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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Kimura et al. engineered Ecballium elaterium trypsin inhibitor (EETI-II) as integrin binding agents. They created a yeast displayed library of EETI-II by substituting 6 residues of trypsin binding loop with 11 amino acids comprising integrin binding motif (R-G-D) and randomized the terminal residues. Engineered knottin peptides showed high binding affinity for αvβ3, αvβ5, and α5β1 integrins. These engineered integrin binding knottin peptides are of great medical importance as they can bind to all three receptors that are co-expressed in tumor cells. Jiang et al. engineered peptides that can bind alpha(V)beta(3) integrin with high affinity and specificity by exploiting agouti related protein (a 4kD cysteine knot peptide) as a scaffold (Jiang et al., 2010). Kimura et al. have also developed knottin peptides that are labeled with both near-infrared fluorescence (NIRF) and positron emission tomography (PET) imaging agents. The resulting dual labeled knottin peptides are being proposed to be used for multimodality imaging and for the detection of deeply located tumors in the body (Kimura et al., 2010).
Aptamers and Cancer Nanotechnology
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Omid C. Farokhzad, Sangyong Jon, Robert Langer
Alpha-v beta-3 (αvβ3) integrin is a transmembrane glycoprotein that mediates numerous processes, including cell migration, cell growth, tumor growth and metastasis, angiogenesis, and vascular healing. The expression of this protein on the endothelial cells of tumor neovasculature is dramatically increased, making αvβ3 an interesting protein for targeting approaches.55 An 85-base-pair 2’-flouropyrimidine RNA aptamer (Apt-αvβ3) has been shown to bind to the αvβ3 protein on the surface of endothelial cells in vitro and inhibit endothelial cell proliferation and survival.56 The future in vivo use of the Apt-αvβ3 may require post-SELEX optimization, including size minimization to facilitate large-scale synthesis, and enhance the pharmacokinetic properties of this molecule. This aptamer may be utilized for targeted cancer diagnostic and therapeutic applications.
Genetically Engineered Oncolytic Salmonella typhimurium
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
The abilities of attenuated S. typhimurium to colonize and proliferate in tumors and to suppress tumor growth have been found to be specific to cancer types. The targeting efficiency of attenuated S. typhimurium in some cancer models was found to be lower, reducing bacterially mediated antitumor activity. Various strategies involving the display of cancer-specific binding domains have therefore been developed to enhance tumor-specific bacterial colonization. For example, the protein alpha V beta 3 (αVβ3) integrin is highly expressed on activated endothelial cells, newly generated blood vessels, and some tumor cells and is regarded essential for cancer angiogenesis [25]. The arginine-glycine-aspartate (RGD) specifically binds to αVβ3 integrin with high affinity and has been utilized in cancer diagnostic imaging after conjugation with certain imaging probes (e.g., fluorochromes for optical imaging, radionuclides for PET imaging, and magnetic compounds for magnetic resonance imaging). In addition, conjugation of RGD with chemotherapeutic agents, such as doxorubicin, chlorambucil, and camptothecin, can greatly increase the anticancer specificity of these agents and reduce their toxicity to normal tissues [26, 27]. Engineered S. typhimurium displaying RGD on its surface showed strongly increased tumor targeting in αVβ3-overexpressing cancer xenografts, inhibiting tumor development and improving animal survival [12]. In addition, the presence of an anti-CD20 single-domain antibody on the surface of attenuated S. typhimurium and expression of a prodrug-converting enzyme further suppressed the growth of human lymphoma xenografts in mouse models [28].
Current progress of miRNA-derivative nucleotide drugs: modifications, delivery systems, applications
Published in Expert Opinion on Drug Delivery, 2022
Charles Asakiya, Liye Zhu, Jieyu Yuhan, Longjiao Zhu, Kunlun Huang, Wentao Xu
MNPs with higher magnetic moments and increased functionalities have recently been developed to address critical clinical needs[53]. Yigit and colleagues designed ultrasmall MNPs conjugated with tripeptide arginine-glycine-aspartic acid (RGD)-targeting functionalities and further modified with LNA oligonucleotides to deliver antimir-10b[54]. During the nano-drug modifications, a tumor-targeting peptide cRGD with a strong ligand binding for alpha-v-beta-3 (αVβ3) integrin was attached to the nanoparticle after being labeled near infrared (NIR) fluorescent dye Cy5.5 and subsequently delivered to the primary tumor and lymph nodes. The results showed 87.8 ± 6.2% miR-10b suppression, preventing the tumor’s migration and invasion, signifying an efficient and effective nanocarrier for gene delivery.
Correlation between the macroscopic severity of Crohn’s disease in resected intestine and bowel wall thickness evaluated by water-immersion ultrasonography
Published in Scandinavian Journal of Gastroenterology, 2019
Katsuki Yaguchi, Tomohiko Sasaki, Tsuyoshi Ogashiwa, Masafumi Nishio, Yu Hashimoto, Aya Ikeda, Misato Izumi, Akiho Hanzawa, Naomi Shibata, Hiromi Yonezawa, Kentaro Sakamaki, Yoko Tateishi, Kazushi Numata, Shin Maeda, Hideaki Kimura, Reiko Kunisaki
Histological changes such as fibrosis, hyperplasia of smooth muscle tissues, and edema could contribute to bowel wall thickening, secondary to inflammation in CD lesions [27–32]. Histological changes in the intestinal wall in fibrosis are well-reported, and fibrostenosis is believed to be caused by exaggerated recruitment and activation of fibrogenic mesenchymal cells in response to chronic inflammation [27,28]. Additionally, smooth muscle hyperplasia/hypertrophy has also been reported in the intestine in CD [29]. A progressive increase in smooth muscle cell numbers might be sustained in chronic inflammation and tissue damage [30]. Chen et al. considered that increased muscularization was not associated with fibrosis, but with chronic inflammation [31]. This smooth-muscle-cell hyperplasia in the strictures in CD might be regulated by increased endogenous insulin-like growth factor 1 and alpha V beta 3 integrin ligands that regulate augmented proliferation and diminished apoptosis [30]. In these studies, it was difficult to completely separate inflammation and fibrosis, and the authors believed that these factors might interact with each other in severe lesions and contribute to increased BWT.
Synergistic photothermal/photodynamic suppression of prostatic carcinoma by targeted biodegradable MnO2 nanosheets
Published in Drug Delivery, 2019
Dewang Zeng, Lei Wang, Lu Tian, Shili Zhao, Xianfeng Zhang, Hongyan Li
Herein, we have designed a nanoplatform by immobilizing chlorin e6 (Ce6) on polyethylene glycol-cyclic arginine-glycineaspartic acid tripeptide (PEG-cRGD) functionalized MnO2 nanosheets (MnO2-PEG-cRGD/Ce6), which can be used for overcoming the hypoxia of cancer cells and synergistic PTT/PDT (Scheme 1). MnO2 nanosheets were prepared by ultrasonicating exfoliation of bulk MnO2, which was initially synthesized based on the oxidation of manganese chloride by H2O2 in the presence of tetramethylammonium hydroxide and then functionalized with PEG-cRGD to enhance their biocompatibility. The extraordinary surface area of MnO2 nanosheets enables it highly efficient loading of small molecules to achieve different functions. Ce6, a widely used commercial photosensitizer was loaded on the surface of MnO2-PEG-cRGD. As expected, MnO2-PEG-cRGD nanosheets shows a high Ce6 loading capacity (351 mg/g) and exhibits pH/NIR responsive DOX release behavior, as well as significantly increase of large singlet oxygen (SO) generation. Interestingly, the fabricated MnO2-PEG-cRGD/Ce6 exhibits superior photothermal conversion efficiency (37.2%), compared with MnO2-PEG-cRGD (21.4%). Owing to the modification of cRGD peptide, MnO2-PEG-cRGD/Ce6 could be specifically taken by alpha-v beta-3 (αvβ3) integrin receptors over-expressed prostatic carcinoma PC3 cells (Tian et al., 2019). This nanoplatform demonstrates a combination therapy including PTT and PDT based on in vitro tests, which exhibits an excellent synergetic anticancer activity under a single 660 nm NIR laser. Overall, our MnO2-PEG-cRGD/Ce6 is a promising biodegradable nanoplatform for synergistic PTT/PDT under a single laser and this work may explore the application of MnO2-based nanomaterials in combinatorial cancer therapy.