Nanoparticles for Cardiovascular Medicine: Trends in Myocardial Infarction Therapy
Harishkumar Madhyastha, Durgesh Nandini Chauhan in Nanopharmaceuticals in Regenerative Medicine, 2022
Solid lipid nanoparticles combine the advantages of colloidal liposome or nano-emulsion systems with polymeric nanoparticles. Generally, solid lipid nanoparticles have superior biocompatibility and biodegradability; can be synthesised without the use of organic solvents that may otherwise damage payloads; have high physical stability, thereby allowing for ease of sterilisation and storage; can control drug release and targeting; can encapsulate both lipophilic and hydrophilic drugs; and they can be manufactured in large scale. Solid lipid nanoparticles are widely used to improve hydrophobic drug delivery to target cells, either through passive mechanisms dependent on the tissue microenvironment, through active mechanisms promoted by the use of surface modification of solid lipid nanoparticles, or via codelivery mechanisms. A popularised modification of solid lipid nanoparticles is PEGylation to facilitate improved circulation time and reduced immune recognition, often resulting in improved bioactivity of loaded drugs in vivo and improved MI therapy (Zhang et al. 2016; Guo et al. 2019). In addition, PEGylation provides an additional modification site (also known as a PEG linker) to further functionalise the nanoparticles.
Interferon Alpha
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
After subcutaneous injection, standard (unpegylated) interferon alpha is rapidly absorbed (absorption half-life: 2.3 hours), reaches plasma maximum concentration (Cmax) within 1–8 hours, is widely distributed throughout body fluids and tissues, and is rapidly metabolized and cleared by the kidneys (Wills et al., 1984; Wills, 1990; Table 260.6). These variables lead to rapid elimination (elimination half-life: of 3–8 hours) and undetectable concentrations in the serum within 24 hours of administration (Wills et al., 1984; Wills, 1990). The pharmacokinetic properties of interferon alpha certainly suggested that the thrice-weekly dosing regimen was suboptimal, especially given that there are two consecutive days each week when patients have no detectable levels of the administered medication. With this in mind, pegylation technology was applied to improve the pharmacokinetics and pharmacodynamics of interferon alpha to avoid large fluctuations in serum concentrations and to improve the inconvenient dosing regimen.
Radiochemistry for Preclinical Imaging Studies
George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos in Handbook of Small Animal Imaging, 2018
99mTc-maraciclatide (previously known as 99mTc-NC100692) is an eight amino acid peptide based on the RGD motif (Edwards et al. 2008). The RGD unit binds to αvβ3 and αvβ5 integrins, which are biomarkers of angiogenesis. This core unit is flanked by a pair of cysteine residues, which together form an intramolecular disulfide bond. This leads to a cyclic, more rigid peptide exposing the RGD unit, which is favorable for binding to the integrins. A second bridge is formed by another pair of outer amino acids forming a thioether; see Figure 16.4. The chelator is a diamine dioxime with similarities to that in 99mTc-exametazime; see Figure 16.2a. The linker is glutaramide extending the sidechain of the N terminal lysine residue. The C terminus is decorated with a chain of two biomodifiers: a polyethyleneglycol (PEG) oligomer with terminal amino groups followed by diglycolamide. PEGylation generally increases molecular hydrophilicity and the systemic clearance rate in vivo.
Advances in the pharmacological management of neutropenia in solid tumors: the advent of biosimilars
Published in Expert Opinion on Pharmacotherapy, 2021
Michele Ghidini, Alice Indini, Olga Nigro, Simona Polito, Erika Rijavec, Fausto Petrelli, Gianluca Tomasello
Pegylation is a process in which polyethylene glycol chains are attached to protein drugs, increasing the mass and allowing drug protection from enzyme degradation and rapid renal clearance. PEG is administered once per CT cycle (injected subcutaneously [sc]) as a single dose of either 100 μg/kg -individualized- or of a total dose of 6 mg as a general approach) [29]. A randomized Phase III trial demonstrated that a single dose of PEG was comparable to multiple daily injections of FIL in providing neutrophil support after myelosuppressive CT, and was as safe and well-tolerated as FIL [31]. Further studies showed that the efficacy of PEG was similar to or greater than FIL, with a schedule of administration characterized by a better treatment compliance and improved patient quality of life [36–39]. Prophylaxis with PEG was also effective and well-tolerated in patients with lymphoma receiving CT, particularly in dose-dense schedules of treatment [40,41]. A novel device (Neulasta® Onpro® kit) can trigger an automatic administration of pegfilgrastim approximately 27 hours after the cycle of CT. An on-body injector is applied on the left or right side of the abdomen or at the back of upper arm (triceps) after being filled with the syringe content at the end of CT. The device inserts directly a subcutaneous cannula and provides automatic administration of pegfilgrastim at the programmed time [42].
Early stage clinical trials for the treatment of hemophilia A
Published in Expert Opinion on Investigational Drugs, 2022
Gianna M Guzzardo, Robert Sidonio, Jr, Michael U Callaghan, Katherine Regling
PEGylation is a technique which covalently attaches polyethylene glycol (PEG) to a protein, peptide or small molecule. In HA, PEG covalently attaches to FVIII which creates a hydrophilic ‘protective’ barrier around the molecule by way of increased molecular weight and size of the protein. This is thought to be protective of activity and subsequent degradation of FVIII, leading to decreased clearance and a prolonged plasma half-life [36,37]. Currently, there are approved PEGylated FVIII products and ongoing investigation of new products. One such product is FRSW117 (Jiangsu Gensciences Inc), a PEGylated rhFVIII-Fc fusion protein for severe hemophilia A. A phase 2, multicenter, open-label study to evaluate the PK, safety and efficacy has been opened but remains in the pre-recruitment phase (NCT05265286) [38].
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
Polyethylene glycol (PEG) is a water-soluble polymer with a structure of repeated units of polyether diols (either linear or branched) chemically formulated as H-(OCH2CH2)n-OH. It has a relative molecular weight of 200 to 8000 or above, but it exists as a mixture of different molecular weights with 44 Da difference. PEGylation is covalent binding with one or more PEG chains with proteins, peptides, or small organic molecules. The aim of most PEGylation is to increase the molecular weight of drugs to reduce kidney filtration for increasing the circulation half-life, but it also brings in multiple improved properties for peptide and protein drugs, including decreasing the accessibility for proteolytic enzymes [127–129]. However, PEGylation has some disadvantages, such as immunogenicity of the PEG, and heterogeneity of the conjugated molecules [130,131].
Related Knowledge Centers
- Antibody
- Chemical Structure
- Peptide
- Polyethylene Glycol
- Protein
- Immunogenicity
- Macrogol
- Kidney
- Pharmacology
- Molecular Binding