Thanekar, Ajinkya Madhukar; Pogu, Sunil Venkanna; Rengan, Aravind Kumar

doi:10.1021/acs.molpharmaceut.2c00811

Cited by 20 publications

(17 citation statements)

References 192 publications

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“…Like other siRNA delivery strategies for TNBC, ZD2/RGD-PEG(Hz)-ECO/siDANCR nanoparticles promote epigenetic and transcriptional gene regulation that results in inhibition of cancer cell invasion and proliferation . While a variety of nanocarrier designs and targeting moieties are prevalent for systemic delivery of siRNA against oncogenes, there are limited developments in applying them to systemic siDANCR delivery for TNBC therapy. − This study demonstrates that ZD2/RGD-PEG(Hz)-ECO/siDANCR nanoparticles can be regularly administered with good safety and efficacy, which indicates promise for clinical translation. DANCR may exert its function on oncogenic processes based on its expression levels in breast cancer .…”

Section: Discussionmentioning

confidence: 88%

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

Nicolescu

Schilb

Kim

et al. 2023

Chemical & Biomedical Imaging

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Differentiation antagonizing noncoding RNA (DANCR) is recognized as an oncogenic long noncoding RNA (lncRNA) overexpressed in triple negative breast cancer (TNBC). We showed in a previous study that RNAi with targeted multifunctional ionizable lipid ECO/siRNA nanoparticles was effective to regulate this undruggable target for effective treatment of TNBC. In this study, we developed dual-targeted ECO/siDANCR nanoparticles by targeting a tumor extracellular matrix oncoprotein, extradomain B fibronectin (EDB-FN), and integrins overexpressed on cancer cells for enhanced delivery of siDANCR. The treatment of Hs578T TNBC cells and MCF-7 estrogen receptor-positive cells in vitro resulted in significant down-regulation of DANCR and EDB-FN and suppressed invasion and 3D spheroid formation of the cells. Magnetic resonance molecular imaging (MRMI) with an EDB-FN-targeted contrast agent, MT218, was used to noninvasively evaluate tumor response to treatment with the targeted ECO/siDANCR nanoparticles in female nude mice bearing orthotopic Hs578T and MCF-7 xenografts. MRMI with MT218 was effective to differentiate between aggressive TNBC with high DANCR and EDB-FN expression and ER+ MCF-7 tumors with low expression of the targets. MRMI showed that the dual-targeted ECO/siDANCR nanoparticles resulted in more significant inhibition of tumor growth in both models than the controls and significantly reduced EDB-FN expression in the TNBC tumors. The combination of MRMI and dual-targeted ECO/siDANCR nanoparticles is a promising approach for image-guided treatment of TNBC by regulating the onco-lncRNA.

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Section: Discussionmentioning

confidence: 88%

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

Nicolescu

Schilb

Kim

et al. 2023

Chemical & Biomedical Imaging

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“…After 72 h, a subcutaneous tumor model was established. The model mice were randomly allocated and received daily intratumoral injections of NS, the MLSV system (125 μg), and the MLSV/Bim (10 μg) complex for eight treatments . The mice were sacrificed on day 11, and the tumors, heart, liver, spleen, lung, and kidney were harvested.…”

Section: Methodsmentioning

confidence: 99%

“…The model mice were randomly allocated and received daily intratumoral injections of NS, the MLSV system (125 μg), and the MLSV/Bim (10 μg) complex for eight treatments. 31 The mice were sacrificed on day 11, and the tumors, heart, liver, spleen, lung, and kidney were harvested. Among them, tumors, heart, liver, spleen, lung, and kidneys were soaked in 4% paraformaldehyde for further analysis.…”

Section: ■ Introductionmentioning

confidence: 99%

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Huang,

Wang,

et al. 2023

Mol. Pharmaceutics

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Messenger ribonucleic acid (mRNA)-based gene therapy has great potential for cancer gene therapy. However, the effectiveness of mRNA in cancer therapy needs to be further improved, and the delivery efficiency and instability of mRNA limit the application of mRNA-based products. Both the delivery efficiency can be elevated by cell-penetrating peptide modification, and the immune response can be enhanced by tumor cell lysate stimulation, representing an advantageous strategy to expand the effectiveness of mRNA gene therapy. Therefore, it is vital to exploit a vector that can deliver high-efficiency mRNA with codelivery of tumor cell lysate to induce specific immune responses. We previously reported that DMP cationic nanoparticles, formed by the self-assembly of DOTAP and mPEG-PCL, can deliver different types of nucleic acids. DMP has been successfully applied in gene therapy research for various tumor types. Here, we encapsulated tumor cell lysates with DMP nanoparticles and then modified them with a fused cell-penetrating peptide (TAT-iRGD) to form an MLSV system. The MLSV system was loaded with encoded Bim mRNA, forming the MLSV/Bim complex. The average size of the synthesized MLSV was 191.4 nm, with a potential of 47.8 mV. The MLSV/mRNA complex promotes mRNA absorption through caveolin-mediated endocytosis, with a transfection rate of up to 68.6% in B16 cells. The MLSV system could also induce the maturation and activation of dendritic cells, obviously promoting the expression of CD80, CD86, and MHC-II both in vitro and in vivo. By loading the encoding Bim mRNA, the MLSV/Bim complex can inhibit cell proliferation and tumor growth, with inhibition rates of up to 87.3% in vitro. Similarly, the MLSV/Bim complex can inhibit tumor growth in vivo, with inhibition rates of up to 78.7% in the B16 subcutaneous tumor model and 63.3% in the B16 pulmonary metastatic tumor model. Our results suggest that the MLSV system is an advanced candidate for mRNA-based immunogene therapy.

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“…Although chemotherapy has been used extensively for the treatment of brain tumors, most chemotherapeutics do not effectively cross the BBB . This is attributed to the overexpression of P-glycoprotein efflux pumps in the tumor cells, resulting in the emergence of multidrug resistance . These shortcomings and the associated side effects render chemotherapy a poor strategy for the treatment of glioblastoma .…”

Section: Introductionmentioning

confidence: 99%

“…6 This is attributed to the overexpression of P-glycoprotein efflux pumps in the tumor cells, resulting in the emergence of multidrug resistance. 7 These shortcomings and the associated side effects render chemotherapy a poor strategy for the treatment of glioblastoma. 8 The primary neoplasma invariably experiences aggressive, therapy-resistant relapse even after maximal treatment.…”

Section: Introductionmentioning

confidence: 99%

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring

et al. 2023

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The blood–brain barrier (BBB) acts as a physical/biochemical barrier that protects brain parenchyma from potential hazards exerted by different xenobiotics found in the systemic circulation. This barrier is created by “a lipophilic gate” as well as a series of highly organized influx/efflux mechanisms. The BBB bottleneck adversely affects the efficacy of chemotherapeutic agents in treating different CNS malignancies such as glioblastoma, an aggressive type of cancer affecting the brain. In the present study, mesoporous silica nanoparticles (MSNs) were conjugated with the transactivator of transcription (TAT) peptide, a cell-penetrating peptide, to produce MSN-NH-TAT with the aim of improving methotrexate (MTX) penetration into the brain. The TAT-modified nanosystem was characterized by Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and N2 adsorption–desorption analysis. In vitro hemolysis and cell viability studies confirmed the biocompatibility of the MSN-based nanocarriers. In addition, in vivo studies showed that the MTX-loaded MSN-NH-TAT improved brain-to-plasma concentration ratio, brain uptake clearance, and the drug’s blood terminal half-life, compared with the use of free MTX. Taken together, the results of the present study indicate that MSN functionalization with TAT is crucial for delivery of MTX into the brain. The present nanosystem represents a promising alternative drug carrier to deliver MTX into the brain via overcoming the BBB.

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Recent Advancements in the Design of Nanodelivery Systems of siRNA for Cancer Therapy

Cited by 20 publications

References 192 publications

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

Tumor Cell Lysate-Based Multifunctional Nanoparticles Facilitate Enhanced mRNA Delivery and Immune Stimulation for Melanoma Gene Therapy

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring

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