Abstract:
:The wet form of age-related macular degeneration (AMD) is a leading cause of blindness among elderly Americans and is characterized by abnormal vessel growth, termed choroidal neovascularization (CNV). Integrin α5β1 is a transmembrane receptor that binds matrix macromolecules and proteinases to stimulate angiogenesis. We recently demonstrated that integrin α5β1 plays a critical role in the development of choroidal neovascularization. In this study, we determined the role and underlying mechanisms of integrin α5β1 in angiogenesis in human choroidal endothelial cells and evaluated the antiangiogenic effects of delivering a combination therapy of ATN-161, an integrin α5β1 inhibitor, and an anti-VEGF monoclonal antibody to rats with laser-induced CNV. Vascular endothelial growth factor (VEGF) is a signaling protein that stimulates vasculogenesis and angiogenesis through a pathway that is distinct from the integrin α5β1 signaling pathway. Our results indicate that fibronectin binds to integrin α5β1 and synergizes VEGF-induced angiogenesis via two independent signaling pathways, FN/integrin α5β1/FAK/ERK1/2 and FN/integrin α5β1/FAK/AKT. Integrin α5 knockdown by shRNA inhibits endothelial cell migration, tube formation, and proliferation, while ATN-161 only partially decreases integrin α5 function. Treatment with ATN-161 combined with anti-VEGF antibody showed joint effects in attenuating angiogenesis. In summary, our results provide the first evidence for the mechanisms by which integrin α5β1 is involved in ocular pathological neovascularization in vivo, suggesting that dual inhibition of integrin α5β1 and VEGF may be a promising novel therapeutic strategy for CNV in wet AMD.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Wang WQ,Wang FH,Qin WX,Liu HY,Lu B,Chung C,Zhu J,Gu Q,Shi W,Wen C,Wu F,Zhang K,Sun XDdoi
10.1021/acs.molpharmaceut.6b00056subject
Has Abstractpub_date
2016-09-06 00:00:00pages
2881-90issue
9eissn
1543-8384issn
1543-8392journal_volume
13pub_type
杂志文章abstract::Combinatorial chemistry has enabled the production of very potent drugs that might otherwise suffer from poor solubility and low oral bioavailability. One approach to increase solubility is to make the drug amorphous, which leads to problems associated with drug stability. To improve stability, one option is to molecu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400712m
更新日期:2014-07-07 00:00:00
abstract::The formulation of drug/polymer amorphous solid dispersions (ASDs) is one of the most successful strategies for improving the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs). Hot-melt extrusion (HME) is one method for preparing ASDs that is growing in importance in the pharmaceutical in...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00188
更新日期:2020-06-01 00:00:00
abstract::Major obstacles in the development of new therapeutic anticancer drugs are the low bioavailability of hydrophilic substances and the nonspecific toxicity toward healthy tissues. As such, cell-targeting oligopeptides have emerged as attractive drug delivery vehicles for a variety of different types of cargo. The recent...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp060122j
更新日期:2007-05-01 00:00:00
abstract::HEPES has been widely employed as an organic buffer agent in cell culture medium as well as uptake and transport experiments in vitro. However, concentrations of HEPES used in such studies vary from one laboratory to another. In this study, we investigated the effect of HEPES on the uptake and bidirectional transport ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900193e
更新日期:2010-04-05 00:00:00
abstract::P-glycoprotein (Pgp) is highly expressed on blood-brain barrier (BBB) and glioblastoma (GB) cells, particularly on cancer stem cells (SC). Pgp recognizes a broad spectrum of substrates, limiting the therapeutic efficacy of several chemotherapeutic drugs in eradicating GB SC. Finding effective and safe inhibitors of Pg...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00018
更新日期:2019-08-05 00:00:00
abstract::Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood-brain barrier (BBB) and in neurons the e...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300496x
更新日期:2013-01-07 00:00:00
abstract::The present work reports a thorough conformational analysis of iodinated contrast media: iomeprol, iopamidol (the world's most utilized contrast agent), and iopromide. Its main aim is the understanding of the complex structural features of these atropisomeric molecules, characterized by the presence of many conformers...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp5007486
更新日期:2015-06-01 00:00:00
abstract::Our previous studies have shown that multidrug resistance protein 2 (MRP2) is overexpressed in tamoxifen-resistant MCF-7 breast cancer cells (TAMR-MCF-7 cells) and forkhead box-containing protein, O subfamily1 (FoxO1), functions as a key regulator of multidrug resistance 1 (MDR1) gene transcription. This study aimed t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400287p
更新日期:2013-07-01 00:00:00
abstract::An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp5006036
更新日期:2015-04-06 00:00:00
abstract::The transfection activity and the phase behavior of two novel cationic O-alkyl-phosphatidylcholines, 1,2-dioleoyl- sn-glycero-3-hexylphosphocholine (C6-DOPC) and 1,2-dierucoyl- sn-glycero-3-ethylphosphocholine (di22:1-EPC), have been examined with the aim of more completely understanding the mechanism of lipid-mediate...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp800011e
更新日期:2008-09-01 00:00:00
abstract::The formation of a gel coat around xanthan (Xan) tablets, empty or loaded with pentoxifylline (PF), and its release in media differing in pH and ionic strength by NMR, MR imaging, and two release methods were studied. The T1 and T2 NMR relaxation times in gels depend predominantly on Xan concentration; the presence of...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00955
更新日期:2016-03-07 00:00:00
abstract::Nanoenabled lipid-based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00097
更新日期:2018-07-02 00:00:00
abstract::Heart transplantation (HT) is an effective treatment for end-stage heart disease. However, acute rejection (AR) is still the main cause of death within one year after HT. AR is an acute immune response mediated by T lymphocytes, mainly CD4+ T lymphocytes. This study innovatively develops a radiolabeled probe 99mTc-HYN...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c01155
更新日期:2021-01-28 00:00:00
abstract::Conventional drug solubilization strategies limit the understanding of the full potential of poorly water-soluble drugs during drug screening. Here, we propose a screening approach in which poorly water-soluble drugs are entrapped in poly(2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylaminoethyl methacr...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00791
更新日期:2020-12-07 00:00:00
abstract::Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous admini...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500737y
更新日期:2015-04-06 00:00:00
abstract::Invasion and metastasis of cancer directly related to human death have been associated with interactions among many different types of cells and three-dimensional (3D) tissue matrices. Precise mechanisms related to cancer invasion and metastasis still remain unknown due to their complexities. Development of tumor micr...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00953
更新日期:2016-07-05 00:00:00
abstract::Within the immune system there is an exquisite ability to discriminate between "self" and "non-self" that is orchestrated by antigen-specific T lymphocytes. Genomic plasticity enables differentiation of naive CD4+ T lymphocytes into either regulatory cells (Treg) that express the transcription factor Foxp3 and activel...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100203a
更新日期:2011-02-07 00:00:00
abstract::The impact of OATP drug uptake transporters in drug-drug interactions (DDIs) is increasingly recognized. OATP1B1 and OATP1B3 are human hepatic uptake transporters that can mediate liver uptake of a wide variety of drugs. Recently, we generated transgenic mice with liver-specific expression of human OATP1B1 or OATP1B3 ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00453
更新日期:2015-12-07 00:00:00
abstract::In this study, a facile strategy for efficient codelivery of gene and drug was developed. Using a coprecipitation method, doxorubicin hydrochloride (DOX), an antitumor drug, and p53 expression plasmid were encapsulated in alginate/CaCO(3)/DNA/DOX nanoparticles with high encapsulation efficiency. The in vitro cell inhi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3002123
更新日期:2012-10-01 00:00:00
abstract::Ipratropium bromide, an anticholinergic drug used for the treatment of asthma and chronic obstructive pulmonary disease, has low oral bioavailability, but systemic exposure, superior to oral administration, can be achieved by inhalation. Therefore, we investigated the pulmonary absorption mechanism of ipratropium usin...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900206j
更新日期:2010-02-01 00:00:00
abstract::The objective was to determine the disposition of polymer nanoparticles and an associated, lipophilic, model "active" component on and within the skin following topical application. Polystyrene and poly(methyl methacrylate) nanoparticles containing covalently bound fluorescein methacrylate and dispersed Nile Red were ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp9001188
更新日期:2009-09-01 00:00:00
abstract::Renal ischemia/reperfusion (I/R) injury causes high mortality and morbidity during renal procedures, yet current drugs should be used at high doses or for long periods due to lack of tissue specificity. In previous work we described a novel mycophenolic acid-glucosamine conjugate (MGC) that targets the proximal tubule...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500282g
更新日期:2014-10-06 00:00:00
abstract::The potential use of poly(dimethylsiloxane) (PDMS) as an in vitro biomimetic analogue of the passive drug absorption process in the human gastrointestinal tract (GI) is assessed. PDMS is biomimetic because of similarities in small molecule transport, such as mechanism, ionization selectivity, lipophilicity. Nine molec...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00798
更新日期:2017-12-04 00:00:00
abstract::Mucus layer, a selective diffusion barrier, has an important effect on the fate of drug delivery systems in the gastrointestinal tract. To study the fate of microemulsions in the mucus layer, four microemulsion formulations with different particle sizes and lipid compositions were prepared. The microemulsion-mucin int...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500475y
更新日期:2015-03-02 00:00:00
abstract::We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00562
更新日期:2020-10-05 00:00:00
abstract::Our objective was to design a polymeric micelle-based doxorubicin and lapatinib combination therapy for treating multidrug resistant (MDR) breast cancers. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonylpropylene carbonate) (PEG-PBC) polymers were synthesized for preparing doxorubicin and lapatinib loaded m...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400687w
更新日期:2014-08-04 00:00:00
abstract::It is a challenge to formulate polymer based nanoparticles of therapeutic proteins as excipients and process conditions affect stability and structural integrity of the protein. Hence, understanding the protein stability and complex aggregation phenomena is an important area of research in therapeutic protein delivery...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp5003653
更新日期:2015-04-06 00:00:00
abstract::Organic anion transporting polypeptide (OATP) 1B1 plays an important role in the hepatic uptake of various drugs. Because OATP1B1 is a site of drug-drug interactions (DDIs), evaluating the inhibitory potential of drug candidates on OATP1B1 is required during drug development. For establishing a highly sensitive, high-...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00664
更新日期:2016-02-01 00:00:00
abstract::A general, easy-to-implement strategy for mapping the structure of organic phases integrated in mesoporous silica drug delivery devices is presented. The approach based on a few straightforward solid-state NMR techniques has no limitations regarding concentrations of the active compounds and enables straightforward di...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00167
更新日期:2017-06-05 00:00:00
abstract:BACKGROUND:For the development of novel buccoadhesive formulations, their physicochemical properties, strength of the interfacial joint, and residence time on the buccal mucosa are considered as a measure for their in vivo mucoadhesive properties. Focusing on these parameters, the predictive power of established in vit...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00254
更新日期:2019-06-03 00:00:00