China
Africa
Explore chapters and articles related to this topic
Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
Substances necessary for brain nutrition and survival are distributed thanks to specific transporters and internalizing receptors localized on the luminal and basolateral side of the endothelial cells that constitute the BBB. These specific transport systems can be used to deliver drugs to the CNS. Some drugs are able to target such transporters, whereas other drugs need to be chemically modified in order to induce and/or increase their transport through the BBB. Targeting may be obtained thanks to specific ligands or antibodies attached to the drug. This approach is based on receptor-mediated transcytosis. Insulin, transferrin, and low-density lipoprotein receptors are commonly used.219 CRM197, a non-toxic mutant of diphtheria toxin, was also used as a possible vector.223 Limitations to this approach are: (1) the necessity to obtain drugs that bind to a specific receptor and easily dissociate once they have crossed the endothelial interface to be delivered to the CNS; and (2) systemic effects due to the presence of such receptors in peripheral organs.
Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
Diphtheria toxins (DT) are secreted by the Corynebacterium dipheriae, a gram-positive bacterium that is known to cause an infectious disease known as diphtheria. This toxic substance is encoded by a tox gene, which is caused by a bacteriophage, that lives inside certain bacteria. To produce DT, a C.diphtheriae bacterium needs to contain the tox+ phages. Recent studies have evaluated mutated DT to validate its anticancer activity. In vivo evaluation was reported (Lubran et al., 1988)to validate the effects of CRM197, a mutated DT carrier protein that is often used for vaccines, on human adrenocortical carcinoma. CRM197 could bind to heparin-binding EGF-like growth factor (HB-EGF), which is common in adrenocortical carcinomas. By binding to HB-EGF, CRM197 reduced angiogenesis and initiated apoptosis. Notably, CRM197 also inhibited cancerous cell migration (Lubran, 1988) that prevented metastasis. Another study (Zhang et al., 2010) carried out by using a DT mutant DT385, in vivo on chick chloroallantoic membrane (CAM), Lewis lung cancer (LLC) mouse model, and 18 different cancer cells. DT385 inhibited angiogenesis in CAM but were resistant to endothelial cells. In LLC cells, the subcutaneous growth was slightly inhibited. The tumor size reduced meaningfully. DT385 showed mild to strong sensitivity in 15 out of 18 tested cancer cell types. Human malignant cell lines U-87 MG (glioma), HEK293 (kidney), Hela (cervical), Calu-3 (lung), U251 (glioblastoma), and 293T (lung) showed high sensitivity to DT385. Moderate sensitivity was noted in MDA-MB-231 (breast), Colo201 (colon), Colo205 (colon), PC-3 (prostate), HT1080 (fibrosarcoma), and LNCap (prostate). Weakly sensitive cell lines were MCF7 (breast), HCT116 (colon/rectum), Hep3 (cervical), NB4 (promyelocytic leukemia), HL-60 (myeloid leukemia), and BT-20 (breast) (Zhang et al., 2010). DT385 prevents cell proliferation by inducing apoptosis.
GMMA as a ‘plug and play’ technology to tackle infectious disease to improve global health: context and perspectives for the future
Published in Expert Review of Vaccines, 2022
Diego Piccioli, Erika Bartolini, Francesca Micoli
GMMA-saccharide glycoconjugate showed a carrier effect, improving saccharide immunogenicity, compared to unconjugated carbohydrates, that were not or poorly immunogenic, as expected [87]. Also, we observed that the carrier effect was superior to those obtained by conjugation to CRM197, a carrier protein extensively used in licensed vaccines [87,89,90]. Interestingly, the carrier effect of GMMA was observed whether saccharides were attached to proteins or LPS molecules [87]. The conjugation of Malaria protein antigens to GMMA elicited an antigen-specific antibody response that was superior to those induced by the physical mixture of antigens and GMMA at the same doses [87]. By using MenB fHbp as protein antigen, despite the antibody response was similar when immunized with GMMA and fHbp conjugated or physically mixed at the same doses, the functionality of antibody response was significantly different [87]. The conjugation to GMMA induced an antigen-driven bactericidal activity, which was notably superior to those elicited by the physical mixture [87]. The bactericidal activity is a correlate of protection for meningococcus diseases in humans, and then it is an optimal functional assay to generate a proof of concept in preclinical studies [23,24]. In addition, the conjugation of MenB fHbp to GMMA promoted a functional antibody response also against MenA and MenW strains bearing heterologous variants of fHbp, confirming that the superior quality of antibody response stimulated by GMMA as an antigen carrier can promote a broad protection among meningococcal strains [87].
Progress in the overall understanding of typhoid fever: implications for vaccine development
Published in Expert Review of Vaccines, 2020
Peter J O’Reilly, Dikshya Pant, Mila Shakya, Buddha Basnyat, Andrew J Pollard
There is much interest in the use of TCVs to assist in the control of enteric fever in high burden areas. In addition to those already licensed there are several other TCVs in various stages of development. These include Vi-CRM197 developed by GSK (now partnered with an Indian manufacturer), a Vi-TT vaccine from Zydus Cadila and Vi-DT (diphtheria toxoid) from the International Vaccine Institute (with manufacturing partners) [94]. Vi-CRM197 is a TCV where the polysaccharide antigen is conjugated to the nontoxic mutant of diphtheria toxin CRM197 [107]. Vi-CRM197 is reported to be safe and immunogenic in endemic populations including infants 6–8 weeks of age. However, it did not show a significant booster response when a second dose was given and in a Pakistani cohort there was no increase seen in anti-Vi antibody at 6-months post vaccine [108]. Further development is ongoing.
Transmission-Blocking Vaccines: Harnessing Herd Immunity for Malaria Elimination
Published in Expert Review of Vaccines, 2021
CRM197 and Tetanus Toxoid (TT) have been extensively studied in polysaccharide conjugate vaccines and are used in approved bacterial vaccines [82]. In a recent study, TBV antigens were assessed as immunogens after conjugation to two commercially available CRM197 products: CRM197 expressed in the periplasm of Pseudomonas fluorescens, and EcoCRM® prepared as soluble, intracellular properly folded protein in E. coli [83]. This study also examined TT, as well as a 50 kDa recombinant N-terminal fragment of tetanus toxin heavy chain (rTThc) expressed in E. coli, as carriers for TBV. In mice, Pfs230 conjugates prepared with CRM197, EcoCRM® and TT all induced greater functional activity compared to conjugates prepared with EPA [84].