Abstract:
:A promising strategy to enable patient stratification for targeted therapies is to monitor the target expression in a tumor by radionuclide molecular imaging. Affibody molecules (7 kDa) are nonimmunoglobulin scaffold proteins with a 25-fold smaller size than intact antibodies. They have shown an apparent potential as molecular imaging probes both in preclinical and clinical studies. Earlier, we found that hepatic uptake can be reduced by the incorporation of negatively charged purification tags at the N-terminus of Affibody molecules. We hypothesized that liver uptake might similarly be reduced by positioning the chelator at the N-terminus, where the chelator-radionuclide complex will provide negative charges. To test this hypothesis, a second generation synthetic anti-HER2 ZHER2:2891 Affibody molecule was synthesized and labeled with (111)In and (68)Ga using DOTAGA and DOTA chelators. The chelators were manually coupled to the N-terminus of ZHER2:2891 forming an amide bond. Labeling DOTAGA-ZHER2:2891 and DOTA-ZHER2:2891 with (68)Ga and (111)In resulted in stable radioconjugates. The tumor-targeting and biodistribution properties of the (111)In- and (68)Ga-labeled conjugates were compared in SKOV-3 tumor-bearing nude mice at 2 h postinjection. The HER2-specific binding of the radioconjugates was verified both in vitro and in vivo. Using the DOTAGA chelator gave significantly lower radioactivity in liver and blood for both radionuclides. The (111)In-labeled conjugates showed more rapid blood clearance than the (68)Ga-labeled conjugates. The most pronounced influence of the chelators was found when they were labeled with (68)Ga. The DOTAGA chelator gave significantly higher tumor-to-blood (61 ± 6 vs 23 ± 5, p < 0.05) and tumor-to-liver (10.4 ± 0.6 vs 4.5 ± 0.5, p < 0.05) ratios than the DOTA chelator. This study demonstrated that chelators may be used to alter the uptake of Affibody molecules, and most likely other scaffold-based imaging probes, for improvement of imaging contrast.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Westerlund K,Honarvar H,Norrström E,Strand J,Mitran B,Orlova A,Eriksson Karlström A,Tolmachev Vdoi
10.1021/acs.molpharmaceut.6b00089subject
Has Abstractpub_date
2016-05-02 00:00:00pages
1668-78issue
5eissn
1543-8384issn
1543-8392journal_volume
13pub_type
杂志文章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::We report on the fabrication and characterization of dry hybrid lipid-silica nanoparticle based microcapsules with an internal porous matrix structure for encapsulation of poorly soluble drugs, and their delivery properties (in vitro release and lipolysis and in vivo pharmacokinetics demonstrated for indomethacin as a...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900063t
更新日期:2009-05-01 00:00:00
abstract::Bacterial capsular polysaccharides are components of many modern vaccines, but they are weakly immunogenic. Herein, we describe the delivery of pneumococcal capsular polysaccharide serotype-1 (PCP-1) in polylactide polymeric particles to enhance its immunogenicity. Immunization with PCP-1-entrapped particles elicited ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400589q
更新日期:2014-03-03 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 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 recogni...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500086e
更新日期:2014-10-06 00:00:00
abstract::Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00475
更新日期:2017-10-02 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::Sodium lauryl sulfate (SLS), as an effective surfactant, is often used as a solubilizer and/or wetting agent in various dosage forms for the purpose of improving the solubility and dissolution of lipophilic, poorly water-soluble drugs. This study aims to understand the impact of SLS on the solution behavior and bioava...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00391
更新日期:2016-08-01 00:00:00
abstract::Despite significant potential of oligonucleotides (ONs) for therapeutic and diagnostic applications, rapid and widespread intracellular delivery of ONs in cells situated in tissues such as skin, head and neck cavity, and eye has not been achieved. This study was aimed at evaluating the synergistic combination of micro...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300717f
更新日期:2013-08-05 00:00:00
abstract::In previous studies, we developed a new technique (ionic gelation vibrational jet flow; IGVJF) in order to encapsulate pancreatic β-cells, for insulin in vivo delivery, and diabetes treatment. The fabricated microcapsules showed good morphology but limited cell functions. Thus, this study aimed to optimize the IGVJF t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00220
更新日期:2017-08-07 00:00:00
abstract::The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cet...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00672
更新日期:2018-11-05 00:00:00
abstract::Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00466
更新日期:2018-08-06 00:00:00
abstract::Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber me...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00279
更新日期:2017-12-04 00:00:00
abstract::Curcumin (CUR) is a unique natural compound with promising anticancer and anti-inflammatory activities. However, the therapeutic efficacy of curcumin was challenged in clinical trials, mostly due to its low bioavailability, rapid metabolism, and elimination. We designed a nanodrug form of curcumin, which makes it stab...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500290f
更新日期:2014-09-02 00:00:00
abstract::Hydrophobic single-wall carbon nanohorns (SWNHs) were dispersed in aqueous media by noncovalently modifying their surfaces with conjugate molecules comprised of polyethylene glycol (PEG) and a peptide aptamer (NHBP-1) that specifically bind to the surfaces of the SWNHs. The conjugates were synthesized by coupling PEG ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp070022t
更新日期:2007-09-01 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::Much interest has been expressed in this work on the role of water diffusivity in the release media as a new parameter for predicting drug release. NMR was used to measure water diffusivity in different media varying in their osmolality and viscosity. Water self-diffusion coefficients in sucrose, sodium chloride, and ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3006209
更新日期:2013-06-03 00:00:00
abstract::Ultrasound-targeted microbubble destruction (UTMD) is a promising technique to facilitate the delivery of chemotherapy in cancer treatment. However, the process typically uses nonspecific microbubbles, leading to low tumor-to-normal tissue uptake ratio and adverse side effects. In this study, we synthesized the LHRH r...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400523h
更新日期:2014-01-06 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::Targeted therapies are emerging as a preferred strategy for treatment of cancer and other diseases. To evaluate the effect of high affinity receptors on the rate and extent of tumor penetration of receptor-targeted drugs, we have characterized the kinetics of folate-rhodamine uptake by folate receptor (FR)-expressing ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900158d
更新日期:2009-11-01 00:00:00
abstract::Subcutaneous allergen-specific immunotherapy (SCIT) qualifies as a promising approach for the permanent cure of IgE-mediated airway allergies, which can often manifest into allergic rhinitis and other allergic respiratory diseases. SCIT entails repeated administration of a high allergen dose into the subcutaneous (sc)...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00447
更新日期:2020-08-03 00:00:00
abstract::The successful applicability of gene therapy approaches will heavily rely on the development of efficient and safe nonviral gene delivery vectors, for example, cell-penetrating peptides (CPPs). CPPs can condense oligonucleotides and plasmid DNA (pDNA) into nanoparticles, thus allowing the transfection of genetic mater...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3003557
更新日期:2013-01-07 00:00:00
abstract::Lung cancer is a kind of malignant tumor with high morbidity and metastasis tendency. Gambogic acid (GA) has demonstrated significant antitumor activity in vitro, but its poor water-solubility and adverse effects restrict its application in vivo and in clinic. In this study, a passive-targeting GA delivery system was ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00161
更新日期:2018-05-07 00:00:00
abstract::Integrin αvβ3 is a cell adhesion molecule involved in the progression and invasion of glioblastoma, making it an attractive target for the diagnosis of glioblastoma. Although some integrin αvβ3 specific ligands, such as RGD and its mimetic peptides (Cilengitide), have been devoted in detecting glioblastoma, their clin...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00602
更新日期:2019-09-03 00:00:00
abstract::Stereoregularity of polymers is known to influence their physicochemical and functional properties in the bulk form. Recent studies have also provided evidence for the effect of polymer stereoregularity on the physicochemical and functional properties of their self-assembled nanostructures. Research in this area has w...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01169
更新日期:2017-08-07 00:00:00
abstract::Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emis...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00891
更新日期:2019-12-02 00:00:00
abstract::The study presents the effects of blending a cationic gemini surfactant into cationic lipid bilayers and its impact on the plasmid DNA compaction and delivery process. Using nanoDSC, dynamic light scattering, zeta potential, and electrophoretic mobility measurements, together with transfection (2D- and 3D-) and viabil...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp4005035
更新日期:2014-02-03 00:00:00
abstract::The ultrasmall nanoparticle AGuIX is a versatile platform that tolerates a range of chemical diversity for theranostic applications. Our previous work showed that AGuIX clears rapidly from normal tissues, while durably accumulating within the tumor microenvironment. On this basis, AGuIX was used to detect tumor tissue...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00264
更新日期:2016-07-05 00:00:00
abstract::Oxidative stress and inflammation are intertwined contributors to numerous acute vascular pathologies. A novel dual bioactive nanoparticle with antioxidant/anti-inflammatory properties was developed based on the interactions of tocopherol phosphate and the manganese porphyrin SOD mimetic, MnTMPyP. The size and drug in...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400677y
更新日期:2014-07-07 00:00:00
abstract::Dysbiosis (alteration of intestinal flora) is associated with various host physiologies, including diseases. The purpose of this study was to clarify the effect of dysbiosis on protein expression levels in mouse liver and kidney by quantitative proteomic analysis, focusing in particular on drug-metabolizing enzymes an...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00259
更新日期:2016-08-01 00:00:00