Abstract:
:The blood-brain barrier (BBB) prevents most drugs from reaching the site of central nervous system (CNS) diseases, intensively confining the therapeutic efficiency. Angiopep-2 (here termed (L)Angiopep), which is a 19-mer peptide derived from human Kunitz domain, can trigger transcytosis and traverse the BBB by recognizing low density lipoprotein-related protein 1 (LRP-1) expressed on the brain capillary endothelial cells. Various enzymes in the blood and the BBB, however, present multiple metabolic barriers to peptide-inspired brain-targeted drug delivery. Here we designed a retro-inverso isomer of (L)Angiopep, termed (D)Angiopep, to inspire brain-targeted drug delivery. Both (D)Angiopep and (L)Angiopep displayed high uptake capacity in LRP-1 overexpressed cells, including bEnd.3 and U87 cells. (D)Angiopep demonstrated lower uptake efficiency in both cell lines than did (L)Angiopep, suggestive of lower binding affinity to LRP-1 of the d-peptide. (D)Angiopep was resistant to proteolysis in fresh rat blood serum, while more than 85% of (L)Angiopep disappeared within 2 h. Endocytosed (D)Angiopep and (L)Angiopep were found to be colocalized with lysosomal compartments of bEnd.3 cells, indicating that susceptibility to proteolysis of (L)Angiopep in the BBB may further attenuate its transcytosis efficiency. In vivo, (D)Angiopep modified PEG-DSPE micelles displayed high distribution in normal brain and intracranial glioblastoma. Due to the expression of LRP-1 on the BBB and glioblastoma cells, proteolytically stable (D)Angiopep holds much potential for designing two-order brain tumor targeted delivery systems.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Wei X,Zhan C,Chen X,Hou J,Xie C,Lu Wdoi
10.1021/mp500086esubject
Has Abstractpub_date
2014-10-06 00:00:00pages
3261-8issue
10eissn
1543-8384issn
1543-8392journal_volume
11pub_type
杂志文章abstract::Effective penetration of drug-carrying nanoparticles into solid tumors is a major challenge in cancer therapy. Exploration of the physicochemical properties of nanoparticles that affect penetration efficiency is required to achieve maximum therapeutic effects. Here, we used confocal laser scanning microscopy to evalua...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00051
更新日期:2017-06-05 00:00:00
abstract::Despite being widely used in the clinical setting for sentinel lymph node detection (SLND), (99m)Tc-based colloids (e.g., (99m)Tc-human serum albumin colloids) present a set of properties that are far from ideal. Aiming to design novel compounds with improved biological properties, we describe herein the first class o...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100425p
更新日期:2011-04-04 00:00:00
abstract::Multidrug resistance (MDR) is the major obstacle for chemotherapy. In a previous study, we have successfully synthesized a novel doxorubicin (DOX) derivative modified by triphenylphosphonium (TPP) to realize mitochondrial delivery of DOX and showed the potential of this compound to overcome DOX resistance in MDA-MB-43...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00793
更新日期:2018-03-05 00:00:00
abstract::Fluid bed coating has been shown to be a suitable manufacturing technique to formulate poorly soluble drugs in glass solutions. Layering inert carriers with a drug-polymer mixture enables these beads to be immediately filled into capsules, thus avoiding additional, potentially destabilizing, downstream processing. In ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01023
更新日期:2017-04-03 00:00:00
abstract::Structural features of lysine-conjugated antibody-drug conjugate (ADC) from humanized IgG1 were studied by small-angle X-ray scattering (SAXS). As the physicochemical properties of the cytotoxic drug (payload) and linker may impact the conformational and colloidal stabilities of the conjugated monoclonal antibody (mAb...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00792
更新日期:2019-12-02 00:00:00
abstract::Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited because of its severe toxic side effects. At the same time, the lack of a well-defined mechanism of selectivity hampers the efforts to rationally design ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00572
更新日期:2018-09-04 00:00:00
abstract::The poor therapeutic efficacy of hydrophobic chemotherapeutic drugs is an intrinsic limitation to successful chemotherapy. In the present study, a multitask delivery system based on arginine-glycine-aspartic acid peptide (RGD) decorated vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/RGD-conjugated d-...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01068
更新日期:2017-04-03 00:00:00
abstract::This study describes a novel nonlinear variant of the well-known Yalkowsky general solubility equation (GSE). The modified equation can be trained with small molecules, mostly from the Lipinski Rule of 5 (Ro5) chemical space, to predict the intrinsic aqueous solubility, S0, of large molecules (MW > 800 Da) from beyond...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00689
更新日期:2020-10-05 00:00:00
abstract::The acetylcholinesterase inhibitor, acotiamide, improves gastric motility and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, wa...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00894
更新日期:2020-04-06 00:00:00
abstract::This study determined intraluminal ethanol concentrations (stomach and duodenum) in fed healthy volunteers after the consumption of common alcoholic beverages (beer, wine, and whisky). The results of this study were compared with a previous study in fasted volunteers. Five healthy volunteers were recruited in a crosso...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00252
更新日期:2017-12-04 00:00:00
abstract::Folate receptor (FR) targeting is an attractive strategy for nuclear imaging of cancer and activated macrophages through application of folic acid radioconjugates. However, significant renal accumulation of folate radioconjugates and hence exceedingly high emission of radiation from the kidneys may mask uptake of radi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300428p
更新日期:2013-03-04 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::The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to smal...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900304p
更新日期:2010-06-07 00:00:00
abstract::As a result of its higher molecular mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissolution of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous ind...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01237
更新日期:2019-03-04 00:00:00
abstract::Safe and effective gene delivery is essential to the success of gene therapy. We synthesized and characterized a novel nonviral gene delivery system in which folate (FA) molecules were functioned as blockers on cationic polyrotaxanes (PR) composed of poly(ethylenimine) (PEI)(600)-grafted α-cyclodextrin rings linearize...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200315c
更新日期:2012-05-07 00:00:00
abstract::The purpose of this study was to determine the effect of PEGylation on the interaction of poly(amidoamine) (PAMAM) dendrimer nanocarriers (DNCs) with in vitro and in vivo models of the pulmonary epithelium. Generation-3 PAMAM dendrimers with varying surface densities of PEG 1000 Da were synthesized and characterized. ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500662z
更新日期:2015-03-02 00:00:00
abstract::Lung-delivered polymer nanoparticles provoked dysfunction of the essential lung surfactant system. A steric shielding of the nanoparticle surface with poloxamers could minimize the unwanted interference of polymer nanoparticles with the biophysical function of lung surfactant. The extent of poly(styrene) and poly(lact...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00477
更新日期:2017-10-02 00:00:00
abstract::The adenovirus (Ad) is widely used as a vaccine because of its ability to induce a cellular and humoral immune response. In addition, human clinical trials have validated the safety and efficacy of Ad as a vaccine vector. The traditional approach for employing the adenovirus as vaccine is to configure the antigen gene...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/acs.molpharmaceut.8b00591
更新日期:2018-12-03 00:00:00
abstract::Preferential interactions of formulation excipients govern their impact on the stability properties of proteins in solution. The ability to predict these interactions without the need to perform experiments would enable formulation design to begin early in the development of a new antibody therapeutic. With that in mi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00629
更新日期:2020-09-08 00:00:00
abstract::Reversible aqueous lipidization (REAL) at the interdisulfide bond has been shown to improve the deliverability of some peptide drugs. Recently, we developed a nonreversible aqueous lipidization method targeted at the interdisulfide bond of salmon calcitonin (sCT). The resultant derivative had comparable hypocalcemic a...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp8000167
更新日期:2008-07-01 00:00:00
abstract::PCPP, a well-defined polyphosphazene macromolecule, has been studied as an immunoadjuvant for a soluble form of the postfusion glycoprotein of respiratory syncytial virus (RSV sF), which is an attractive vaccine candidate for inducing RSV-specific immunity in mice and humans. We demonstrate that RSV sF-PCPP formulatio...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00118
更新日期:2017-07-03 00:00:00
abstract::We report herein on the preparation of thermoresponsive hydrogels by taking advantage of the interaction of cyclodextrins (CDs) and a hydrophobically modified polymer. A hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC) gel formed thermoresponsive hydrogels when small amounts of α-CD were added to the s...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00291
更新日期:2017-08-07 00:00:00
abstract::A redox-sensitive prodrug, octreotide(Phe)-polyethene glycol-disulfide bond-paclitaxel [OCT(Phe)-PEG-ss-PTX], was successfully developed for targeted intracellular delivery of PTX. The formulation emphasizes long-circulation-time polymer-drug conjugates, combined targeting based on EPR and OCT-receptor mediated endocy...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00280
更新日期:2015-08-03 00:00:00
abstract::The present work investigates the influence of electrostatic surface potential distribution of monoclonal antibodies (MAbs) on intermolecular interactions and viscosity. Electrostatic models suggest MAb-1 has a less uniform surface charge distribution than MAb-2. The patches of positive and negative potential on MAb-1...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200566k
更新日期:2012-04-02 00:00:00
abstract::There are an increasing number of studies showing the order of drug presentation plays a critical role in achieving optimal combination therapy. Here, a nanoparticle design is presented using ion pairing and drug-polymer conjugate for the sequential delivery of gefitinib (Gi) and doxorubicin (Dox) targeting epidermal ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00669
更新日期:2017-12-04 00:00:00
abstract::Preferential interactions of formulation excipients govern their overall interactions with protein molecules, and molecular dynamics simulations allow for the examination of the interactions at the molecular level. We used molecular dynamics simulations to examine the interactions of sorbitol, sucrose, and trehalose w...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00545
更新日期:2019-08-05 00:00:00
abstract::As microRNAs (miRNAs) have been reported to be a type of novel high-value small molecule (SM) drug targets for disease treatments, many researchers are engaged in the field of exploring new SM-miRNA associations. Nevertheless, because of the high cost, adopting traditional biological experiments constrains the efficie...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00384
更新日期:2019-07-01 00:00:00
abstract::Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positro...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01123
更新日期:2017-05-01 00:00:00
abstract::In the present age of pharmaceutical research and development, focused delivery of decision making data is more imperative than ever before. Resulting from several years' success, failure and consequential learning, this article also proffers advice and guidance on which in vitro and in vivo experiments to perform to ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300476z
更新日期:2013-04-01 00:00:00
abstract::The barrier epithelia of the cornea and retina control drug and nutrient access to various compartments of the human eye. While ocular transporters are likely to play a critical role in homeostasis and drug delivery, little is known about their expression, localization and function. In this study, the mRNA expression ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300429e
更新日期:2013-02-04 00:00:00