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Pharmacokinetics, Biodistribution, and Therapeutic Applications of Recently Developed siRNA and DNA Repair Genes Recurrence
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
EphA2 is a well-known receptor tyrosine kinase belonging to the Eph family, overexpressed in many cancers including breast cancers and ovarian cancers, implicated in poor clinical outcomes [44]. Contact-dependent cell–cell interactions controlled by Eph receptors and ephrin (ligand of Eph receptors) signaling are tightly regulated in normal embryonic development and maintenance of homeostasis [45]. During oncogenesis, normal EphA2–EphrinA1 signaling is disrupted due to the loss of cell contacts, leading to overexpression of EphA2 and oncogenic signal transduction [45]. This dysregulated signaling is implicated in several critical aspects of oncogenesis such as cytoskeleton modulation, cell adhesion, migration, metastasis, proliferation, and angiogenesis [45]. Plk1, a serine/threonine-protein kinase, is responsible for cell mitosis in mammalian cells. It is overexpressed in various human cancers as a proto-oncogene, which inactivates tumor suppressor proteins like p53 [46,47]. CDKs are also serine/threonine kinases and essential for the regulation of the cell cycle progression [48]. The abnormal expression or activity of distinct CDK complexes causes cells to escape from a well-controlled cell cycle, resulting in malignant transformation [49–51]. Palbociclib, an inhibitor of CDK4/6, received breakthrough therapy designation from the FDA in April 2013, for the initial treatment of patients with breast cancer [52].
Emerging Trends in Nanotechnology for Diagnosis and Therapy of Lung Cancer
Published in Alok Dhawan, Sanjay Singh, Ashutosh Kumar, Rishi Shanker, Nanobiotechnology, 2018
Nanda Rohra, Manish Gore, Sathish Dyawanapelly, Mahesh Tambe, Ankit Gautam, Meghna Suvarna, Ratnesh Jain, Prajakta Dandekar
In another study, delivery of an apoptotic siRNA with MWNT was investigated for lung cancer studies. The polo-like Kinase (PLK1) gene is overexpressed in variety of tumors, including lung (Golsteyn et al. 1994, Holtrich et al. 1994). The PLK1 gene was targeted by delivering the apoptotic siRNA (siPLK1) using an ammonia-functionalized MWNT (MWNT-NH3+) vector. The gene-silencing efficacy of synthesized siPLK1-MWNT-NH3+ complex was checked in in-vitro human lung carcinoma Calu6 cell lines, and in vivo in female Swiss nude mice bearing Calu6 xenograft tumors by intratumoral delivery. In-vitro studies showed ineffective gene silencing by siPKL1: MWNT complex, as compared to that shown by siPKL1 and cationic liposomal (DOTAP: cholesterol) complex. However, in-vivo studies of the siPLK1-MWNT-NH3+ complex significantly improved the animal survival as compared to liposomal complex. PKL1 knockdown-mediated tumor suppression using biologically active siRNA was confirmed through intratumoral studies. Tumor inhibition was observed due to longer retention time of CNT complexes than that of liposomal complex. These results demonstrated the tremendous potential of MWNTs as vectors for gene therapy in lung cancer (Guo et al. 2015).
How to Untangle Complex Systems?
Published in Pier Luigi Gentili, Untangling Complex Systems, 2018
A more complex model to describe the cell cycle of Xenopus embryo (see the previous exercise) consists of three components (Ferrell et al. 2011). Besides CDK1 and APC, there is a third protein that is Polo-like kinase 1 (Plk1), as shown in Figure 13.29.
‘Borono-lectin’ based engineering as a versatile platform for biomedical applications
Published in Science and Technology of Advanced Materials, 2018
Akira Matsumoto, Yuji Miyahara
It was demonstrated that the specific binding between the pendent PBA and 3′end ribose at both ends of the double stranded siRNA, along with the hydrophobic interaction of PBA, cooperatively contribute to the stability of the complex in quasi-extracellular conditions. The complex could be optimized to cause disruption in response to adenosine triphosphate (ATP) only when the concentration exceeds that of intracellular environment, while remaining insensitive to any other competing sugars. As a result, the optimized complex exhibited a dose-dependent silencing capability of the polo-like kinase 1 (PLK-1) gene, a well-known proto-oncogene in the human renal carcinoma cell (OSRC-2) line, with no appreciable cytotoxicity [47]. Such PBA-assisted PIC-micelle may have potential for intracellular environment-selective delivery of siRNA and other small RNAs.
Lipid-based nanocarrier mediated CRISPR/Cas9 delivery for cancer therapy
Published in Journal of Biomaterials Science, Polymer Edition, 2023
Aisha Aziz, Urushi Rehman, Afsana Sheikh, Mohammed A. S. Abourehab, Prashant Kesharwani
IlP181(ionizable lipid nanoparticle) having pKa value 6.43 reliable to lipid iLY1809 has been reported by Li et al. that has allowed robust in vitro and in vivo editing of a genomic sequence, and has been effectively paired with a nucleic acid core of the psgPLK1 plasmid that has shown superior performance in the Cas9 protein expression and the sgRNA [71]. Polo-like kinase 1 (PLK1) are overexpressed in a variety of cancers offers researchers to develop formulations targeting them. Four sgRNA’s were designed to target PLK1 gene with the help CRISPR based technology by incorporating them with the sgPLK1 plasmid to make the Cas9-sgPLK1 plasmid. The luciferase activity in the mice treated with iLP181/psgPLK1 was very slow compared to other groups. Upon isolating the tumors and extracting the RNA, the PLK1 mRNA was seen to be significantly inhibited by the iLP181/psgPLK1 formulation, implying gene editing occurred in that group The serum biochemistry parameters were found to be normal with no major change in main organs suggesting its nontoxic nature [71]. LNPs do not trigger the immune system as much as the other nonviral carriers, hence repeated doses can be administered and a cumulative effect can be seen in gene editing. Immunosuppresant drugs can also be co-delivered [72]. Wang et al. demonstrated a 8-O14B lipid based drug delivery system where the lipid was designed to be degraded inside the cells. The lipidic system owes disulfide bond that destructs the nanoparticles, escapes endosome and release the therapeutic agent. As such, bioreducible lipids can be used to control the release of proteins for showing therapeutic action. The lipid has an encapsulation efficiency of >90% for (−27)GFP-Cre complex and the recombination efficiency was found to be up to 80% [73]. Finn et al. showed in vivo delivery of LNPs made of DSPC, cholesterol, and PEGylated lipid, carrying Cas9 mRNA and sgRNA into rat’s livers, aiming at reducing the expression of the gene for transthyretin. The serum transthyretin levels successfully dropped by more than 97%. It was also seen that upon being injected once every week or every month, cumulative gene editing was observed, which is preferred for high degrees of rectification required to normalize the phenotype in a genetic disease [74]. Advancements in CRISPR-based therapeutics have been made by Miller and team. Long RNA’s consisting of Cas9 mRNA and sgRNA were delivered using zwitterionic amino lipids that carry and deliver that showed a reduction of protein expression in more than 90% of cells. To prevent cationic lipid from being high in density, which can reduce the interactions between phospholipids and long RNA’s that would increase stabilization, a combination of zwitterionic and cationic lipids was used to improve stability [75].