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1.
Food Chem ; 340: 128056, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33032152

RESUMO

In the study, a novel kind of peptides-zinc (AKP-Zn) chelate was obtained using the Antarctic krill (Euphausia superba) peptides (AKP) as raw material, the reaction was carried out with the mass ratio of the AKP to ZnSO4·7H2O of 1:2 at pH 6.0 and 60 °C for 10 min. The structure and composition of the AKP, including particle size, Zeta potential, molecular weight distribution, amino acid composition, microstructure and surface elemental composition, changed significantly after chelating with zinc. The result of Fourier transform infrared spectroscopy indicated that zinc could be chelated by carboxyl oxygen and amino nitrogen atoms of the AKP. Furthermore, compared with zinc sulfate and zinc gluconate, the AKP-Zn chelate was more stable at various pH conditions and the simulated gastrointestinal digestion experiment. These findings would provide a scientific basis for developing new zinc supplements and the high-value utilization of Antarctic krill protein resource.


Assuntos
Proteínas de Artrópodes/química , Quelantes/química , Peptídeos/química , Peptídeos/farmacocinética , Zinco/química , Aminoácidos/análise , Animais , Proteínas de Artrópodes/farmacocinética , Suplementos Nutricionais , Digestão , Euphausiacea/química , Concentração de Íons de Hidrogênio , Peso Molecular , Nitrogênio/química , Espectroscopia de Infravermelho com Transformada de Fourier , Zinco/análise
2.
Yakugaku Zasshi ; 140(11): 1305-1312, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132265

RESUMO

Recently, biologics including peptides, proteins, antibodies, and nucleic acids have attracted interest as drug candidates for new modalities, since these compounds can act on target molecules that are not be affected by conventional drugs with a small molecular weight to promote greater selectivity, potency, and safety. Generally, to administer biologics, parenteral routes like intravenous and intramuscular injections have been mainly selected due to their poor oral absorbability and stability in the gastrointestinal tract, which can adversely affect patient compliance. Depending on the target diseases, inhalable formulations can be used to achieve both topical effects in the respiratory tracts and systemic actions due to the characteristics of the pulmonary site, including a large surface area, abundant capillary network, thin membrane with adequate permeability for macromolecules, reduced enzymatic degradation, and a lack of first-pass metabolism. In this study, to achieve desirable delivery of peptide drugs with an inhalable formulation to target sites in the respiratory tract and/or absorption sites in the lung, peptide-loaded inhalable formulations were designed by the application of flash nanoprecipitation, one of the precipitation methods to prepare functional nanoparticles, and the fine droplet drying process, a powderization technique using printing technology, to control the pharmacokinetic behavior. From the findings of the study, the strategic applications of these techniques could contribute to provide peptide-loaded inhalable formulations to enhance their biopharmaceutical potentials.


Assuntos
Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Precipitação Química , Inaladores de Pó Seco , Nanopartículas
3.
J Med Chem ; 63(21): 12853-12872, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33073986

RESUMO

Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease with a high morbidity and mortality rate, for which no pharmacologic treatment is currently available. Our previous studies discovered that a pivotal step in the disease process is the activation of the nuclear factor of activated T cells (NFAT) c3 in lung macrophages, suggesting that inhibitors against the upstream protein phosphatase calcineurin should be effective for prevention/treatment of ARDS. Herein, we report the development of a highly potent, cell-permeable, and metabolically stable peptidyl inhibitor, CNI103, which selectively blocks the interaction between calcineurin and NFATc3, through computational and medicinal chemistry. CNI103 specifically inhibited calcineurin signaling in vitro and in vivo and exhibited a favorable pharmacokinetic profile, broad tissue distribution following different routes of administration, and minimal toxicity. Our data indicate that CNI103 is a promising novel treatment for ARDS and other inflammatory diseases.


Assuntos
Calcineurina/metabolismo , Fatores de Transcrição NFATC/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Sequência de Aminoácidos , Animais , Sítios de Ligação , Calcineurina/química , Inibidores de Calcineurina/química , Inibidores de Calcineurina/metabolismo , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Meia-Vida , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Fatores de Transcrição NFATC/química , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual
4.
J Vis Exp ; (162)2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32831304

RESUMO

Several negatively charged tissues in the body, like cartilage, present a barrier to the targeted drug delivery due to their high density of negatively charged aggrecans and, therefore, require improved targeting methods to increase their therapeutic response. Because cartilage has a high negative fixed charge density, drugs can be modified with positively charged drug carriers to take advantage of electrostatic interactions, allowing for enhanced intra-cartilage drug transport. Studying the transport of drug carriers is, therefore, crucial towards predicting the efficacy of drugs in inducing a biological response. We show the design of three experiments which can quantify the equilibrium uptake, depth of penetration and non-equilibrium diffusion rate of cationic peptide carriers in cartilage explants. Equilibrium uptake experiments provide a measure of the solute concentration within the cartilage compared to its surrounding bath, which is useful for predicting the potential of a drug carrier in enhancing therapeutic concentration of drugs in cartilage. Depth of penetration studies using confocal microscopy allow for the visual representation of 1D solute diffusion from the superficial to deep zone of cartilage, which is important for assessing whether solutes reach their matrix and cellular target sites. Non-equilibrium diffusion rate studies using a custom-designed transport chamber enables the measurement of the strength of binding interactions with the tissue matrix by characterizing the diffusion rates of fluorescently labeled solutes across the tissue; this is beneficial for designing carriers of optimal binding strength with cartilage. Together, the results obtained from the three transport experiments provide a guideline for designing optimally charged drug carriers which take advantage of weak and reversible charge interactions for drug delivery applications. These experimental methods can also be applied to evaluate the transport of drugs and drug-drug carrier conjugates. Further, these methods can be adapted for the use in targeting other negatively charged tissues such as meniscus, cornea and the vitreous humor.


Assuntos
Cartilagem/metabolismo , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Peptídeos/farmacocinética , Animais , Cartilagem/efeitos dos fármacos , Cátions/química , Difusão , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Peptídeos/administração & dosagem , Peptídeos/química , Eletricidade Estática
5.
Nat Rev Drug Discov ; 19(6): 389-413, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494050

RESUMO

Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) - nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.


Assuntos
Desenho de Fármacos , Peptídeos , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Terapia de Alvo Molecular , Biblioteca de Peptídeos , Peptídeos/farmacocinética , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Ligação Proteica , Transdução de Sinais
6.
Mol Pharm ; 17(7): 2518-2531, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32421341

RESUMO

M2-like tumor-associated macrophages (M2 TAMs) play important roles in the resistance of tumors to immunotherapies. Selective depletion or reprogramming of M2 TAMs may sensitize the nonresponsive tumors for immune-mediated eradication. However, precision delivery of payloads to M2 TAMs, while sparing healthy tissues, has remained an unresolved challenge. Here, we studied the application of a short linear peptide (CSPGAK, "mUNO") for the delivery of molecular and nanoscale cargoes in M2 TAMs in vitro and the relevance of the peptide for in vivo targeting of early-stage primary breast tumors and metastatic lung foci. First, we performed in silico modeling and found that mUNO interacts with mouse CD206 via a binding site between lectin domains CTLD1 and CTLD2, the same site previously demonstrated to be involved in mUNO binding to human CD206. Second, we showed that cultured M2 macrophages take up fluorescein-labeled (FAM) polymersomes conjugated with mUNO using the sulfhydryl group of its N-terminal cysteine. Pulse/chase studies of FAM-mUNO in M2 macrophages suggested that the peptide avoided lysosomal entrapment and escaped from early endosomes. Third, our in vivo studies with FAM-mUNO demonstrated that intraperitoneal administration results in better pharmacokinetics and higher blood bioavailability than can be achieved with intravenous administration. Intraperitoneal FAM-mUNO, but not FAM-control, showed a robust accumulation in M2-skewed macrophages in mouse models of early primary breast tumor and lung metastasis. This targeting was specific, as no uptake was observed in nonmalignant control organs, including the liver, or other cell types in the tumor, including M1 macrophages. Collectively, our studies support the application of the CD206-binding mUNO peptide for delivery of molecular and nanoscale cargoes to M2 macrophages and manifest the relevance of this mode of targeting primary and metastatic breast tumors.


Assuntos
Imunoterapia/métodos , Lectinas Tipo C/química , Neoplasias Pulmonares/diagnóstico , Metástase Linfática/diagnóstico , Lectinas de Ligação a Manose/química , Peptídeos/química , Receptores de Superfície Celular/química , Neoplasias de Mama Triplo Negativas/diagnóstico , /imunologia , Animais , Sítios de Ligação , Diferenciação Celular , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Feminino , Fluorescência , Humanos , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/imunologia , Lisossomos/metabolismo , Maleimidas/química , Lectinas de Ligação a Manose/imunologia , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Peptídeos/farmacocinética , Poliésteres/química , Polietilenoglicóis/química , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacologia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/patologia , /metabolismo
7.
Biomater Sci ; 8(9): 2682-2693, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32266897

RESUMO

Pancreatic cancer has a high mortality rate and efforts towards diagnosis and therapy at an early stage are particularly appealing. Recently, a small peptide, BBN7-14, has attracted much attention for its specific binding ability to gastrin releasing peptide receptor (GRPR), which is highly overexpressed in various types of cancer, including pancreatic cancer. However, its poor stability in vivo restricts its direct clinical application. Herein, by rational design and transformation of BBN7-14, a novel six-amino acid peptide, GB-6, which maintains a specific GRPR-binding feature and exhibits enhanced stability in vitro and in vivo, was designed. Competitive binding with BBN7-14 and cellular uptake related to GRPR expression levels verified the specific affinity of GB-6 to GRPR. Additionally, this novel peptide was conjugated with near-infrared dye and the radionuclide 99mTc for pancreatic cancer diagnosis in cells and in vivo. Surprisingly, despite having the same cellular affinity as BBN7-14, GB-6 showed much higher pancreatic cancer-targeting ability than BBN7-14 by both fluorescence imaging and radionuclide imaging. It was proven that this strange phenomenon was attributed to the distinct in vivo stability of GB-6 and its more favorable pharmacokinetic properties and metabolic stability relative to BBN7-14. Altogether, this novel peptide GB-6, with GRPR-targeting ability and enhanced stability, is a more promising candidate for the clinical diagnosis of pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/diagnóstico por imagem , Peptídeos/administração & dosagem , Receptores da Bombesina/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Humanos , Masculino , Camundongos Nus , Imagem Óptica , Neoplasias Pancreáticas/metabolismo , Peptídeos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Tecnécio/administração & dosagem , Tecnécio/farmacocinética
8.
Biomater Sci ; 8(8): 2274-2282, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32162618

RESUMO

Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Cumarínicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Micelas , Paclitaxel/administração & dosagem , Peptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tiazóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos ICR , Paclitaxel/sangue , Paclitaxel/química , Paclitaxel/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética , Polietilenoglicóis/química , Esferoides Celulares/efeitos dos fármacos , Tiazóis/química , Carga Tumoral/efeitos dos fármacos
9.
Molecules ; 25(5)2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32150848

RESUMO

There are many areas in medicine and industry where it would be advantageous to orally deliver bioactive proteins and peptides (BPPs), including ACE inhibitors, antimicrobials, antioxidants, hormones, enzymes, and vaccines. A major challenge in this area is that many BPPs degrade during storage of the product or during passage through the human gut, thereby losing their activity. Moreover, many BPPs have undesirable taste profiles (such as bitterness or astringency), which makes them unpleasant to consume. These challenges can often be overcome by encapsulating them within colloidal particles that protect them from any adverse conditions in their environment, but then release them at the desired site-of-action, which may be inside the gut or body. This article begins with a discussion of BPP characteristics and the hurdles involved in their delivery. It then highlights the characteristics of colloidal particles that can be manipulated to create effective BPP-delivery systems, including particle composition, size, and interfacial properties. The factors impacting the functional performance of colloidal delivery systems are then highlighted, including their loading capacity, encapsulation efficiency, protective properties, retention/release properties, and stability. Different kinds of colloidal delivery systems suitable for encapsulation of BPPs are then reviewed, such as microemulsions, emulsions, solid lipid particles, liposomes, and microgels. Finally, some examples of the use of colloidal delivery systems for delivery of specific BPPs are given, including hormones, enzymes, vaccines, antimicrobials, and ACE inhibitors. An emphasis is on the development of food-grade colloidal delivery systems, which could be used in functional or medical food applications. The knowledge presented should facilitate the design of more effective vehicles for the oral delivery of bioactive proteins and peptides.


Assuntos
Coloides/química , Portadores de Fármacos/química , Composição de Medicamentos , Peptídeos/química , Proteínas/química , Administração Oral , Biopolímeros , Fenômenos Químicos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Absorção Gastrointestinal , Humanos , Nanopartículas/química , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Proteínas/administração & dosagem , Proteínas/farmacocinética , Eletricidade Estática
10.
J Pharmacol Exp Ther ; 373(2): 193-203, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32075870

RESUMO

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS. SIGNIFICANCE STATEMENT: Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiates it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections.


Assuntos
Peptídeo 2 Semelhante ao Glucagon/agonistas , Peptídeos/farmacologia , Síndrome do Intestino Curto/tratamento farmacológico , Animais , Receptor do Peptídeo Semelhante ao Glucagon 2/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 2/fisiologia , Células HEK293 , Meia-Vida , Humanos , Macaca fascicularis , Masculino , Peptídeos/farmacocinética , Peptídeos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Suínos , Porco Miniatura
11.
ACS Appl Mater Interfaces ; 12(10): 12075-12082, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32057221

RESUMO

Extracting, stabilizing, or delivering biomacromolecules such as proteins and peptides in organic phases have potential applications in biocatalysis, protein extraction, and food antioxidation. However, most current delivery/stabilization platforms face various limitations such as protein/peptide molecular size, platform stability/reusability, and/or potential damage to the cargos. A potential solution to these problems is micellar self-assemblies from amphiphilic invertible polymers, which have recently been demonstrated to be powerful as molecular hosts to deliver both small molecular drugs and functional polypeptides in the aqueous phase. To better understand the function of biomacromolecules and predict the usefulness of the formed invertible micellar assemblies (IMAs) as biomacromolecular hosts in organic phases, it is critical to characterize the spatial distribution, structure, and dynamics of biomacromolecules in the IMA including those upon release. However, the background signals of the IMAs limit the application of most peptide characterization approaches. In this work, we overcome the technical barriers by using site-directed spin labeling electron paramagnetic resonance to probe the spatial arrangement and release of a model, the hemagglutinin (HA) peptide, in the IMAs formed from two different amphiphilic invertible polymers. By site-specifically probing three residues along the peptide chain, for the first time, we depict the possible spatial distribution of HA within the IMAs. By triggering the disassembly of the IMAs with a thermodynamically good solvent (in this study, acetone), we detailed the stability of IMAs in toluene and the peptide release conditions once the polarity of the medium changes. Our findings are important for the application of peptides/proteins at the polar-nonpolar interface or using this interface to extract or deliver biomacromolecules. Our work also demonstrates the power of SDSL-EPR on probing peptide or micelle dynamics, which can be generalized to understand proteins or other biomacromolecules in micellar polymer assemblies in varied applications.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Micelas , Peptídeos/química , Solventes/química , Tensoativos/química , Espectroscopia de Ressonância de Spin Eletrônica , Hemaglutininas/química , Interações Hidrofóbicas e Hidrofílicas , Peptídeos/farmacocinética , Polímeros/química
12.
ACS Appl Mater Interfaces ; 12(10): 12143-12154, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32078286

RESUMO

The development of valuable theranostic agents for overcoming the blood-brain barrier (BBB) to achieve efficient imaging-guided glioma-targeting delivery of therapeutics remains a great challenge for personalized glioma therapy. We herein developed a novel functional star-shaped polyprodrug amphiphile (denoted as CPP-2) via a combination of successive reversible addition-fragmentation chain transfer (RAFT) polymerization and click functionalization. In a diluted solution, the star amphiphile existed as structurally stable unimolecular micelles, containing hydrophobic cores conjugated with reduction-responsive camptothecin prodrugs Camptothecin (CPT) prodrug monomer (CPTM) and a tertiary amine monomer (2-(diethylamine) ethyl methacrylate, DEA) and hydrophilic oligo-(ethylene glycol) monomethyl ether methacrylat (OEGMA) outer coronas covalently decorated with dual-targeting moieties Angiopep2 (ANG) and small magnetic resonance imaging (MRI) contrast agents DOTA-Gd. In vitro and in vivo data in this study demonstrated that the ANG-modified micelles were capable of efficiently penetrating the BBB and delivering loaded cargoes such as CPT and Gd3+ contrast agents to glioma cells, leading to a considerably enhanced t1 relaxivity as well as antiglioma efficacy. Simultaneously, the targeted antiglioma efficacy and noninvasive MR imaging for a visualized therapy were realized. These collective findings augured well for the star polyprodrug amphiphiles to be utilized as a novel theranostic platform for clinical application in glioma therapy.


Assuntos
Antineoplásicos , Glioma , Peptídeos , Pró-Fármacos , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Portadores de Fármacos/química , Glioma/diagnóstico por imagem , Glioma/metabolismo , Imagem por Ressonância Magnética , Micelas , Peptídeos/química , Peptídeos/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos , Ratos Sprague-Dawley
13.
Regul Toxicol Pharmacol ; 112: 104591, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32006673

RESUMO

Accurate assessment of the HER2 expression is an essential issue for predicting response to anti-HER2 therapy in breast cancer patients. The aim of this study was to evaluate 99mTc-HYNIC-(Ser)3-LTVPWY (99mTc-HYNIC-LY) peptide as a novel HER2-targeted radiolabeled peptide in healthy mice to examine the applicability of this imaging agent in a first-in-human clinical trial. To this end, pharmacokinetic and dosimetry studies were performed according to the ICH guideline M3 (R2) with 99mTc-HYNIC-LY. To estimate the radiation-absorbed doses in humans, the accumulated activity in each mouse organ was calculated based on biodistribution data. In addition, toxicology assessment was performed based on mortality events, body weights, and serum biochemical, hematological, and histopathological assays. The pharmacokinetic study showed rapid blood clearance. Based on the results of biodistribution study, the highest radioactivity was observed in the kidneys. The projected absorbed doses to the kidneys, liver, lungs, stomach, and spleen were obtained as 1.70E-02, 1.42E-02, 1.02E-02, 8.62E-03, and 8.34E-03 mSv/MBq, respectively. The results also revealed that serum biochemical and hematological parameters were in the normal range. No significant morphologic alterations were observed in the liver, kidneys, and spleen tissues. Consequently, the results were indicative of the suitability of 99mTc-HYNIC-LY peptide for advancement to a first-in-human clinical trial.


Assuntos
Compostos de Organotecnécio/farmacocinética , Peptídeos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Receptor ErbB-2/antagonistas & inibidores , Administração Intravenosa , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Compostos de Organotecnécio/sangue , Peptídeos/sangue , Radiometria , Compostos Radiofarmacêuticos/sangue , Receptor ErbB-2/metabolismo , Distribuição Tecidual
14.
J Pept Sci ; 26(3): e3241, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31984553

RESUMO

The dual interaction with integrins and neuropilin-1 receptor is the peculiar feature of iRGD peptide. Hence, in the present study, two iRGD peptide analogs were synthesized with DOTAGA and NODAGA as bifunctional chelator and aminohexanoic acid as a spacer for radiometalation with 68 GaCl3 . Negatively charged 68 Ga-DOTAGA-iRGD and neutral 68 Ga-NODAGA-iRGD radiotracers were investigated through in vitro cell uptake studies and in vivo biodistribution studies. Significant internalization of radiotracers in murine melanoma B16F10 cells was observed during in vitro studies. During in vivo studies, tumor uptake was higher for neutral 68 Ga-NODAGA-iRGD, but 68 Ga-DOTAGA-iRGD exhibited better tumor-to-blood ratio due to faster blood clearance. High kidney uptake of the two radiotracers was the limitation, which needs to be resolved through modification either in the peptide backbone or spacer/chelator.


Assuntos
Quelantes/química , Radioisótopos de Gálio/química , Melanoma Experimental/metabolismo , Peptídeos/farmacocinética , Acetatos/química , Administração Intravenosa , Anidridos/química , Animais , Linhagem Celular Tumoral , Compostos Heterocíclicos com 1 Anel/química , Integrinas/química , Camundongos , Neuropilina-1/química , Peptídeos/administração & dosagem , Peptídeos/química
15.
Int J Pharm ; 576: 119019, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31911116

RESUMO

Combination therapy in Type 2 Diabetes Mellitus is necessary to achieve tight glycaemic control and reduce complication risk. Current treatment plans require patients to take several drugs concomitantly leading to low therapy adherence. This study describes the development and characterisation of a stable parenteral co-formulation of a sodium glucose co-transporter 2 inhibitor (dapagliflozin) and a therapeutic lipidated peptide, using hydroxypropyl-ß-cyclodextrin as an enabling excipient. Using NMR, calorimetry, computational modelling and spectroscopic methods, we show that besides increasing the solubility of dapagliflozin, cyclodextrin prevents self-association of the peptide through interaction with the lipid chain and amino acids prone to aggregation including aromatic groups and ionisable residues. While those interactions cause a dramatic secondary structure change, no impact on potency was seen in vitro. A subcutaneous administration of the co-formulation in rat showed that both drugs reach exposure levels previously shown to be efficacious in clinical mono-therapy studies. Interestingly, a faster absorption rate was observed for the peptide formulated within the cyclodextrin vehicle with respect to the buffer vehicle, which could trigger an earlier onset of action. The cyclodextrin based co-formulation is therefore a promising approach to develop a fixed dose combination of a therapeutic peptide and a small molecule drug for increased patient adherence and better blood glucose control.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Compostos Benzidrílicos/farmacocinética , Glicemia/efeitos dos fármacos , Excipientes/química , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Peptídeos/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Animais , Compostos Benzidrílicos/química , Glicemia/metabolismo , Células CHO , Cricetulus , Combinação de Medicamentos , Composição de Medicamentos , Absorção Gastrointestinal , Glucosídeos/química , Hipoglicemiantes/química , Injeções Subcutâneas , Masculino , Peptídeos/administração & dosagem , Peptídeos/química , Agregados Proteicos , Estrutura Secundária de Proteína , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/química , Solubilidade
16.
Sci Transl Med ; 12(528)2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996466

RESUMO

Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II-deficient mice and hAPOC3-transgenic (Tg) mice. In hAPOC3-Tg mice, D6PV treatment reduced plasma apoC-III by 80% and apoB by 65%. Furthermore, low-density lipoprotein (LDL) cholesterol did not accumulate but rather was decreased by 10% when hAPOC3-Tg mice lacking the LDL-receptor (hAPOC3-Tg × Ldlr-/- ) were treated with the peptide. D6PV lowered TG by 50% in whole-body inducible Lpl knockout (iLpl-/- ) mice, confirming that it can also act independently of LPL. D6PV displayed good subcutaneous bioavailability of about 80% in nonhuman primates. Because it binds to high-density lipoproteins, which serve as a long-term reservoir, it also has an extended terminal half-life (42 to 50 hours) in nonhuman primates. In summary, D6PV decreases plasma TG by acting as a dual apoC-II mimetic and apoC-III antagonist, thereby demonstrating its potential as a treatment for HTG.


Assuntos
Apolipoproteína C-III/antagonistas & inibidores , Apolipoproteína C-II/agonistas , Peptídeos/farmacologia , Triglicerídeos/sangue , Animais , Modelos Animais de Doenças , Feminino , Meia-Vida , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/tratamento farmacológico , Lipólise , Lipase Lipoproteica/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/uso terapêutico , Primatas
17.
Int J Pharm ; 577: 119044, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954866

RESUMO

This research aims to investigate the potential of N-[4-[1-(3-Aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl]-1,3-propanediamine (SPM-NONOate) for promoting the absorption of poorly absorbed macromolecules delivered by intrapulmonary route. Influence of SPM-NONOate on the drug absorption was characterized by using a series of fluorescein isothiocyanate-labeled dextrans (FDs) as affordable models of hydrophilic macromolecules with established tools for quantitative analysis. SPM-NONOate increased concentration-dependently within 1-10 mM the pulmonary absorptions of FDs in rats. Moreover, this promoting effect varied with the molecular weight of FDs, and the largest absorption enhancement effect was obtained for FD70. SPM-NONOate also showed promising enhancement potential on the absorption of some therapeutic peptides, where obvious hypoglycemic and hypocalcemic effects were observed after intrapulmonary delivery of insulin and calcitionin, respectively, with SPM-NONOate to rats. The safety of SPM-NONOate was confirmed based on measurement of some biological markers in bronchoalveolar lavage fluid (BALF) of rats. Additionally, mechanism underling the absorption enhancement action of SPM-NONOate was explored by combinatorial administration of FD4 and SPM-NONOate with various scavengers and generator to rat lungs. Results indicated that NO released from SPM-NONOate induced the enhancement in the drug absorption, and peroxynitrate, a NO metabolite, possibly participated in the absorption enhancing action of SPM-NONOate.


Assuntos
Dextranos/administração & dosagem , Fluoresceína-5-Isotiocianato/análogos & derivados , Óxido Nítrico/metabolismo , Peptídeos/administração & dosagem , Espermina/análogos & derivados , Animais , Líquido da Lavagem Broncoalveolar , Calcitonina/administração & dosagem , Calcitonina/farmacocinética , Calcitonina/farmacologia , Dextranos/química , Dextranos/farmacocinética , Sistemas de Liberação de Medicamentos , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacocinética , Insulina/administração & dosagem , Insulina/farmacocinética , Insulina/farmacologia , Masculino , Peso Molecular , Peptídeos/química , Peptídeos/farmacocinética , Ratos , Ratos Sprague-Dawley , Absorção pelo Trato Respiratório , Espermina/química
18.
Nanoscale ; 12(5): 3359-3369, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31984408

RESUMO

The tumor microenvironment (TME) acts as an ecosystem that includes not only tumor cells, but also stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). In addition, the abnormal extracellular environment (ECM), of which the mechanical forces are regulated by fibronectin (Fn) and collagen I, orchestrates tumorigenesis and progression by directly promoting invasion and cellular transformation of the ecosystem. Herein, we develop a novel peptide-modified liposome incorporated into doxorubicin (FnBPA5-AAN-Dox) as an ecological therapy system, which targets not only the cellular compartment but also non-cellular components of breast cancer. FnBPA5 is a Fn-binding peptide showing high affinity with relaxed Fn and collagen I in the ECM as well as α-SMA-expressing CAFs. However, the fast clearance by Fn-excreting organs such as the liver and spleen limits the accumulation of FnBPA5-Dox in the TME. The AAN peptide, which targets legumain overexpressed in the TAMs, could extend the circulation time and improve the therapeutic response as well as modulate the tumor immune microenvironment (TMIE). Given twice at an equivalent dose of 5 mg kg-1 intravenously, the multi-in-one 'ecological therapy' applied AAN-FnBPA5-Dox showed excellent antitumor efficacy in 4T1 breast cancer mice, and the tumor growth inhibition (TGI) is up to 98.20% compared with saline. Immunofluorescence, flow cytometry and reverse transcription polymerase chain reaction (RT-PCR) results revealed that the dramatic improvement in antitumor efficacy can be attributed to the multifunctional targets of the drug delivery system.


Assuntos
Doxorrubicina/análogos & derivados , Sistemas de Liberação de Medicamentos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Peptídeos , Microambiente Tumoral/efeitos dos fármacos , Células 3T3 , Animais , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
19.
Org Lett ; 22(3): 804-808, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31927933

RESUMO

A new class of organosilicon-based radiosynthons, heteroaromatic silicon-fluoride acceptors, namely, HetSiFAs, that readily undergo isotope exchange with dry [18F]fluoride at room temperature in high radiochemical yield (up to 94%) with good molar activity is reported. Radiofluorination proceeds in a single step in 2 min without high-performance liquid chromatography purification to provide an operationally simple method for 18F-PET tracer production. This method was used to prepare an 18F-labeled commercial tetrapeptide, and positron emission tomography imaging confirmed in vivo stability.


Assuntos
Marcação por Isótopo , Compostos de Organossilício/química , Peptídeos/química , Compostos Radiofarmacêuticos/química , Animais , Radioisótopos de Flúor/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Compostos de Organossilício/síntese química , Compostos de Organossilício/farmacocinética , Peptídeos/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Estereoisomerismo
20.
Mol Cell Biochem ; 464(1-2): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31679100

RESUMO

We have previously demonstrated that Cationic Arginine-Rich Peptides (CARPs) and in particular poly-arginine-18 (R18; 18-mer of arginine) exhibit potent neuroprotective properties in both in vitro and in vivo neuronal injury models. Based on the current literature, there is a consensus that arginine residues by virtue of their positive charge and guanidinium head group is the critical element for imparting CARP neuroprotective properties and their ability to traverse cell membranes. This study examined the importance of guanidinium head groups in R18 for peptide cellular uptake, localization, and neuroprotection. This was achieved by using poly-ornithine-18 (O18; 18-mer of ornithine) as a control, which is structurally identical to R18, but possesses amino head groups rather than guanidino head groups. Epifluorescence and confocal fluorescence microscopy was used to examine the cellular uptake and localization of the FITC-conjugated R18 and O18 in primary rat cortical neurons and SH-SY5Y human neuroblastoma cell cultures. An in vitro cortical neuronal glutamic acid excitotoxicity model was used to compare the effectiveness of R18 and O18 to inhibit cell death and intracellular calcium influx, as well as caspase and calpain activation. Fluorescence imaging studies revealed cellular uptake of both FITC-R18 and FITC-O18 in neuronal and SH-SY5Y cells; however, intracellular localization of the peptides differed in neurons. Following glutamic acid excitotoxicity, only R18 was neuroprotective, prevented caspases and calpain activation, and was more effective at reducing neuronal intracellular calcium influx. Overall, this study demonstrated that for long chain cationic poly-arginine peptides, the guanidinium head groups provided by arginine residues are an essential requirement for neuroprotection but are not required for entry into neurons.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores , Peptídeos , Animais , Linhagem Celular Tumoral , Neurônios/patologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley
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