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Peptide drug conjugate

Ignacio Melgar-Asensio, Irawati Kandela, Fraser Aird, Soesiawati R Darjatmoko, Cristobal de Los Rios, Christine M Sorenson, Daniel M Albert, Nader Sheibani, Jack Henkin
Purpose: Drug delivery by intravitreal injection remains problematic, small agents and macromolecules both clearing rapidly. Typical carriers use microparticles (>2 μm), with size-related liabilities, to slow diffusion. We recently described cationic nanoparticles (NP) where conjugated Arg peptides prolonged residence in rat eyes, through ionic interaction with vitreal poly-anions. Here we extended this strategy to in vivo tracking of NP-conjugate (NPC) clearance from rabbit eyes...
August 1, 2018: Investigative Ophthalmology & Visual Science
Francisco Morales-Zavala, Nathalie Casanova-Morales, Raúl B Gonzalez, América Chandía-Cristi, Lisbell D Estrada, Ignacio Alvizú, Victor Waselowski, Fanny Guzman, Simón Guerrero, Marisol Oyarzún-Olave, Cristian Rebolledo, Enrique Rodriguez, Julien Armijo, Heman Bhuyan, Mario Favre, Alejandra R Alvarez, Marcelo J Kogan, Jerónimo R Maze
BACKGROUND: Stable and non-toxic fluorescent markers are gaining attention in molecular diagnostics as powerful tools for enabling long and reliable biological studies. Such markers should not only have a long half-life under several assay conditions showing no photo bleaching or blinking but also, they must allow for their conjugation or functionalization as a crucial step for numerous applications such as cellular tracking, biomarker detection and drug delivery. RESULTS: We report the functionalization of stable fluorescent markers based on nanodiamonds (NDs) with a bifunctional peptide...
August 10, 2018: Journal of Nanobiotechnology
Fatemeh Ostadhossein, Santosh K Misra, Indu Tripathi, Valeriya Kravchuk, Gururaja Vulugundam, Denae LoBato, Laura E Selmic, Dipanjan Pan
The removal of tenacious dental plaque is of paramount importance; however, early diagnosis can be a challenging task in dental clinics due to the limitations of current approaches, specifically X-ray-based techniques. We have approached this problem by integrating antibacterial properties and X-ray contrast enhancement in a single probe specific to colonies of Streptococcus mutans as the most predominant and carious oral bacteria. We report the synthesis of an inherently therapeutic polymeric silane conjugated hafnium oxide nanoparticles (Hf PS NPs)...
July 30, 2018: Biomaterials
Zoltán Bánóczi, András Keglevich, Ildikó Szabó, Ivan Ranđelović, Zita Hegedüs, Fruzsina L Regenbach, Péter Keglevich, Zsófia Lengyel, Álmos Gorka-Kereskényi, Zsófia Dubrovay, Viktor Háda, Áron Szigetvári, Csaba Szántay, László Hazai, József Tóvári, Ferenc Hudecz
Some Vinca alkaloids (eg, vinblastine, vincristine) have been widely used as antitumor drugs for a long time. Unfortunately, vindoline, a main alkaloid component of Catharanthus roseus (L.) G. Don, itself, has no antitumor activity. In our novel research program, we have prepared and identified new vindoline derivatives with moderate cytostatic activity. Here, we describe the effect of conjugation of vindoline derivative with oligoarginine (tetra-, hexa-, or octapeptides) cell-penetrating peptides on the cytostatic activity in vitro and in vivo...
August 6, 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Liberty François-Moutal, David Donald Scott, Samantha Perez-Miller, Vijay Gokhale, May Khanna, Rajesh Khanna
Drug discovery campaigns directly targeting the voltage-gated sodium channel NaV1.7, a highly prized target in chronic pain, have not yet been clinically successful. In a differentiated approach, we demonstrated allosteric control of trafficking and activity of NaV1.7 by prevention of SUMOylation of collapsin response mediator protein 2 (CRMP2). Spinal administration of a SUMOylation incompetent CRMP2 (CRMP2 K374A) significantly attenuated pain behavior in the spared nerve injury (SNI) model of neuropathic pain, underscoring the importance of SUMOylation of CRMP2 as a pathologic event in chronic pain...
August 6, 2018: Channels
Yingwei Wu, Qi Fan, Feng Zeng, Jinyu Zhu, Jian Chen, Dandan Fan, Xinwei Li, Wenjia Duan, Qinghua Guo, Zhonglian Cao, Karen Briley-Saebo, Cong Li, Xiaofeng Tao
Malignant gliomas are the most common primary brain tumors associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in about 30% glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor, by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the free peptide (KD = 3...
August 1, 2018: Nano Letters
Sushant Lakkadwala, Jagdish Singh
Drug delivery to the brain has been a major challenge due to the presence of the blood brain barrier (BBB), which limits the uptake of most chemotherapeutics into brain. We developed a dual-functionalized liposomal delivery system, conjugating cell penetrating peptide penetratin to transferrin-liposomes (Tf-Pen-conjugated liposomes) to enhance the transport of an anticancer chemotherapeutic drug, 5-fluorouracil (5-FU), across the BBB into the tumor cells. The in vitro cellular uptake study showed that the dual-functionalized liposomes are capable of higher cellular uptake in glioblastoma (U87) and brain endothelial (bEnd...
July 25, 2018: Journal of Pharmaceutical Sciences
Hae-Duck Bae, Moonhee Kim, Joohyun Lee, Kyunglim Lee
Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43...
November 2018: Drug Delivery
Toshihiko Tashima
Cancer is one of the major causes of death globally. The current treatment options are insufficient, leading to unmet medical needs in cancer treatment. Off-target side effects, multidrug resistance, selective distribution to cancerous tissues, and cell membrane permeation of anti-cancer agents are critical problems to overcome. There is a method to solve these problems by using receptor-mediated endocytosis (RME). It is well known that proteins such as integrin, HER2, EGFR, or other cancer biomarkers are specifically overexpressed on the surface of target cancer cells...
July 11, 2018: Bioorganic & Medicinal Chemistry Letters
Hyunjin Jeon, Euiyeon Lee, Dahee Kim, Minhyung Lee, Jeahee Ryu, Chungwon Kang, Soyoun Kim, Youngeun Kwon
Live-cell-based biosensors have emerged as a useful tool for biotechnology and chemical biology. Genetically encoded sensor cells often use bimolecular fluorescence complementation or fluorescence resonance energy transfer to build a reporter unit that suffers from nonspecific signal activation at high concentrations. Here, we designed genetically encoded sensor cells that can report the presence of biologically active molecules via fluorescence-translocation based on split intein-mediated conditional protein trans-splicing (PTS) and conditional protein trans-cleavage (PTC) reactions...
August 3, 2018: Analytical Chemistry
Megumi Ichikawa, Tetsuya Hirayama, Masanobu Fukushima, Ikue Kitazawa, Kazuhiro Kojima, Tokiko Sakai, Yoshihiro Takatsu, Tetsuya Ohtaki
Glucagon-like peptide-1 (GLP-1) is an incretin peptide that plays a crucial role in lowering blood glucose levels and holds promise for treating type II diabetes. In this study, we synthesized GLP-1 derivatives that were conjugated with glycosaminoglycans (GAGs), i.e., chondroitin (CH) or heparosan (HPN), to address the major limitation in their clinical use of GLP-1, which is its short half-life in the body. After exploring a variety of CHs with different molecular sizes and heterobifunctional linkers having different alkyl chains, we obtained CH-conjugated GLP-1 derivatives that stayed in blood circulation much longer ( T 1/2 elim > 25 h) than unconjugated GLP-1 and showed blood glucose-lowering efficacy up to 120 h after subcutaneous injection in mice...
May 31, 2018: ACS Omega
Nancy M Okuda-Shinagawa, Yulia E Moskalenko, Helena C Junqueira, Maurício S Baptista, Carlos M Marques, M Terêsa Machini
Conjugates based on cell-penetrating peptides (CPPs) are scientifically relevant owing to their structural complexity; their ability to enter cells and deliver drugs, labels, antioxidants, bioactive compounds, or DNA fragments; and, consequently, their potential for application in research and biomedicine. In this study, carboxyamidated fluorescently labeled conjugates FAM-GG-TAT(47-57)-NH2 and FAM-PEG6 -TAT(47-57)-NH2 and photosensitizer-labeled conjugate Chk -PEG6 -TAT(47-57)-NH2 [where TAT(47-57) is the CPP, 5(6)-carboxyfluorescein is the (FAM) fluorophore, chlorin k (Chk ) is the photosensitizer, and the dipeptide glycyl-glycine (GG) or hexaethylene glycol (PEG6 ) is the spacer] were originally designed, prepared, and fully characterized...
November 30, 2017: ACS Omega
Chandran Murugan, Srinivasan Venkatesan, Soundarapandian Kannan
The cargo-loaded mesoporous silica nanoparticles (MSNs) with convenient surface modification can facilitate the development of the innovative nanodrug system. Herein, the present investigation described the electrostatically self-assembled MSNs as a nanosized drug carrier to realize potent synergistic chemotherapy based on the specificity in targeting cytoplasm and nucleus of tumor cells. In this context, the primarily constructed MSNs were subjected with anticancer drug topotecan (TPT) into its large pores...
November 30, 2017: ACS Omega
Amrita Saha, Badri Narayan Acharya, Raj Priya, Nagesh K Tripathi, Ambuj Shrivastava, M Kameswara Rao, Pooja Kesari, Manju Narwal, Shailly Tomar, Sameer S Bhagyawant, Manmohan Parida, Paban Kumar Dash
Chikungunya virus has emerged as one of the most important global arboviral threats over the last decade. Inspite of large scale morbidity, with long lasting polyarthralgia, so far no licensed vaccine or antiviral is available. CHIKV nsP2 protease is crucial for processing of viral nonstructural polypeptide precursor to release enzymes required for viral replication, thus making it a promising drug target. In this study, high cell density cultivation (HCDC) of Escherichia coli in batch process was carried out to produce rCHIKV nsP2pro in a cost-effective manner...
July 17, 2018: Scientific Reports
E Ragozin, A Hesin, A Bazylevich, H Tuchinsky, A Bovina, T Shekhter Zahavi, M Oron-Herman, G Kostenich, M A Firer, T Rubinek, I Wolf, G Luboshits, M Y Sherman, G Gellerman
Pancreatic cancer poorly responds to available drugs, and finding novel approaches to target this cancer type is of high significance. Here, based on a common property of pancreatic cancer cells to express somatostatin receptors (SSTR), we designed drug conjugates with novel somatostatin-derived cyclic peptides (SSTp) with broad selectivity towards SSTR types to facilitate drug targeting of the pancreatic cancer cells specifically. Uptake of our newly designed SSTps was facilitated by SSTRs expressed in the pancreatic cancers, including SSTR2, SSTR3, SSTR4 and SSTR5...
July 30, 2018: Bioorganic & Medicinal Chemistry
Sunan Cao, Zhi Li, Jinyuan Zhao, Mi Chen, Nan Ma
Optical sensing of cancer-relevant protease is of great value for cancer diagnostics, prognosis, and drug discovery. Multiplex sensing is known to improve predicative accuracy yet remains challenging because of severe fluorescence signal crosstalk in a single assay. Herein, we developed a multichannel optical sensor based on upconversion nanoparticles for multiplex ratiometric sensing of proteolytic activities of two matrix metalloproteinases (MMP-2 and MMP-7). To this end, we rationally designed a NaYF4 :Gd3+ /Yb3+ @NaYF4 :Yb3+ /Tm3+ /Er3+ core-shell structure that favors multicolor narrow-band emission of both Tm3+ and Er3+ dopants and efficient luminescence resonance energy transfer (LRET) between the dopants in the shell and the fluorophores on the particle surface...
July 31, 2018: ACS Sensors
Livia Polgár, Eszter Lajkó, Pál Soós, Orsolya Láng, Marilena Manea, Béla Merkely, Gábor Mező, László Kőhidai
Background: Cardiomyopathy induced by the chemotherapeutic agents doxorubicin and daunorubicin is a major limiting factor for their application in cancer therapy. Chemotactic drug targeting potentially increases the tumor selectivity of drugs and decreases their cardiotoxicity. Increased expression of gonadotropin-releasing hormone (GnRH) receptors on the surface of tumor cells has been reported. Thus, the attachment of the aforementioned chemotherapeutic drugs to GnRH-based peptides may result in compounds with increased therapeutic efficacy...
2018: Beilstein Journal of Organic Chemistry
Nadda Muhamad, Tullayakorn Plengsuriyakarn, Kesara Na-Bangchang
Patients treated with conventional cancer chemotherapy suffer from side effects of the drugs due to non-selective action of chemotherapeutic drugs to normal cells. Active targeting nanoparticles that are conjugated to targeting ligands on the surface of nanoparticles play an important role in improving drug selectivity to the cancer cell. Several chemotherapeutic drugs and traditional/herbal medicines reported for anticancer activities have been investigated for their selective delivery to cancer cells by active targeting nanoparticles...
2018: International Journal of Nanomedicine
Feihu Wang, Qian Huang, Yun Wang, Wenjun Zhang, Ran Lin, Yanna Yu, Yuanyuan Shen, Honggang Cui, Shengrong Guo
Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer...
July 20, 2018: Acta Biomaterialia
Terry W Moody, Irene Ramos-Alvarez, Robert T Jensen
Neuropeptide G protein-coupled receptors (GPCRs) are overexpressed on numerous cancer cells. In a number of tumors, such as small cell lung cancer (SCLC), bombesin (BB) like peptides and neurotensin (NTS) function as autocrine growth factors whereby they are secreted from tumor cells, bind to cell surface receptors and stimulate growth. BB-drug conjugates and BB receptor antagonists inhibit the growth of a number of cancers. Vasoactive intestinal peptide (VIP) increases the secretion rate of BB-like peptide and NTS from SCLC leading to increased proliferation...
2018: Frontiers in Endocrinology
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