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Peptide drug conjugate

Yiyang Lin, Manuel M Mazo, Stacey C Skaalure, Michael R Thomas, Simon R Schultz, Molly M Stevens
Spatio-temporally tailoring cell-material interactions is essential for developing smart delivery systems and intelligent biointerfaces. Here we report new photo-activatable cell-material interfacing systems that trigger cellular uptake of various cargoes and cell adhesion towards surfaces. To achieve this, we designed a novel photo-caged peptide which undergoes a structural transition from an antifouling ligand to a cell-penetrating peptide upon photo-irradiation. When the peptide is conjugated to ligands of interest, we demonstrate the photo-activated cellular uptake of a wide range of cargoes, including small fluorophores, proteins, inorganic ( e...
January 28, 2019: Chemical Science
Şenay Hamarat Şanlıer, Güliz Ak, Habibe Yılmaz, Ayşe Ünal, Ümmühan Fulden Bozkaya, Gökçe Tanıyan, Yeliz Yıldırım, Gülbeyaz Yıldız Türkyılmaz
Non-small cell lung cancer (NSCLC) constitutes more than 85% of lung cancer case. Pemetrexed is used to treat types of NSCLC, and pazopanib is used for some types of soft tissue sarcoma. The aim of the study was development of pemetrexed and pazopanib carrying nanobubble system with magnetic responsiveness and ultrasound sensitivity properties for targeted NSCLC therapy. Drugs were linked to newly designed peptide, and peptide drug conjugates were attached to amine-modified magnetite. Resulting nanoparticles were encapsulated into liposomes, and liposomes were extruded, then nanobubble system was prepared...
March 2019: Journal of Pharmaceutical Sciences
Alexander A Vinogradov, Yizhen Yi, Hiroaki Suga
Peptides as a therapeutic modality attract much attention due to their synthetic accessibility, high degree of specific binding, and the ability to target protein surfaces traditionally considered "undruggable". Unfortunately, at the same time, other pharmacological properties of a generic peptide, such as metabolic stability and cell permeability, are quite poor, which limits the success of de novo discovered biologically active peptides as drug candidates. Here, we review how macrocyclization as well as the incorporation of non-proteogenic amino acids and various conjugation strategies may be utilized to improve on these characteristics to create better drug candidates...
February 15, 2019: Journal of the American Chemical Society
Shouta Miyatake, Yoshitaka Mizobe, Maria K Tsoumpra, Kenji Rowel Q Lim, Yuko Hara, Fazel Shabanpoor, Toshifumi Yokota, Shin'ichi Takeda, Yoshitsugu Aoki
Exon skipping using phosphorodiamidate morpholino oligomers (PMOs) is a promising treatment strategy for Duchenne muscular dystrophy (DMD). The most significant limitation of these clinically used compounds is their lack of delivery systems that target muscles; thus, cell-penetrating peptides are being developed to enhance uptake into muscles. Recently, we reported that uptake of peptide-conjugated PMOs into myofibers was mediated by scavenger receptor class A (SR-A), which binds negatively charged ligands...
January 25, 2019: Molecular Therapy. Nucleic Acids
Di Jiang, Minjun Xu, Yuanyuan Pei, Yukun Huang, Yu Chen, Fenfen Ma, Huiping Lu, Jun Chen
Emergence of drug resistance in tumors causes therapeutic failure or tumor relapse. Combination of chemotherapy and photodynamic therapy holds significant promise to treat drug-resistant tumors. However, stubborn hydrophobicity of photosensitizer (PS), low encapsulation efficiency and leaking problem of PS in organic carrier, and disparate physicochemical properties of PS and chemotherapeutics make the combination unachievable. Thus how to efficiently co-deliver the two functional agents to enable photo-chemotherapy seems to be one of the key challenges...
February 11, 2019: Acta Biomaterialia
Parisa Yousefpour, Lucie Ahn, Joel Tewksbury, Soumen Saha, Simone A Costa, Joseph J Bellucci, Xinghai Li, Ashutosh Chilkoti
Short circulation time and off-target toxicity are the main challenges faced by small-molecule chemotherapeutics. To overcome these shortcomings, an albumin-binding peptide conjugate of chemotherapeutics is developed that binds specifically to endogenous albumin and harnesses its favorable pharmacokinetics and pharmacodynamics for drug delivery to tumors. A protein-G-derived albumin-binding domain (ABD) is conjugated with doxorubicin (Dox) via a pH-sensitive linker. One to two Dox molecules are conjugated to ABD without loss of aqueous solubility...
February 13, 2019: Small
Ajmeeta Sangtani, Eleonora Petryayeva, Kimihiro Susumu, Eunkeu Oh, Alan L Huston, Guillermo Lasarte-Aragones, Igor L Medintz, W Russ Algar, James B Delehanty
Multidrug resistance (MDR) is a significant challenge in the treatment of many types of cancers as membrane-associated transporters actively pump drugs out of the cell, limiting therapeutic efficacy. While nanoparticle (NP)-based therapeutics have emerged as a mechanism for overcoming MDR, they often rely on the delivery of multiple anticancer drugs, nucleic acid hybrids, or MDR pump inhibitors. The effectiveness of these strategies, however, can be limited by their off-target toxicity or the need for genetic transfection...
February 8, 2019: Bioconjugate Chemistry
Wenjun Shan, Haiping Zheng, Guofeng Fu, Chenfeng Liu, Zizhen Li, Yuhan Ye, Jie Zhao, Dan Xu, Liping Sun, Xin Wang, Xiao Lei Chen, Shengli Bi, Lei Ren, Guo Fu
Protein nanocages are promising multifunctional platforms for nanomedicine owing to the ability to decorate their surfaces with multiple functionalities through genetic and/or chemical modification to achieve desired properties for therapeutic and diagnostic purposes. Here, we describe a model antigen (OVA peptide), was conjugated to the surface of a naturally occurring hepatitis B core protein nanocage (HBc NC) by genetic modification. The engineered OVA-HBc nanocages (OVA-HBc NCs), displaying high density repetitive array of epitopes in a limited space by self-assembling into symmetrical structure, can not only induce bone marrow derived dendritic cells (BMDC) maturation effectively, but also be enriched in the draining lymph nodes...
February 6, 2019: Nano Letters
Xin Chen, Yunzhen Xu, Xiaoxu Li, Shiqi Liao
Fluorescein diester which is conjugated with cell membrane permeable Arg9 peptide was proposed as probe for ester prodrug stability and drug release study in living cells. α-Amino protected d-Val and l-Ala which bear differently hindered side chains were used to afford model diesters of 5-maleimide-fluorescein. Such fluorescein diesters were further conjugated with a Cys containing cell membrane permeable Arg9 peptide via thiol-ene crosslink reaction. The resulted conjugates of fluorescein diester and Arg9 peptide were purified with HPLC and characterized with MALDI-TOF MS...
January 29, 2019: Bioorganic & Medicinal Chemistry
Siwen Wu, Wen Bin, Biyun Tu, Xifeng Li, Wei Wang, Suling Liao, Changshan Sun
Proteins/peptides are poorly absorbed via oral administration because of the gastrointestinal tract environment and lysosomal digestion after apical endocytosis. A delivery system, consisting of a deoxycholic acid-conjugated nanometer-sized carrier, may enhance the absorption of proteins/peptides in the intestine via the bile acid pathway. Deoxycholic acid is first conjugated to chitosan. Liposomes are then prepared and loaded with the model drug insulin. Finally, the conjugates are bound to the liposome surface to form deoxycholic acid conjugate-modified liposomes (DC-LIPs)...
February 2, 2019: Journal of Pharmaceutical Sciences
Nisar Sayyad, Eirinaios I Vrettos, Theodoros Karampelas, Christos M Chatzigiannis, Katerina Spyridaki, George Liapakis, Constantin Tamvakopoulos, Andreas G Tzakos
Peptide-drug conjugates have emerged as a potent approach to enhance the targeting and pharmacokinetic profiles of drugs. However, the impact of the linker unit has not been explored/exploited in depth. Gemcitabine (dFdC) is an anticancer agent used against a variety of solid tumours. Despite its potency, gemcitabine suffers mostly due to its unspecific toxicity, lack of targeting and rapid metabolic inactivation. To minimize these limitations and enable its targeting to tumours overexpressing the GnRH receptor, we examined the peptide-drug conjugation approach...
January 18, 2019: European Journal of Medicinal Chemistry
Maria Pia Savoca, Elisa Tonoli, Adeola G Atobatele, Elisabetta A M Verderio
The biocatalytic activity of transglutaminases (TGs) leads to the synthesis of new covalent isopeptide bonds (crosslinks) between peptide-bound glutamine and lysine residues, but also the transamidation of primary amines to glutamine residues, which ultimately can result into protein polymerisation. Operating with a cysteine/histidine/aspartic acid (Cys/His/Asp) catalytic triad, TGs induce the post-translational modification of proteins at both physiological and pathological conditions (e.g., accumulation of matrices in tissue fibrosis)...
October 31, 2018: Micromachines
Sameer Sachdeva, Hyun Joo, Jerry Tsai, Bhaskara Jasti, Xiaoling Li
This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture studies, designed peptides specifically bind and internalize to EGFR overexpressing cells with three to four-fold higher uptake compared to control cells that do not overexpress EGFR...
January 30, 2019: Scientific Reports
Yong Cong, Lei Ji, Yu-Juan Gao, Fu-Hua Liu, Dong-Bing Cheng, Zhiyuan Hu, Zeng-Ying Qiao, Hao Wang
Nanoparticles preferentially target and accumulate in tumor due to the abnormality of tumor vasculature. However, unsatisfactory solid tumor penetration somewhat limits the therapeutic efficacy. Herein, by employing 'in vivo self-assembly' strategy, we have designed an acid-induced hydrophobicity-increasing polymer-peptide conjugates (PPCs) with narrow pH response range (from 7.4 to 6.5) under proper molecular concentration (around IC50 of PPCs), successfully realizing in-situ self-assembly process in tumor microenvironment for tumor-deeper drug delivery...
January 29, 2019: Angewandte Chemie
Divya Dheer, Julien Nicolas, Ravi Shankar
Cathepsins are an important category of enzymes that have attracted great attention for the delivery of drugs to improve the therapeutic outcome of a broad range of nanoscale drug delivery systems. These proteases can be utilized for instance through actuation of polymer-drug conjugates (e.g., triggering the drug release) to bypass limitations of many drug candidates. A substantial amount of work has been witnessed in the design and the evaluation of Cathepsin-sensitive drug delivery systems, especially based on the tetra-peptide sequence (Gly-Phe-Leu-Gly, GFLG) which has been extensively used as a spacer that can be cleaved in the presence of Cathepsin B...
January 25, 2019: Advanced Drug Delivery Reviews
Kavita Yadav, Sandeep Kumar, Deepakkumar Mishra, Mohammad Asad, Madhurima Mitra, Prabhu Srinivas Yavvari, Siddhi Gupta, Madhukar Vedantham, Pavit Ranga, Varsha Komalla, Sanjay Pal, Priyanka Sharma, Arti Kapil, Archana Singh, Nirpendra Singh, Aasheesh Srivastava, Lipi Thukral, Avinash Bajaj
Presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gram-negative bacterial infections highly challenging. Herein, we present the synthesis and antibacterial activities of Cholic Acid-Peptide conjugates (CAPs) demonstrating that Valine-Glycine dipeptide-derived CAP 3 is the most effective antimicrobial. MD simulations and structural analysis revealed that precise intramolecular network of CAP 3 is maintained in the form of evolving edges suggesting intramolecular connectivity...
January 28, 2019: Journal of Medicinal Chemistry
Shuaishuai Feng, Zi-Xin Wu, Ziyan Zhao, Jinhu Liu, Kaoxiang Sun, Chuanyou Guo, Hongbo Wang, Zimei Wu
This study aimed to develop an efficient step-by-step osteosarcoma (OS)-targeting liposome system functionalized with a redox-cleavable, bone- and cluster of differentiation 44 (CD44)-dual-targeting polymer. Furthermore, the effect of coadministration of a tumor-penetrating peptide, internalizing-RGD (iRGD), was investigated. First, a bone-targeting moiety, alendronate (ALN), was conjugated with hyaluronic acid (HA), a ligand for CD44. This ALN-HA conjugate was coupled with DSPE-PEG2000-COOH through a bioreducible disulfide linker (-SS-) to obtain a functionalized lipid, ALN-HA-SS-L, to be post-inserted into preformed liposomes loaded with doxorubicin (DOX)...
January 25, 2019: ACS Applied Materials & Interfaces
Jui-Chih Chang, Huei-Shin Chang, Yao-Chung Wu, Wen-Ling Cheng, Ta-Tsung Lin, Hui-Ju Chang, Shou-Jen Kuo, Shou-Tung Chen, Chin-San Liu
BACKGROUND: The transfer of whole mitochondria that occurs during cell contact has been found to support cancer progression. However, the regulatory role of mitochondria alone is difficult to elucidate due to the complex microenvironment. Currently, mitochondrial transplantation is an available approach for restoring mitochondrial function in mitochondrial diseases but remains unclear in breast cancer. Herein, effects of mitochondrial transplantation via different approaches in breast cancer were investigated...
January 23, 2019: Journal of Experimental & Clinical Cancer Research: CR
Yan Lin, Chunhong Li, Jian Li, Ruolan Deng, Juan Huang, Qinglian Zhang, Jiayao Lyu, Na Hao, Zhirong Zhong
BACKGROUND: Frequent injection of high-dose methylprednisolone (MP) is used to treat spinal cord injury (SCI), but free MP is associated with various side effects and its water solubility is low, limiting potential dosing regimes and administration routes. Albumin-based nanoparticles, which can encapsulate therapeutic drugs and release cargo in a controlled pattern, show high biocompatibility and low toxicity. The Nogo protein, expressed on the surface of oligodendrocytes, can inhibit axonal growth by binding with the axonal Nogo receptor (NgR)...
January 22, 2019: Journal of Nanobiotechnology
Xinxin Yu, Renshu Zhang, Lei Lei, Qianqian Song, Xingyi Li
Purpose: To develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis. Materials and methods: We designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis. Results: An in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period...
2019: International Journal of Nanomedicine
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