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Peptide drug conjugate

Michael J Gait, Andrey A Arzumanov, Graham McClorey, Caroline Godfrey, Corinne Betts, Suzan Hammond, Matthew J A Wood
The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs...
October 9, 2018: Nucleic Acid Therapeutics
Xueqing Yong, Xuan Yang, Steven R Emory, Jun Wang, Jie Dai, Xiaoya Yu, Ling Mei, Jinbing Xie, Gang Ruan
Targeted delivery of nanomaterials to specific intracellular locations is essential for the development of many nanomaterials-based biological applications. Thus far the targeting performance has been limited due to various intracellular transport barriers, especially intracellular vesicle trapping. Here we report the application of permeation enhancers based on organic solvents in small percentage to enhance the intracellular targeted delivery of nanomaterials. Previously permeation enhancers based on organic solvents and ionic liquids have been used in overcoming biological transport barriers at tissue, organ, and cellular levels, but this strategy has so far rarely been examined for its potential in facilitating transport of nanometer-scale entities across intracellular barriers, particularly intracellular vesicle trapping...
October 10, 2018: Biomaterials Science
Chunhui Liang, Lushuai Zhang, Wene Zhao, Linlin Xu, Yaoxia Chen, Jiafu Long, Fuqiang Wang, Ling Wang, Zhimou Yang
Antibody-based medicines and nanomedicines are very promising for cancer therapy due to the high specificity and efficacy of antibodies. However, antibody-drug conjugates and antibody-modified nanomaterials frequently suffer from low drug loading and loss of functions due to the covalent modification of the antibody. A novel and versatile strategy to prepare supramolecular nanomaterials by the coassembly of an affibody (antiHER2) and drug-peptide amphiphiles is reported here. During the enzyme-instructed self-assembly process, the drug-peptide amphiphile can coassemble with the affibody, resulting in supramolecular nanofibers in hydrogels...
October 9, 2018: Advanced Healthcare Materials
Gang Niu, Guohao Wang, Joseph Lau, Lixin Lang, Orit Jacobson, Ying Ma, Dale O Kiesewetter, Shaoliang Zhang, Xiaoyuan Chen
Abextide, synthesized by conjugating an albumin-binding moiety-truncated Evans blue-to glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. The aim of this study is to evaluate the pharmacodynamics of Abextide in nonhuman primates. Two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. During the whole experiment period, no abnormalities such as swelling at the injection site, lethargy, or hypoglycemia are observed in all animals...
October 9, 2018: Advanced Healthcare Materials
Baozhen Zhang, Mingbin Zheng, Lintao Cai, Xiujun Fan
An effective cancer therapeutic method reduces and eliminates tumors with minimal systemic toxicity. Actively targeting nanoparticles offer a promising approach to cancer therapy. The glycosaminoglycan placental chondroitin sulfate A (plCSA) is expressed on a wide range of cancer cells and placental trophoblasts, and malarial protein VAR2CSA can specifically bind to plCSA. A reported placental chondroitin sulfate A binding peptide (plCSA-BP), derived from malarial protein VAR2CSA, can also specifically bind to plCSA on cancer cells and placental trophoblasts...
September 18, 2018: Journal of Visualized Experiments: JoVE
Pahweenvaj Ratnatilaka Na Bhuket, Jittima Amie Luckanagul, Pornchai Rojsitthisak, Qian Wang
The unique characteristics of enveloped viruses including nanometer size, consistent morphology, narrow size distribution, versatile functionality and biocompatibility have attracted attention from scientists to develop enveloped viruses for biomedical applications. The biomedical applications of the viral-based nanoparticles include vaccine development, imaging and targeted drug delivery. The modification of the structural elements of enveloped viruses is necessary for the desired functions. Here, we review the chemical approaches that have been utilized to develop bionanomaterials based on enveloped viruses for biomedical applications...
October 8, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Malin Källsten, Rafael Hartmann, Konstantin Artemenko, Sara Bergström Lind, Fredrik Lehmann, Jonas Bergquist
Antibody-drug conjugates (ADCs) are an emerging type of biotherapeutics that utilize multiple tissue-specific antibodies combined with a range of linker designs to enable the transportation and selective release of cytotoxic drugs in close proximity to tumours. Consisting of antibodies conjugated to small drug molecules through a variety of linkers, ADCs are chemically complex analytes. Here we present a unique experimental comparison of four techniques for ADC analysis: hydrophobic interaction chromatography (HIC-UV/Vis), reversed phase liquid chromatography mass spectrometry (RPLC-MS), using either a QToF or an Orbitrap analyser, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)...
October 5, 2018: Analyst
Rong Huang, Zhihong Li, Yao Sheng, Jianghui Yu, Yue Wu, Yuexiong Zhan, Hongli Chen, Biao Jiang
Use of N-methyl- N-phenylvinylsulfonamides to perform chemoselective modification of cysteine-containing peptides and proteins is reported. Probes linked to the drug were applicable to prepare antibody-drug conjugates (ADCs). The drug-antibody ratio for ADCs was controlled by rationally tuning the electron deficiency and linker hydrophilicity of the probes.
October 4, 2018: Organic Letters
Tazeem Shaik, Gulam M Rather, Nitu Bansal, Tamara Minko, Olga Garbuzenko, Zoltan Szekely, Emine E Abali, Debabrata Banerjee, John E Kerrigan, Kathleen W Scotto, Joseph R Bertino
E2F1-3a overexpression due to amplification or to mutation or loss of the retinoblastoma gene, induces genes involved in DNA synthesis and leads to abnormal cellular proliferation, tumor growth, and invasion. Therefore, inhibiting the overexpression of one or more of these activating E2Fs is a recognized target in cancer therapeutics. In previous studies we identified by phage display, a novel 7-mer peptide (PEP) that bound tightly to an immobilized consensus E2F1 promoter sequence, and when conjugated to penetratin to increase its uptake into cells, was cytotoxic to several malignant cell lines and human prostate and small cell lung cancer xenografts...
September 7, 2018: Oncotarget
Éva Bartus, Gábor Olajos, Ildikó Schuster, Zsolt Bozsó, Mária A Deli, Szilvia Veszelka, Fruzsina R Walter, Zsolt Datki, Zsolt Szakonyi, Tamás A Martinek, Livia Fülöp
Alzheimer's disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates...
October 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Edward A Greenfield, James DeCaprio, Mohan Brahmandam
Haptens, which are small antigens such as peptides and drug compounds, are very weakly or nonimmunogenic by themselves and require the assistance of carrier proteins: complex molecules capable of eliciting a strong immune response in the host on injection. The haptens serve as epitopes for binding to the antibodies on the B-cell surface, and the carriers provide the MHC class II-T-cell receptor binding sites. Keyhole limpet hemocyanin (KLH) is one of the most widely used of such carrier proteins. KLH-hapten conjugates are commonly used in antibody generation in a variety of hosts such as mice, rats, and rabbits...
October 1, 2018: Cold Spring Harbor Protocols
Yaoxia Chen, Xinjing Li, Jing Bai, Fang Shi, Tengyan Xu, Qingqiu Gong, Zhimou Yang
Short peptide-based hydrogels have attracted extensive research interests in drug delivery because of their responsive properties. So far, most drug molecules have been conjugated with short peptides via an amide bond, restricting the release of the native drug molecules. In this study, we demonstrated the effectiveness of an auxin-based hydrogelator linked by a hydrolysable ester bond. Hydrogel I, formed by the gelator (NAA-G'FFY) linked with an ester bond, was able to release 1-naphthaleneacetic acid (NAA), whereas hydrogel II, formed by the gelator without an ester bond (NAA-GFFY), was not...
October 1, 2018: Chemical Communications: Chem Comm
Nian-Qiu Shi, Yan Li, Yong Zhang, Zheng-Qiang Li, Xian-Rong Qi
Introduction: Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated active targeting drug delivery...
2018: International Journal of Nanomedicine
Patrick J Kennedy, Flavia Sousa, Daniel Ferreira, Carla Pereira, Marika Nestor, Carla Oliveira, Pedro L Granja, Bruno Sarmento
Targeting of CD44 isoforms containing exon v6 (CD44v6) represents a viable strategy for the therapy and/or early diagnosis of metastatic cancers of the epithelium (e.g. gastric and colorectal cancer). We developed and characterized poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) modified with polyethylene glycol (PEG) and engrafted, by site-directed conjugation, with an engineered human Fab that specifically target human CD44v6 (v6 Fab-PLGA NPs). The v6 Fab-PLGA NPs displayed spherical morphology around 300 nm and were negatively charged...
September 27, 2018: Acta Biomaterialia
Yixuan Tang, Shuang Wu, Jiaqi Lin, Liting Cheng, Jing Zhou, Jing Xie, Kexin Huang, Xiaoyou Wang, Yang Yu, Zhangbao Chen, Guojian Liao, Chong Li
Inspired by the fact that chitosan is a representative constituent of the ectocellular structure of Cryptococcus neoformans and a typical biomaterial for improving drug oral absorption, we designed an elegant and efficient C. neoformans-targeted drug delivery system via oral administration. A chitosan-binding peptide screened by phage display was used as the targeting moiety, followed by conjugation to the surface of poly(lactic- co-glycolic acid) nanoparticles as the drug carrier, which was then incubated with free chitosan...
October 1, 2018: Nano Letters
Min Qiu, Xiuxiu Wang, Huanli Sun, Jian Zhang, Chao Deng, Zhiyuan Zhong
Monomethyl auristatin E (MMAE) is an extremely potent peptide drug that is currently used in the form of antibody drug conjugates (ADCs) for treating different cancers. ADCs are, however, associated with low drug conjugation, immunogenicity, small scale production, and high costs. Here, cRGD-functionalized polylipopeptide micelles (cRGD-Lipep-Ms) were explored for enhanced loading and targeted delivery of MMAE to HCT-116 colorectal tumor xenografts. Interestingly, cRGD-Lipep-Ms achieved an MMAE loading content of 5...
September 27, 2018: Molecular Pharmaceutics
Libin Zhang, Yixin Fang, Lian Li, Jiyuan Yang, D Christopher Radford, Jindřich Kopeček
A therapeutic platform-drug-free macromolecular therapeutics (DFMT)-that induces apoptosis in B cells by cross-linking of CD20 receptors, without the need for low molecular weight cytotoxic drug, is developed. In this report, a DFMT system is synthesized and evaluated based on human serum albumin (HSA) and two complementary coiled-coil forming peptides, CCE and CCK. Fab' fragment of anti-CD20 monoclonal antibody rituximab is attached to CCE (Fab'-CCE); multiple grafts of CCK are conjugated to HSA (HSA-(CCK)7 )...
September 27, 2018: Macromolecular Bioscience
Mariana Nogueira Batista, Paulo Ricardo da Silva Sanches, Bruno Moreira Carneiro, Ana Cláudia Silva Braga, Guilherme Rodrigues Fernandes Campos, Eduardo Maffud Cilli, Paula Rahal
In recent years, synthetic peptides have been considered promising targets for drug development that possess low side-effects, are cost-effective and are susceptible to rational design. Hecate was initially described as a potent bacterial inhibitor and subsequently as an anticancer drug with functions related to its lipid interaction property. Viruses, such as hepatitis C virus (HCV), have a lipid-dependent life cycle and could be affected by Hecate in many ways. Here, we assessed modifications on Hecate's N-terminus region and its effects on HCV and hepatotoxicity...
September 25, 2018: Scientific Reports
Soohyun Kwon, Joao N Duarte, Zeyang Li, Jingjing J Ling, Olivier Cheneval, Thomas Durek, Christina I Schroeder, David J Craik, Hidde L Ploegh
Many naturally occurring peptides have poor proteolytic stability, which limits their therapeutic applications. Cyclotides are plant-derived cyclic peptides that resist proteolysis due to their highly constrained structure, comprising a head-to-tail cyclic backbone and three disulfide bonds that form a cystine-knotted core. This structure makes them useful as scaffolds onto which peptide sequences (epitopes) can be grafted. In this study, VHH7, an alpaca-derived nanobody that targets murine class II MHC molecules, was used for the targeted delivery of cyclotides to antigen-presenting cells (APCs)...
October 5, 2018: ACS Chemical Biology
Baozhen Zhang, Zhilong Chen, Jinyu Han, Mengxia Li, Nihar R Nayak, Xiujun Fan
No effective treatments currently exist for placenta-associated pregnancy complications, and developing strategies for the targeted delivery of drugs to the placenta while minimizing fetal and maternal side effects remains challenging. Targeted nanoparticle carriers provide new opportunities to treat placental disorders. We recently demonstrated that a synthetic placental chondroitin sulfate A binding peptide (plCSA-BP) could be used to guide nanoparticles to deliver drugs to the placenta. In this protocol, we describe in detail a system for assessing the efficiency of drug delivery to the placenta by plCSA-BP that employs three separate methods used in combination: in vivo imaging, high-frequency ultrasound (HFUS), and high-performance liquid chromatography (HPLC)...
September 10, 2018: Journal of Visualized Experiments: JoVE
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