Abstract:
:For efficient and receptor-specific siRNA delivery, a new post-PEGylation strategy was established to provide siRNA polyplexes with targeting and shielding agents. For this purpose, core nanoparticles were formed by complexing siRNA with sequence-defined cationic lipo-oligomers. The T-shaped bis-oleoyl-oligoethanamino amides 454 and 595, containing stabilizing tyrosine and cysteine residues, were applied. These core nanoparticles were surface-shielded by reaction with maleimido-polyethylene glycol (Mal-PEG) reagents, optionally containing the targeting ligand folic acid (FolA). The PEGylation had two unpredicted consequences. First, FolA-PEG surface-modified polyplexes agglomerated due to the hydrophobicity of folic acid, resulting in ligand-independent gene silencing. This problem was solved by the use of tetra-γ-glutamyl folic acid (gE4-FolA) as targeting ligand. Post-PEGylated gE4-FolA siRNA polyplexes displayed sizes of 100-200 nm and mediated receptor specific uptake and effective gene silencing. Second, PEGylation triggered a destabilization of polyplexes, which was uncritical in cell culture but a limiting factor in vivo, as revealed by biodistribution studies in mice. This problem was partially overcome by selecting 595 (containing two CRC stability motifs) for polyplex core formation and an optimized lower degree of gE4-FolA PEGylation reagent. Biodistribution in L1210 tumor bearing mice demonstrated a significantly reduced lung signal and extended persistence of siRNA polyplexes (up to 8 h), with moderate delivery into the tumor. Further polyplex stabilization will be required for effective tumor-targeted delivery.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Müller K,Kessel E,Klein PM,Höhn M,Wagner Edoi
10.1021/acs.molpharmaceut.6b00102subject
Has Abstractpub_date
2016-07-05 00:00:00pages
2332-45issue
7eissn
1543-8384issn
1543-8392journal_volume
13pub_type
杂志文章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::Most vaccines contain aluminum adjuvants; however, their exact mechanism of action remains unclear. A novel mechanism by Shi and colleagues proposes aluminum adjuvants may enhance immune activation by binding and reorganizing lipids that are key components of lipid rafts. To better understand the specificity of intera...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00111
更新日期:2016-05-02 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::As a chronic inflammatory and angiogenic disease with increased morbidity and mortality, rheumatoid arthritis (RA) is characterized by the proliferation of synovial tissue and the accumulation of excessive mononuclear infiltration, which always results in the joint deformity, disability, and eventually the destruction...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00505
更新日期:2017-09-05 00:00:00
abstract::A novel design of anticancer drug delivery system, based on an electrostatic binding of negatively charged liposomes and cationic metalloporphyrins under physiological conditions, is reported. A lack of cytotoxicity of the iron(III) porphyrin-loaded liposomes and an efficient generation of a toxic hydroxyl radical (OH...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp049936v
更新日期:2004-09-01 00:00:00
abstract::Biophysical tools have been invaluable in formulating therapeutic proteins. These tools characterize protein stability rapidly in a variety of solution conditions, but in general, the techniques lack the ability to discern site-specific information to probe how solution environment acts to stabilize or destabilize the...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp2004109
更新日期:2012-04-02 00:00:00
abstract::Delivery of antigenic protein to the cytosol of antigen-presenting cells (APCs), such as macrophages (MPhi) and dendritic cells (DCs), is required for an efficient CD8 T-cell-mediated immune response. We have previously shown that co-encapsulation of antigenic protein inside pH-sensitive liposomes with listeriolysin O...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp049896v
更新日期:2005-01-01 00:00:00
abstract::In the present research a salt of vincamine, a poorly bioavailable indole alkaloid derived from the leaves of Vinca minor L., was synthesized in the solid state by means of a mechanochemical process employing citric acid as a reagent. The mechanochemical process was adopted as a solvent-free alternative to classical c...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300371f
更新日期:2013-01-07 00:00:00
abstract::Plant or microbial lectins are known to exhibit potent antiviral activities against viruses with glycosylated surface proteins, yet the mechanism(s) by which these carbohydrate-binding proteins exert their antiviral activities is not fully understood. Hepatitis C virus (HCV) is known to possess glycosylated envelope p...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400399b
更新日期:2013-12-02 00:00:00
abstract::In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the improved control of systemic disease with new therapies has unmasked brain metastases that historically would have remained clinically silent. The efficacy of therapeutic agents against brain metastases is limited by their inability to pe...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b01167
更新日期:2020-02-03 00:00:00
abstract::Our primary objective is to characterize the self-association of rafoxanide in alkaline media. The second objective is to illustrate the feasibility of using rafoxanide micellar solution as the feed solution to prepare amorphous solid dispersion via spray drying. Rafoxanide is a poorly water-soluble drug. It is a weak...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00068
更新日期:2017-05-01 00:00:00
abstract::PLGA was functionalized with PEG and biotin using click chemistry to generate a biotin receptor targeted copolymer (biotinylated-PEG-PLGA) which in turn was used to fabricate ultrafine nanoparticles (BPNP) of doxorubicin hydrochloride (DOX) for effective delivery in 4T1 cell induced breast cancer. However, adequate en...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00310
更新日期:2017-08-07 00:00:00
abstract::Polymer therapeutics has emerged as a new clinical option for the treatment of human diseases. However, little is known about pharmacogenetic responses to drugs formulated with polymers. In this study, we demonstrate that a formulation containing the block copolymer Pluronic P85 and antineoplastic drug doxorubicin (Do...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp050050g
更新日期:2006-03-01 00:00:00
abstract::The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition-fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nano...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00737
更新日期:2017-12-04 00:00:00
abstract::Intra-articular (IA) injection of thermoresponsive hydrogels coupled with microparticles (MPs) possess the benefit of sustaining the anti-inflammatory drug effect within the joint cavity for rheumatoid arthritis treatment. Star-shaped thermoresponsive poly(polyethylene glycol) methacrylate [Poly(PEGMA)] copolymers wer...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00126
更新日期:2020-06-01 00:00:00
abstract::The ATP-binding cassette (ABC) drug transporter ABCG2 can actively efflux a wide variety of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular accumulation of these drugs. Therefore, the overexpression of ABCG2 often contributes to the development of multidrug resistance (MDR) in can...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00334
更新日期:2017-08-07 00:00:00
abstract::Despite holding promise for cancer immunotherapy, the strong pro-inflammatory properties of lipopolysaccharide (LPS) also account for severe localized and systemic side effects, restricting its administrable dosage and the possibility of chronic dosing. Herein, we exploited the surface-active properties of LPS molecul...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00631
更新日期:2019-11-04 00:00:00
abstract::Today, about 50% of men and 15-30% of women suffer from hair loss as well as the associated psychological impact. Drug therapy, especially through topical administration, is the main treatment strategy for stimulating hair regrowth. However, challenges exist due to the skin barrier that hinders drug penetration. To th...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00041
更新日期:2021-02-01 00:00:00
abstract::Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b-PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 ± 4....
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00612
更新日期:2017-10-02 00:00:00
abstract::Colistin has been increasingly used for the treatment of respiratory infections caused by Gram-negative bacteria. Unfortunately parenteral administration of colistin can cause severe adverse effects. This study aimed to develop an inhaled combination dry powder formulation of colistin and rifapentine for the treatment...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500586p
更新日期:2015-08-03 00:00:00
abstract::Amino acids derivative are well established molecular probes for diagnosis of a variety of cancer using positron emission tomography (PET). Recently, boramino acid (BAAs) was found as a prospective molecular platform for developing PET tracer. The objective of this study was to develop a 18F-labeled alanine derivative...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00884
更新日期:2018-03-05 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::Gene therapy represents a potential efficient approach of disease prevention and therapy. However, due to their poor in vivo stability, gene molecules need to be associated with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. Cationic polymeric nanoparticle...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp5007213
更新日期:2015-02-02 00:00:00
abstract::TGX-221 is a highly potent phosphoinositide 3-kinase β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200007b
更新日期:2011-06-06 00:00:00
abstract::The objective of this work was to investigate the feasibility of using a novel granulation technique, namely, fluidized hot melt granulation (FHMG), to prepare gastroretentive extended-release floating granules. In this study we have utilized FHMG, a solvent free process in which granulation is achieved with the aid o...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500242q
更新日期:2014-10-06 00:00:00
abstract::Pyropheophorbide-a (Pyro) is a highly promising photosensitizer for tumor photodynamic therapy (PDT), although its very limited tumor-accumulation ability seriously restricts its clinical applications. A higher accumulation of photosensitizers is very important for the treatment of deeply seated and larger tumors. The...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b01064
更新日期:2018-04-02 00:00:00
abstract::Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00451
更新日期:2017-10-02 00:00:00
abstract::L cells have attracted particular interest because of the pleiotropic effects of their secreted peptides (i.e., glucagon-like peptide (GLP) 1 and 2, peptide YY (PYY)). L cells express different G-protein-coupled receptors (GPCRs) that can be activated by endogenous ligands found in the gut lumen. We herein hypothesize...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00871
更新日期:2016-12-05 00:00:00
abstract::Although tumor-targeting nanovehicles for hepatocellular carcinoma (HCC) chemotherapy have attracted great research and clinic interest, the poor cancer penetration, inefficient cellular uptake, and slow intracellular drug release greatly compromise their therapeutic outcomes. In this work, a multifunctional mixed mic...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00404
更新日期:2017-11-06 00:00:00
abstract::Encapsulation and release behavior of a water-insoluble drug, magnolol, using a core-shell polysaccharide-based nanoparticle, manipulating the cellular internalization and controlled cytotoxic effect of magnolol-loaded nanoparticles over the A10 vascular smooth muscle cells (VSMCs) was reported. A magnolol-polyvinylpy...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200257y
更新日期:2011-12-05 00:00:00