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Dendrimer–Guest Interaction Chemistry and Mechanism
Published in Neelesh Kumar Mehra, Keerti Jain, Dendrimers in Nanomedicine, 2021
Valamla Bhavana, Thakor Pradip, Keerti Jain, Neelesh Kumar Mehra
Nucleolin (NCL) is a nuclear and cytoplasmic nucleolus ribosomal phosphor-protein that plays a crucial role in polymerase I transcription for biological and cellular function (Behrooz et al. 2017). Colorectal cancer is a vital cause of cancer associated death worldwide, and CPT drugs and their derivatives have been considered as first-line chemotherapeutic regimens. However, their limited application in cancer therapy is reported owing to their poor aqueous solubility, low bioavailability, systemic toxicity and short half-life. The CPT-loaded PEGylated G5.0 PAMAM dendrimers were synthesised, and then functionalised with AS1411 antinucleolin aptamers for targeting against colon adenocarcinoma by over-expressing nucleolin receptors. AS1411, a 26-mer single strand DNA (ssDNA) aptamer, has high and specific binding affinity to nucleolin (Alibolandi et al. 2017). The synthesis of PEGylated dendrimers and conjugation of AS1411 aptamers to the maleimide groups of MAL-PEG-PAMAM-CPT and preparation of Apt-PEG-PAMAM-CPT are shown in Figure 9.3. Similarly, smart bomb AS1411 aptamers (APTAS1411)-functionalised with PAMAM-PEG complex for delivery of 5-FU were synthesised. The nanoparticle-PAMAM dendrimer-aptamer-5-FU complex aids in effective delivery of 5-FU to cancer cells (Behrooz et al. 2017).
Aptamers and Cancer Nanotechnology
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Omid C. Farokhzad, Sangyong Jon, Robert Langer
Nucleolin was originally described as a nuclear and cytoplasmic protein; however, a number of recent studies have shown that it can also be expressed at the cell surface.59,60 Nucleolin is involved in the organization of the nuclear chromatin, rDNA transcription, packaging of the pre-RNA, ribosome assembly, nucleocytoplasmic transport, cytokinesis, nucleogenesis, and apoptosis. AS-1411 (formerly AGRO100) is an aptamer capable of making G-quadruplexes that bind to nucleolin on the cell surface61 and interact with the nuclear factor kappa B (NFκB) essential modulator (NEMO) inside the cell.62 The cytosolic localization of AS-1411 after binding to cell surface nucleolin may be exploited for the intracellular delivery of nanoparticles to cancer cells. The use of AS-1411 as a therapeutic modality has also shown promise for the treatment of cancer in humans, and Antisoma of United Kingdom is evaluating this aptamer in phase-I clinical trials.63 The therapeutic benefit of AS-1411 is presumably attributed to the disruption of the NFκB signaling inside the cells.64
Cell Biology for Bioprocessing
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
The cytosol side of the outer membrane of the nucleus is associated with many ribosomes. As will be discussed later, the endoplasmic reticulum is the site of active translation. These ribosomes on the outer membrane continue to present in the cytosol side of the endoplasmic membrane surface. Much trafficking occurs between the nucleoplasm and cytosol through nuclear pore complexes that transverse both the outer and inner nuclear membrane (Panel 2.11). DNA replication, the synthesis of various RNAs (mRNA, tRNA, rRNA, non-coding (nc)RNA, snRNA, etc.), and ribosome assembly occur in the nuclear compartment. They are segregated from the metabolic processes and protein synthesis occurring in the cytosol. The nucleotides and deoxynucleotides that are synthesized in the cytosol are imported into the nucleus for RNA and DNA synthesis. Many of the RNA products, including mRNAs and tRNAs, are exported to the cytosol where translation takes place. Ribosomes are assembled from ribosomal proteins and rRNAs in nucleoli and are subsequently exported to the cytosol to participate in protein synthesis. Since translation occurs in cytosol, the ribosomal proteins are also synthesized in cytosol before being imported into the nucleus for ribosome assembly. The task of sorting out which segments of DNA, or which genes, are to be transcribed into RNA at a given moment occurs in the nucleus. A large array of transcription factors and other transcription regulators are also synthesized in the cytoplasm and then imported into the nucleus where they bind to specific genetic loci to perform their role in transcription.
Aptamerized silica/gold nanocapsules for stimulated release of doxorubicin through remote two-photon excitation
Published in International Journal of Smart and Nano Materials, 2022
Lih Shin Tew, Tsung-Hsi Lee, Leu-Wei Lo, Yit Lung Khung, Nai-Tzu Chen
Before evaluating the efficacy of our proposed nanoconstruct in animal model, it was necessary to conduct physical and biological profiling assay to determine the in vitro cellular uptake of nanoconstruct, drug release profile, as well as other post-thermal exfoliation behaviors. Generally, AS1411 aptamer would gain cellular entry via nucleolin receptor that were typically overexpressed in cancer cells, while the surface of non-cancerous cells does not normally present them in large quantities [31,32]. Derenzini et al. had described the expression of nucleolin as inversely proportional to the cell doubling time, and hence, the level of nucleolin is usually presented at higher levels in cancer cells compared to normal healthy cells [33]. In this study, GNS-PEG (without aptamer) and GNS-PEG-Apt (with aptamer) was introduced to MDA-MB-231 cancer cells to determine the uptake efficacy of the nanoconstruct model under in vitro conditions. Inductively coupled plasma mass spectrometry (ICP-MS) was then used to quantify the absolute amount of gold that was internalized within MDA-MB-231 cell,s and the results are presented in Figure 3c. ICP-MS analysis had indicated that the total amount of gold internalized by MDA-MB-231 cells after the aptamer conjugation was significantly higher (approximately 8 fold higher) than that of GNS-PEG. This suggested that the presence of the aptamer had help improve on the level of entry into MDA-MB-231 cells, and its presence had increased the overall efficiency for cellular internalization. Next, we tested the aptamer specificity by co-incubating Cy5-tagged aptamers with non-targeted MCF-10A (non-cancerous) cell lines and MDA-MB-231 cells (cancerous), respectively, and observed the differences in uptake through confocal microscopy visualization (Figure 3d). It was obvious that Cy5-tagged aptamer (red) were found to be more prevalent within the cytoplasm of MDA-MB-231 cells after 2 hours of incubation even at 17 pmoles concentration (Figure 3d). Furthermore, the visualization of intracellular uptake was observed to have increased with rising concentrations of the aptamer. In contrast, MCF-10A cells did not shown any noticable uptake from confocal visualization, even at high concentration (68 pmoles) of aptamer. From these studies, we had demonstrated the usefulness of AS1411 DNA aptamer as a targeting moiety on the surface of the nanocapsule. Furthermore, in view of the fact for low uptake of the nanoparticles in the absence of the AS1411 due to the underlying PEG layer, the author felt that a direct comparison between non-functionalized nanoparticle and functionalized nanoparticle would not be meaningful due to non-binding/aggregation effects even as observed during the course of our experimentation.